Комплексное исследование двустороннего взаимодействия между микробиомами человека и злокачественными заболеваниями крови и гематологическими условиями: акцент на новых терапевтических стратегиях.

Abbreviations

5‐hydroxyeicosatetraenoic Acid

6‐trans‐12‐epi‐leukotriene B4

allogeneic hematopoietic stem cell transplantation

acute lymphoblastic leukemia

alanine aminotransferase

acute myelogenous leukemia

antimicrobial peptides

antigen presenting cells

aspartate aminotransferase

adolescent/young adult Hodgkin lymphoma

Parvovirus B19

bone marrow

bone marrow mesenchymal stromal cells

Bacteroides ovatus

branched short‐chain fatty acids

bile salt hydrolase

cytotoxin‐associated Gene A

cytolethal distending toxins

cell‐free culture supernatants

colony‐forming units

chronic lymphoblastic leukemia

chronic myelogenous leukemia

cytomegalovirus

C‐reactive protein

cytotoxic T lymphocytes

damage‐associated molecular patterns

dendritic cells

diffuse large B‐cell lymphoma

Divalent Metal Transporter 1

Epstein–Barr Virus

epidermal growth factor

extracellular‐signal‐reduced Kinase

Food and Agriculture Organization of the United Nations

Flavin Monooxygenase

Fecal Microbiota Transplantation

ferroportin

germ‐free

gastrointestinal

Granulocyte‐monocyte progenitors

graft‐versus‐host disease

fetal hemoglobin

hemoglobin

Hodgkin Lymphoma

human microbiome project

human progenitor cells

human stem cells

hematopoietic stem cell transplantation

hematopoietic stem and progenitor cells

inflammatory bowel disease

irritable bowel syndrome

interferon‐α

interferon‐γ

interleukin‐6

immunosuppressive therapy

lactic acid bacteria

low‐density lipoprotein

Lymphocyte Function Antigen‐1

lipopolysaccharides

leukotoxin A

Mucosa‐associated Lymphoid Tissue

Mean Corpuscular Hemoglobin

Mean Corpuscular Hemoglobin Concentration

Mean Corpuscular Volume

Multidrug‐resistant

Megakaryocyte‐erythroid Progenitor

monoclonal gammopathy of undetermined significance

multiple myeloma

neutrophil extracellular trap

The Nuclear Factor Kappa B

Non‐Hodgkin Lymphoma

natural killer

nonsevere aplastic anemia

Operational Taxonomic Units

plasminogen activator inhibitor type 1

pathogen‐associated molecular patterns

Poly ADP‐ribose Polymerase

peripheral blood mononuclear cells

polymerase chain reaction

platelet‐derived growth factor

pattern recognition receptors

Panton‐Valentine Leukocidin

red blood cell

reactive oxygen species

Resolvin D2

severe aplastic anemia

short‐chain fatty acids

severe congenital neutropenia

smoldering multiple myeloma

tissue factor pathway inhibitor

transferrin receptor 1

T Helper 17

toll‐like receptors

trimethylamine

trimethylamine N‐oxide

tumor necrosis factor‐α

tissue‐type plasminogen activator

total parenteral nutrition

regulatory t cells

Von Willebrand Factor

white blood cells

World Health Organization

washed microbiome transplantation

Introduction

Microbiota (normal flora) is a community of microbes present in or on the surface of the human body and has a significant diversity between environmental surfaces and their location in healthy and diseased hosts. They colonize various areas of the human body, including the gastrointestinal (GI) tract, respiratory system, oral cavity, skin, and vagina. In general, it is estimated that the composition of the microbiota is more than 10 times the number of human cells [ 1 , 2 , 3 , 4 , 5 ]. Most microbes connected to humans are found in the colon, with this community being formed during the first 3 years of life. Among the microbes in the lower intestine, most bacteria belong to just two of the roughly seventy phyla: Bacteroidetes and Firmicutes alongside smaller contributions from the Actinobacteria, Proteobacteria, Verrucomicrobia , and Fusobacteria phyla [ 6 , 7 ]. However, the term microbiome refers to the entire set of microbial genomes in the microbiota, which includes approximately 3.3 million genes, a much higher number compared to the 23,000 genes in the human genome [ 4 , 8 ]. Based on the above definitions, the term dysbiosis is expressed as follows: the destruction and disruption of microbiota that leads to microbial imbalance [ 4 ]. Immune suppression may alter immune surveillance of commensal microbes and induce selective pressures. In this regard, a disruption of the ecological balance is likely to play a key role, one in which the immune system controls bacterial overgrowth and, conversely, the microbiome participates in processes related to immune development and maturation [ 4 , 8 ]. Finally, the shift of microbiome from eubiosis to dysbiosis can also increase the incidence of atherosclerosis, cardiovascular diseases, neurological and psychiatric diseases, liver diseases, inflammatory bowel disease (IBD), emerging infectious diseases, irritable bowel syndrome (IBS), metabolic syndromes, obesity, diabetes mellitus, and hematological disorders, etc. [ 5 ]. Additionally, there is a growing emphasis within the medical field on the gut microbiota and its capacity to alter the chemical composition of xenobiotics. Recent studies have revealed that gut microbiota play a pivotal role in metabolizing xenobiotics, potentially influencing future therapeutic approaches for a range of diseases, particularly those related to hematology [ 9 ]. In hematology, dysbiosis provides conditions for the stimulation of both nonneoplastic diseases (iron deficiency anemia, thrombosis, thrombocytosis, or thrombocytopenia) and neoplastic disorders (lymphoma, leukemia, and multiple myeloma), which constitute approximately 6.5% of cancers [ 10 ]. In addition, microbiome alterations may reflect treatment‐related ecological shifts rather than disease‐driven changes; dysbiosis may interfere with the effectiveness of treatment in these patients (including the use of iron supplements, chemotherapy, immunotherapy, and hematopoietic stem cell transplantation) and affect their treatment outcome [ 5 ].

The distinction between correlation and causation represents a fundamental challenge in microbiome research. As noted in a comprehensive review, “it remains unclear whether dysbiosis is a cause or a consequence of the diseases, including hematologic malignancies.” This uncertainty stems from the bidirectional nature of microbiome‐host interactions—disease states can alter microbial communities through changes in immunity, metabolism, and tissue environments, while microbial alterations can simultaneously influence disease pathogenesis. Establishing causality requires multiple lines of evidence, including longitudinal studies demonstrating that microbial changes precede disease onset, mechanistic studies identifying specific microbial effectors, and interventional studies showing that microbiome modulation alters disease outcomes. In hematology, the strongest causal evidence exists for Helicobacter pylori in gastric MALT lymphoma, where bacterial eradication leads to disease remission in approximately 80% of cases. For most other associations discussed in this review, the evidence remains correlational, highlighting critical knowledge gaps that warrant investigation [ 11 ]. The aim of this study is to investigate the impact of microbial communities on normal hematopoietic processes and the role of dysbiosis in the development and progression of various hematological disorders. It also describes the role of specific microbial infections in the development or exacerbation of the aforementioned conditions. In addition, it outlines the relationship between changes in the microbiome and treatment outcomes and suggests microbiome‐based therapeutic strategies as a potential approach to improve patient health in the context of hematological diseases.

Microbiome

The human microbiome is composed of a wide variety of organisms, including bacteria, viruses, and archaea, with bacteria being the predominant group in the gut microbiota. This complex and ever‐changing ecosystem within the intestines is strongly affected by external factors like diet, medications, and illnesses, all of which can significantly alter its composition. Maintaining balance and preventing the spread and growth of harmful microbes depends on key elements such as an intact intestinal lining—which provides a physical barrier between gut microbes and host tissues—and the mucus layer secreted by goblet cells, which helps block bacterial movement and protects the mucosal surface from injury [ 7 ]. Anaerobic commensal bacteria in the gut help defend against invaders by resisting pathogen colonization and producing metabolites that limit the growth of harmful microbes. Additionally, molecules from these beneficial bacteria interact with Paneth cells through toll‐like receptors (TLRs), prompting the release of antimicrobial peptides (AMPs) like defensins and regenerating gene proteins, which regulate the microbial community by capturing vital nutrients and disrupting bacterial membranes [ 12 , 13 , 14 ]. The microbiome plays an important metabolic role in producing short‐chain fatty acids (SCFAs) and increased proteolytic activities. SCFAs, in turn, play an important role as metabolic and immune mediators; their reduction in the elderly favors the development of age‐related IBD [ 5 ]. SCFAs provide energy for colonocytes, stimulate mucus production, strengthen the expression of tight junction proteins, trigger the release of anti‐inflammatory cytokines, and encourage the development of regulatory T cells by activating G‐protein coupled receptors on both epithelial and immune cells. Indoles, another group of metabolites, prompt lymphocytes that express the aryl hydrocarbon receptor to produce IL‐22, which improves the integrity of the epithelial barrier and increases the production of AMPs [ 13 , 15 , 16 , 17 ]. The microbiome and its products have a significant impact on many homeostatic processes of the host and, in other words, have functional redundancy; the microbiome mainly plays a role in the maturation, regulation, and modulation of the immune system, as well as in the production of vitamins (such as folic acid, vitamin K, and B vitamins) and amino acids, as well as fat storage (Figure 1 ) [ 5 , 8 ]. The host's genetic predisposition, environmental factors, antibiotic therapy, chemotherapy, use of immunosuppressive drugs, and the occurrence of occasional infections can affect the composition of the microbiome [ 8 , 10 ]. The creation of genetic variations in the host genome can affect the expression of microbial receptors and be effective on the colonization and survival of specific microbial species [ 10 ]. Environmental factors such as smoking, exposure to ionizing radiation or pollutants, diet, lifestyle—stress levels and physical activity, etc., and other such factors can cause changes in the microbiome by affecting the host's physiology and metabolism [ 10 ]. The body's microbiome, especially the gut microbiota, plays an important role in protecting the host against invasion by pathogenic organisms. Therefore, prolonged use of broad‐spectrum antibiotics, by suppressing the gut microbiota and consequently interfering with their defense mechanisms, leads to colonization by pathogenic organisms or overgrowth of specific populations of microbial flora, thus paving the way for the development of various diseases [ 8 , 10 ]. Chemotherapy reduces the abundance of beneficial bacteria such as Bifidobacterium , Lactobacillus , and Faecalibacterium prausnitzii , while increasing the proportion of potentially harmful bacteria such as Escherichia coli and Enterococcus faecium [ 18 , 19 , 20 ].

Recent developments in biological methods like 16S rRNA sequencing have greatly improved our knowledge of the connection between the human microbiome and hematological diseases. This approach enables the detection of unculturable bacteria by examining their genetic material. The process includes amplifying the 16S rRNA genes through polymerase chain reaction (PCR), followed by sequencing with technologies such as Illumina. The resulting sequences are then categorized into Operational Taxonomic Units (OTUs) and matched against reference databases for analysis [ 9 ]. However, differences in targeted 16S rRNA regions, sequencing depth, and bioinformatics pipelines across studies can lead to variability in reported microbial profiles.

While the link between the microbiome and products of the hematopoietic system is well recognized, a detailed mechanistic insight into how the microbiome directly or indirectly influences hematopoiesis remains limited. Research has demonstrated a strong correlation between the size of the bone marrow myeloid cell pool and the diversity of the gut microbiota. The immune system starts developing before birth, but its complete maturation depends on both genetic factors and environmental signals that continue to shape immunity after birth [ 6 ]. In germ‐free (GF) mice, the mucosal immune system is underdeveloped, characterized by fewer secondary lymphoid tissues, reduced secretory immunoglobulin A levels, and a decreased number of intestinal plasma cells. Moreover, these GF mice exhibit lower serum antibody concentrations and heightened vulnerability to both intestinal and systemic bacterial infections. Key intestinal structures—such as lymph nodes, Peyer's patches, and intestinal lymphoid follicles—only reach full development postnatally, undergoing a programmed shift to accommodate the microbiome and maintain immune homeostasis [ 6 ].

The development of the gut microbiota is an intricate, ongoing journey that starts at birth and evolves over a person's lifetime. One influential factor in its initial establishment is the mode of delivery: babies born vaginally typically receive microbial communities similar to their mother's vaginal flora, whereas those delivered by cesarean section are seeded primarily with microbes from the skin and surrounding environment [ 21 ]. For example, infants born through the vaginal canal are colonized by bacteria such as Lactobacillus , Prevotella , and Sneathia , while those delivered by C‐section tend to harbor skin‐associated microbes like Staphylococcus, Corynebacterium , and Propionibacterium . This nascent microbiome plays a pivotal role in shaping the developing immune system. Specific microbes, like segmented filamentous bacteria, are known to encourage the maturation of T helper 17 (Th17) cells, whereas others promote the formation of regulatory T cells (Tregs), which are essential for immune tolerance [ 22 ]. Birth‐related differences in microbial colonization can persist well into the first year of life; notably, babies born via C‐section often show an absence of Bacteroides species until between 6 and 18 months, and they also experience delayed colonization of beneficial bacteria like Bifidobacterium (Figure 2 ) [ 23 , 24 ]. Such variations in the gut microbial community may contribute to prolonged immaturity of the immune system, potentially affecting the development of gut‐associated lymphoid tissue and the regulation of Th1/Th2 immune responses [ 25 ]. Initial microbial colonization lays the foundation for the ongoing evolution of the microbiome, with dramatic shifts in microbial diversity and composition occurring over the first 3 years of life. Additional influences, including whether the infant is breastfed, the timing of introducing solid foods, exposure to antibiotics, and various environmental factors, also play crucial roles in molding the early microbiome. These formative years are vital for immune system training and metabolic programming, and disruptions during this period may have lasting effects on health and disease risk [ 26 ].

Research suggests that antibiotics given during infancy can disrupt microbiome composition in a manner that persists into later childhood and adulthood, potentially elevating the risks for conditions such as asthma, allergies, and IBS [ 27 ]. Supporting this, a comprehensive study involving 100 newborns revealed that imbalances in the gut microbiota within the first 3 months were linked to increased levels of circulating endothelial cells, activated T cell populations, and elevated pancreatic enzyme concentrations [ 27 ]. Moreover, early‐life microbial profiles have been associated with susceptibility to metabolic disorders, such as obesity, later in childhood. Altogether, these findings highlight how early‐life microbial exposures are instrumental in establishing a robust and balanced microbiome, which is foundational to optimal immune and metabolic health over the long term [ 28 ]. These findings may not be directly translatable to adult populations, given the fundamental differences in microbiome maturation and immune system development.

Diet, particularly the intake of dietary fiber, is vital for supporting gut health and influencing the diversity of the gut microbiota. Diets high in fiber—especially those abundant in plant‐based foods—and prebiotic compounds like inulin have been demonstrated to foster a more diverse microbial community. This enrichment includes beneficial bacteria such as Bifidobacteria , Roseburia , and Faecalibacterium , which are recognized for their anti‐inflammatory properties. Conversely, Western dietary habits characterized by excessive consumption of processed foods and saturated fats, coupled with low fiber intake, are linked to gut dysbiosis, diminished microbial diversity, and increased permeability of the intestinal lining. Such dietary patterns profoundly impact both the composition and function of the gut microbiota [ 28 ]. Research examining traditional communities, including the Yanomami of Venezuela and the Hadza in Tanzania, shows these groups possess markedly greater gut microbiota diversity compared to populations in industrialized nations [ 29 , 30 , 31 ]. Moreover, diets centered on plant‐based or Mediterranean food choices encourage the generation of beneficial metabolites like SCFAs while concurrently reducing levels of trimethylamine N‐oxide (TMAO) [ 32 ]. Among SCFAs, butyrate plays a key role in preserving the integrity of the gut barrier and mitigating inflammation. In contrast, Western diets have been associated with the proliferation of harmful bacteria, lowered SCFA production, and disruption of microbial balance. These dietary influences can impair the expression of tight junction proteins, weakening the gut barrier and allowing bacterial components such as lipopolysaccharides (LPS) to enter the bloodstream, which may provoke systemic inflammatory responses [ 33 ].

Despite these findings, interpretation of microbiome studies in hematologic disorders is limited by several factors, including small cohort sizes, variability in sequencing platforms and analytical pipelines, and significant clinical heterogeneity. In particular, antibiotic exposure, chemotherapy regimens, and hospitalization significantly confound microbiome composition and complicate causal inference. Additionally, differences between adult and pediatric populations—especially in baseline microbiome composition and immune development—limit the generalizability of findings across age groups.

Microbiome and Hematopoiesis

The normal process of hematopoiesis is controlled by a series of extrinsic regulators—factors produced outside the bone marrow—including growth factors and cytokines, and a series of intrinsic regulators—factors produced inside the bone marrow—including transcription factors. These two regulatory processes typically allow the differentiation of human stem cells (HSCs) into human progenitor cells (HPCs) and their eventual maturation into circulating blood cells [ 5 ]. Among the intrinsic regulators, STAT1 is a transcription factor involved in the hematopoiesis process. This protein is activated by contact with molecules such as interferon‐α (IFN‐α), interferon‐γ (IFN‐γ), epidermal growth factor (EGF), platelet‐derived growth factor (PDGF), and interleukin‐6 (IL‐6). On the other hand, compounds and metabolites derived from gut microbiota such as phosphatidylcholines, gamma‐glutamylalanine, and NOD1L—γ‐D‐glutamyl‐meso‐diaminopimelic acid dipeptide present in the peptidoglycan of bacterial cell walls—can induce gene expression related to type‐I interferons (IFN‐α and IFN‐β). Activation of this cytokine also activates STAT1, thereby causing transcription and expression of genes involved in hematopoiesis (Figure 3 ) [ 34 ]. Therefore, gut microbiota can affect the occurrence of hematopoiesis through the STAT1 signal, and according to this, any dysbiosis in order to reduce the amount of the above metabolites can cause a disturbance in this signaling pathway and ultimately a disturbance in hematopoiesis.

The gut microbiota's influence goes beyond merely supporting HSCs, as it also affects the patterns of HSC output. To preserve intrinsic immune homeostasis, the host constantly detects and reacts to foreign antigens. Pathogen‐associated molecular patterns (PAMPs), which are relatively conserved molecular structures present on the surface of gut microbes, interact with pattern recognition receptors (PRRs) located on the immune cells of the host. Among these PRRs, the TLRs family—found both on the cell surface and within cells—plays a crucial role in identifying a range of immune stimuli such as PAMPs, LPS, and viral RNA [ 35 ]. The probiotic strain Lactobacillus rhamnosus GG is commonly utilized as a food additive and is distinguished by the presence of pili. These pili grant it immunomodulatory properties that allow it to activate specific responses in human immune‐related cells. Specifically, the pili of Lactobacillus rhamnosus GG can stimulate TLR2‐dependent pathways, leading to activation of the nuclear factor kappa B (NF‐κB) inflammatory signaling cascade. Moreover, this strain can influence the secretion of pro‐inflammatory cytokines—including tumor necrosis factor‐α (TNF‐α), IL‐6, IL‐10, and IL‐12—from human monocyte‐derived dendritic cells [ 36 ].

Bacterial metabolites within the gut microbiota can influence allergic airway diseases by interacting with cells in the bone marrow. SCFAs play multiple critical roles, including regulating ion absorption and gut motility, as well as modulating immune responses. These effects are mediated through the activation of several G protein–coupled receptors, such as GPR43—found on granulocytes and some myeloid cells—and GPR109a, a receptor for niacin and C4, which is expressed by gut epithelial cells, adipocytes, macrophages, and dendritic cells (DCs). SCFAs inhibit nuclear factor κB and reduce production of inflammatory cytokines like IL‐6 and TNF‐α, while increasing the anti‐inflammatory cytokine IL‐10 [ 6 ]. These molecules enhance the generation of Th1, Th17, and IL‐10‐producing cells but simultaneously decrease the proliferation of T and B cells in the oral cavity. Butyrate, a specific SCFA, promotes T‐cell apoptosis and reduces T‐cell accumulation in inflamed colonic tissue by increasing Fas expression. Retinoic acid, derived from dietary vitamin A, supports the induction of regulatory T cells and suppresses Th17 and type 1 regulatory T‐like cell responses. Polysaccharide A, a carbohydrate produced by the human commensal bacterium Bacteroides fragilis , can alleviate T cell–mediated colitis through an IL‐10‐dependent mechanism [ 6 ]. Given the growing evidence that the microbiome contributes to normal hematopoiesis, it is expected that alterations in the microbiome composition or specific microbial species are linked with hematologic disorders. In some instances, pathogens may trigger these disorders, while in others, disruption of microbiome homeostasis correlates with significant clinical consequences in patients suffering from hematologic conditions. Microbial agents have been shown to affect every component of the hematopoietic system to some extent [ 6 ]. HSCs detect the microbial community through TLRs, and the induction of specific myeloid cell populations can be initiated in both humans and mice via various TLR ligands. For instance, the TLR1/2 agonist PAM3CSK4 promotes their differentiation into mature myeloid cells, either of monocytic or DC lineage. TLR agonists strongly suppress B‐cell lineage development bias while favoring myeloid differentiation by acting directly on hematopoietic stem and progenitor cells (HSPCs). Further investigation revealed that PAM3CSK4 markedly increases the expression of transcription factors GATA‐1, C/EBPα, and PU.1 in HSCs, thereby shifting the transcriptional program toward myeloid lineage commitment. Bone marrow mesenchymal stromal cells (BM‐MSCs), key components of the bone marrow niche, also express TLRs. Activation of TLR4 by LPS enhances BM‐MSCs' capacity to support myeloid differentiation from HSPCs and improves HSC proliferation. Treatment of adult bone marrow HSCs with a TLR7/8‐specific ligand triggers TLR7/8 signaling, inducing differentiation of CD34+ progenitors into CD11c + CD14+ myeloid dendritic cells [ 35 ]. In mice devoid of gut microbiota, significant reductions are observed in splenic and bone marrow phagocytes, monocytes, and neutrophils, along with diminished proliferative ability of splenic phagocytes. GF mice also exhibit a decreased frequency of granulocyte‐monocyte progenitors (GMPs) in the bone marrow. Since myeloid differentiation originates from bone marrow HSCs, this impairment may be linked to gut microbiota‐mediated signaling pathways involving MyD88 and TICAM. These findings confirm that the absence of gut microbiota disrupts myelopoiesis and illustrates the connection between TLR family‐mediated recognition of intestinal flora and HSC functionality [ 37 , 38 , 39 ]. Additionally, antibiotic treatment induces comprehensive alterations in murine hematopoiesis, notably suppressing multipotent progenitors. Upon infection with Escherichia coli , Lin − c‐kit+Sca‐1+ cells in the bone marrow of Balb/c mice markedly expand, paralleling an increase in granulocyte/macrophage colony‐forming units (CFU‐GM). While this experiment does not directly prove the influence of gut‐resident microbes on mouse bone marrow HSCs, it highlights the gut microbiota's role in shaping hematopoiesis. The influence of the gut microbiota on megakaryocytic lineage development remains unclear [ 40 , 41 , 42 ]. Some studies suggest that the absence of gut microbes alters bone marrow adipocyte size and morphology. Fatty acids secreted by these adipocytes may facilitate megakaryocyte maturation, thereby indirectly affecting this process. Furthermore, certain research groups propose that gut microbiota‐derived propionate, a type of SCFA, decreases the number and proportion of megakaryocyte‐erythroid progenitor (MEP) cells in mouse bone marrow, leading to reduced megakaryocyte production. Conversely, microbial metabolites can stimulate megakaryocyte maturation and platelet formation. Overall, the role of gut microbiota in regulating megakaryocytic lineage development is still poorly understood and warrants more detailed investigation in future research endeavors [ 43 ].

Mechanistic Insights and Evidence Gaps in Microbiome‐Hematopoiesis

Despite accumulating evidence linking the gut microbiome to hematopoietic regulation, significant knowledge gaps remain. A recent review emphasizes that although the specific mechanism of the gut microbiota affecting the hematopoietic system remains to be further clarified, recent studies have shown that its regulation of the hematopoietic system involves a variety of cells and molecules. The complexity arises from the multifaceted nature of microbiome‐host interactions, which involve (1) microbial components (LPS, peptidoglycan, flagellin) interacting with pattern recognition receptors on hematopoietic stem and progenitor cells, influencing differentiation decisions. (2) Short‐chain fatty acids, secondary bile acids, and tryptophan metabolites produced by gut bacteria enter circulation and modulate bone marrow niches. (3) Microbiome‐derived signals shape systemic immune cell populations, which in turn produce cytokines that influence hematopoiesis. (4) Microbial metabolites may alter the bone marrow microenvironment, including mesenchymal stromal cells and endothelial cells that support hematopoiesis [ 35 , 44 ].

The relative contribution of each pathway, their potential redundancy, and their specific roles in different hematopoietic lineages remain poorly understood. Furthermore, whether these mechanisms operate similarly in homeostasis versus disease states, and how they are altered by aging, diet, medications, and underlying hematologic conditions, requires systematic investigation.

Microbiome and Hematologic Disorders

Both bacterial and viral infections contribute to hematologic disease pathogenesis through distinct yet overlapping mechanisms (Table 1 ). A recent review highlights several key mechanisms by which infections trigger hematologic disorders: chronic inflammatory triggering, epithelial barrier alteration, antigen dissequestration, and molecular mimicry. Bacterial triggers, such as H. pylori in MALT lymphoma and various gut bacteria in dysbiosis‐associated conditions, often act through persistent antigenic stimulation, production of genotoxic metabolites (e.g., colibactin from E. coli ), or modulation of the local immune microenvironment. Viral triggers, including Epstein–Barr virus (EBV), cytomegalovirus (CMV), and hepatitis viruses, frequently employ molecular mimicry—where viral antigens resemble host antigens, leading to cross‐reactive immune responses—and direct transformation of lymphocytes. For example, EBV establishes latent infection in B cells and can drive lymphoproliferation through expression of viral oncoproteins. The integration of these microbial triggers in hematologic disease pathogenesis underscores the need for comprehensive approaches that consider both bacterial and viral contributors, as well as their potential interactions. Understanding these distinct mechanisms is essential for developing targeted preventive and therapeutic strategies [ 8 , 45 , 46 , 47 ].

Interpretation of microbiome changes in hematological diseases is challenging because many patients are exposed to factors that independently alter the gut microbiota. These include broad‐spectrum antibiotics, chemotherapy, hospitalization, neutropenia, and antimicrobial prophylaxis. In clinical practice, these exposures often occur together, making it difficult to determine whether observed microbiome changes are caused by the disease itself or by treatment‐related factors [ 48 , 49 , 50 , 51 ]. Among these, antibiotic use is one of the strongest confounders. Patients with hematologic conditions frequently receive broad‐spectrum antibiotics for infection treatment or prophylaxis. These drugs can significantly reduce microbial diversity and eliminate beneficial bacteria, while allowing the overgrowth of opportunistic pathogens such as Enterococcus . Importantly, studies in hematopoietic stem cell transplantation (HSCT) have shown that antibiotic exposure is a major driver of microbiome disruption, often more influential than the disease or transplant‐related immune responses themselves. This highlights that microbiome changes observed in these patients may largely reflect antibiotic effects rather than underlying pathology [ 51 ]. Chemotherapy and neutropenia also play a key role. Chemotherapy damages the intestinal barrier and alters immune function, leading to reduced microbial diversity and shifts toward more pathogenic bacterial populations. These changes are closely linked with complications such as infections and febrile neutropenia. In addition, neutropenia reduces immune surveillance, allowing certain bacteria to expand and increasing the risk of bloodstream infections originating from the gut. These effects further complicate interpretation, as microbiome alterations may reflect treatment toxicity and immune suppression rather than disease‐specific mechanisms [ 48 , 50 ]. Hospitalization and prophylactic antimicrobial use introduce additional confounding influences. Hospital environments expose patients to resistant microorganisms, while routine prophylaxis further alters microbial composition and promotes dysbiosis. In hematology patients, these combined pressures often lead to a simplified microbiome dominated by a limited number of taxa, particularly in those undergoing intensive treatments such as HSCT [ 49 ]. These confounding factors frequently occur simultaneously and interact with each other, creating a highly dynamic and unstable microbiome. As a result, caution is required when interpreting microbiome data in hematology.

Disruptions in gut microbiota composition have important clinical consequences, particularly in patients with hematologic malignancies and those undergoing hematopoietic stem cell transplantation (HSCT). Loss of microbial diversity—often driven by antibiotic exposure—has been consistently associated with increased risk of bloodstream infections, especially due to intestinal domination by opportunistic pathogens such as Enterococcus and members of the Enterobacteriaceae family. Clinical studies have demonstrated that such domination events frequently precede bacteremia, supporting the concept of microbial translocation from the gut as a key pathogenic mechanism. In addition to infection risk, reduced microbiota diversity at the time of engraftment has been linked to impaired immune recovery and increased nonrelapse mortality. Notably, preservation of commensal anaerobic bacteria, including butyrate‐producing taxa, correlates with improved survival outcomes, suggesting that microbiome composition may serve as both a biomarker and a modifiable determinant of clinical prognosis in these patients [ 52 , 53 , 54 ].

Beyond infection risk, microbiome alterations also significantly influence treatment‐related toxicities and therapeutic responses. In HSCT recipients, intestinal dysbiosis has been strongly associated with the development and severity of graft‐versus‐host disease (GVHD), one of the leading causes of morbidity and mortality. Loss of beneficial commensals, particularly Clostridia species that produce short‐chain fatty acids such as butyrate, contributes to disruption of epithelial barrier integrity and amplification of inflammatory pathways, thereby exacerbating GVHD. Furthermore, microbiota‐derived metabolites have been shown to modulate host immune responses, potentially affecting both the efficacy and toxicity of chemotherapy and immunotherapy. These findings have led to growing interest in microbiome‐targeted interventions, including antibiotic stewardship strategies, prebiotic and probiotic supplementation, and fecal microbiota transplantation (FMT), which have demonstrated potential in restoring microbial balance and improving clinical outcomes. Therefore, these observations highlight the microbiome as a critical mediator of treatment response and a promising target for translational therapeutic approaches [ 55 , 56 , 57 ].

Microbiome and Aplastic Anemia

Aplastic anemia is a type of anemia in which the bone marrow does not produce enough new blood cells. In typical anemia, only the number of red blood cells is reduced, but in this type of anemia; in addition to the reduction in red blood cells, there is also a reduction in the production of other types of blood cells, which is called pancytopenia. Viral infections such as viral hepatitis (such as A, B, C, E, and G), Cytomegalovirus (CMV), Epstein–Barr virus (EBV), and Parvovirus B19 (B19V) may be associated with the development of aplastic anemia. Antigen mimicry, particularly in the case of CMV and EBV, is one of the mechanisms proposed to explain this association [ 5 ]. In IBD, which is characterized by an imbalance of intestinal bacteria, nondrug‐dependent aplastic anemia may also occur. It is possible that the mechanism involved in this case is the same as the effect of a microbial dysbiosis on hematopoiesis disorder [ 58 , 59 ]. A preliminary study was conducted to profile the oral microbiota in patients with severe aplastic anemia (SAA) throughout their treatment period. Therapeutic approaches included HSCT or immunosuppressive therapy (IST). Linear discriminant analysis combined with LefSe identified 14 taxa showing statistically significant differences ( p < 0.05) over various time points in the HSCT group. One‐way plots depicting the relative abundance of two bacterial species— Haemophilus parainfluenzae and Rothia mucilaginosa —in HSCT patients demonstrated variations in their levels across the treatment timeline. In contrast, the IST group exhibited only one bacterial species, Prevotella histicola , with a p ‐value of 0.065. Furthermore, when comparing tongue dorsum samples from healthy controls with data from the Human Microbiome Project (HMP), it was observed that roughly 35% of bacterial taxa ( N = 229) found in HSCT patients were unique to this cohort and absent in the HMP tongue dorsum samples. Among patients receiving IST, about 45% ( N = 351) of the bacterial taxa identified were exclusive to this group and not represented in the HMP dataset [ 60 ]. A Mendelian randomization study was conducted to investigate the causal links between the gut microbiota and aplastic anemia. The inverse variance weighted method identified a significant association between aplastic anemia and 10 distinct bacterial taxa. Nevertheless, current evidence remains inadequate to conclusively establish a causal effect of gut microbiota composition on aplastic anemia. The results indicated a negative correlation between aplastic anemia and the genus Parasutterella . In contrast, positive correlations were found between aplastic anemia and several microbial groups, including the class Bacteroidia , family Oxalobacteraceae , genera Anaerotruncus , Eubacterium hallii group, Family XIII UCG001 , Intestinibacter , as well as orders Bacteroidales and Mollicutes RF9, and the phylum Bacteroidetes . These findings imply a potential causal relationship between certain gut microbiota and aplastic anemia. Further research into how specific bacterial populations interact with aplastic anemia could advance strategies for its prevention, monitoring, and treatment [ 61 ]. Another investigation employed a cross‐sectional survey involving 12 aplastic anemia patients, of whom 6 had SAA and 6 had nonsevere aplastic anemia (NSAA), along with 6 healthy controls. The findings demonstrated compositional differences in gut microbiota structure between the aplastic anemia and control groups. Specifically, bacterial populations belonging to the class Clostridia —such as Lachnospiraceae ND3007 , Lachnospiraceae XPB1014 , Lachnolostridium , Ruminococcaceae UCG 013 , and the genus Butyricicoccus —were reduced in the aplastic anemia group, particularly among those with SAA. Conversely, the relative abundance of genera Lactobacillus and Streptococcus from the class Bacilli was significantly elevated in SAA patients. Additionally, the relative levels of Lachnospiraceae , Clostridiaceae , and Clostridiales vadinBB60 group families (all within the Clostridia class) showed a positive correlation with Treg counts. It is suggested that the decline of certain Clostridia bacteria may contribute to the pathophysiology of aplastic anemia by diminishing Treg cell numbers [ 62 ].

Microbiome and Anemia of Chronic Diseases

During an infection, the production of pro‐inflammatory cytokines increases. One of the most important of these cytokines is IL‐6. This cytokine can induce the expression of the protein hepcidin; this protein, in turn, prevents the iron absorption in the intestine and, on the other hand, prevents the release of iron from macrophages and the protein ferritin. These events are considered a defense mechanism in the host body during an infection because many microorganisms—mainly bacteria—need iron for growth and if iron is unavailable to them, their growth also stops, thus preventing the progression of the infection. However, subsequently, the reduction in iron levels causes disruption in hemoglobin (HGB) synthesis, disruption in red blood cell synthesis and ultimately the occurrence of a type of anemia called anemia of chronic diseases. For this reason, in these cases, it is recommended that the eradication of the infection be given priority in the treatment of anemia [ 5 , 63 ]. A study was conducted to analyze the gut microbiota characteristics in patients suffering from anemia of chronic disease and to evaluate the therapeutic potential of washed microbiome transplantation (WMT) for this condition. Compared to healthy individuals, patients with anemia of chronic disease exhibited reduced gut microbial diversity, along with distinct alterations in microbial composition and functional capacity. Notably, the relative abundances of two butyrate‐producing bacterial genera, Lachnospiraceae NK4A136 group and Butyricicoccus , were found to be positively associated with HGB concentrations and were diminished in anemia of chronic disease patients relative to controls. Treatment with WMT led to a significant elevation in HGB levels among these patients. Following the first, second, and third WMT sessions, normal HGB levels were achieved in 27.02%, 27.78%, and 36.37% of the patients, respectively (all p < 0.05). Furthermore, WMT enhanced the abundance of butyrate‐producing microbes while suppressing gut microbial functions that had been upregulated in the anemia of chronic disease cohort [ 64 ].

Microbiome and Hemochromatosis

Hemochromatosis refers to iron overload in the bloodstream, which occurs due to an inherited disorder of iron metabolism. The main problem is excessive absorption of iron from the GI tract. The liver, endocrine glands such as the adrenal glands, pancreas, and heart are among the main organs that accumulate iron. Thus, as in hemochromatosis, the host's iron levels will be high in these cases. As mentioned, many microorganisms—mainly bacteria—depend on iron for their growth. Accordingly, bacterial infections can be both a cause and a consequence of hemochromatosis the occurrence of these conditions, due to iron overload, makes the host susceptible to bacterial infections; on the other hand, the above conditions may also occur due to a bacterial infection in order to increase access to iron and, consequently, to spread the infection, by the microorganisms [ 5 ]. A study investigated the relationship between elevated transferrin saturation and dysbiosis of the subgingival microbiota, as well as its link to severe periodontitis in individuals with genetic hemochromatosis. Analysis of microbial cooccurrence patterns revealed marked differences based on transferrin saturation levels. In patients with normal transferrin saturation (≤ 45%), healthy bacterial communities and periopathogenic clusters appeared to be in competitive balance. Conversely, elevated transferrin saturation was significantly correlated with increased relative abundances of Porphyromonas and Treponema , two genera known to include prominent periopathogenic species. Enhanced iron bioavailability was found to exacerbate periodontitis severity and facilitate the proliferation of periopathogens such as Treponema . Overall, these findings suggest that iron availability within biological fluids plays a crucial role in maintaining the balance between host and microbial communities [ 65 ]. An additional study investigated the development and severity of colitis and colon cancer in a hereditary hemochromatosis mouse model (Hfe −/− ), aiming to identify contributing factors. The findings demonstrated that both induced colitis and colon cancer exhibited more aggressive progression in Hfe −/− mice compared to their wild‐type counterparts. The mechanisms involved were multifaceted. Colons from Hfe −/− mice showed increased permeability and a reduced capacity for crypt cell proliferation, which compromised tissue repair and intensified inflammation‐mediated damage. Moreover, the host‐microbiome interaction was disrupted. Analysis of fecal 16S rRNA sequencing revealed significant alterations in the colonic microbiota of Hfe −/− mice, characterized by an enrichment of pathogenic bacteria from the Proteobacteria and TM7 phyla. These mice also exhibited a greater bacterial load adhered to the mucosal surface of the colonic epithelium compared to wild‐type mice. In addition, expression levels of innate AMPs, critical for first‐line bacterial defense, were diminished in Hfe −/− colons. Concurrently, inflammatory stimuli triggered higher pro‐inflammatory cytokine release in Hfe −/− mice relative to wild‐type controls. Collectively, these results indicate that iron overload in colonic tissues, as seen in hereditary hemochromatosis, contributes to the progression of colitis and colon cancer, alongside dysbiosis and compromised intestinal barrier function [ 66 ].

Microbiome and Iron Deficiency Anemia

Iron deficiency anemia is one of the most common types of anemia worldwide, characterized by insufficient iron intake, absorption disorders, or increased demand, leading to systemic iron deficiency and impaired HGB synthesis. Dietary iron exists in two forms: heme iron, which is efficiently absorbed and mainly found in animal‐based foods, and nonheme iron. Insufficient dietary iron intake or reduced iron bioavailability is one of the leading causes of high iron deficiency anemia prevalence in many countries [ 67 ]. The relationship between the host and its microbiome is closely linked to the element iron, which is essential for the survival of most living organisms. Iron plays a critical role not only for humans but also for the growth and maintenance of nearly all bacterial species. For instance, iron‐dependent enzymes such as cytochromes and succinate dehydrogenases are integral to bacterial energy production through the electron transport chain. In the human proximal colon, the main iron transporter is divalent metal transporter 1 (DMT1), which is positioned on the apical surface of epithelial cells in this region. This specific anatomical and functional placement enhances iron availability in the large intestine, an area densely populated with bacteria [ 5 ]. Conversely, excessive oral iron intake, particularly in conditions involving malabsorption, can lead to two major effects: (i) the overgrowth of certain intestinal pathogens, which decreases the proportion of beneficial gut microbiota and triggers inflammatory gastrointestinal disorders, resembling those observed in hemochromatosis; and (ii) an increase in reactive oxygen species (ROS) generation, causing oxidative stress that hyperactivates the host immune response and results in inflammatory injury to the intestinal epithelium. This oxidative damage may increase susceptibility to various infections [ 5 ]. A pilot study investigated gut microbiota dysbiosis associated with iron deficiency anemia in infants and young children. Patients with iron deficiency anemia exhibited distinct microbial profiles characterized by an increased relative abundance of Enterobacteriaceae and Veillonellaceae , along with a decreased presence of Coriobacteriaceae , compared to healthy controls. Additionally, a reduced Bifidobacteriaceae to Enterobacteriaceae ratio was noted in those affected by iron deficiency anemia. Despite the limited sample size, these findings emphasize the existence of microbiome imbalance in iron deficiency anemia, underscoring the need for further research to elucidate how iron deficiency influences microbiome development during early life and to assess potential long‐term effects [ 68 ]. Insights from Mendelian randomization combined with in vivo experiments explored the causal links between iron deficiency anemia, gut microbiota, and metabolic profiles. Using inverse‐variance‐weighted analysis, significant correlations were identified between specific gut microbial taxa and iron deficiency anemia. The genus Desulfovibrio was found to have a protective effect, whereas Actinomyces and the family XIII were associated with an increased risk of iron deficiency anemia. Additionally, glycine showed a protective role, while elevated levels of low‐density lipoprotein (LDL) phospholipids corresponded with higher risk. These findings were supported by animal model data demonstrating decreased abundance of Desulfovibrio , increased levels of Actinomyces , and metabolic alterations involving amino acids and phospholipids [ 67 ]. A cohort study conducted in Pakistan investigated how iron deficiency anemia affects gut microbial diversity and its association with microbial metabolites. Anaerobic bacterial genera, including Coprococcus and members of the Anaerovoracaceae family, showed strong links to iron deficiency anemia and were negatively associated with the consumption of red meat and fish. Additionally, these bacteria were positively correlated with the production of branched short‐chain fatty acids (BSCFAs), which have significant roles in metabolic disorders. This research offers insights into the ways iron deficiency anemia influences gut microbial diversity and metabolite production, potentially affecting iron metabolism [ 69 ].

Microbiome and Sickle Cell Anemia

Sickle cell disease is the most prevalent inherited blood disorder worldwide, with over 300,000 newborns affected annually, leading to considerable illness and premature death. Emerging research highlights the crucial role of the gut microbiota in triggering vaso‐occlusive crises, primarily through its influence on neutrophil aging regulation. It has been proposed that individuals with sickle cell disease experience a disrupted intestinal barrier caused by vaso‐occlusive events, making them more vulnerable to recurring bacterial translocation and microbial dysbiosis. This condition likely contributes to the elevated presence of activated neutrophils in circulation. Additionally, the gut microbiota has been found to affect the production of endothelial adhesion molecules. Inflammatory states cause impairment of the intestinal epithelial barrier's integrity and function, allowing these adhesion molecules to facilitate the binding of lymphocytes, neutrophils, and other inflammatory cells to endothelial cells [ 70 ]. In patients with sickle cell disease, the gut microbiota—which plays an essential role in metabolism and immune function—is often imbalanced, characterized by an increase in pro‐inflammatory bacterial populations. The pathological mechanisms of sickle cell disease alter the colonization patterns of gut bacteria, further aggravating dysbiosis. This disruption in microbial communities may intensify the disease's progression. Targeting the gut microbiota through therapeutic interventions presents an appealing and cost‐effective strategy to mitigate sickle cell disease complications and reduce chronic pain. In regions with limited resources where sickle cell disease is prevalent, focusing on affordable treatment options such as microbiome modulation is crucial. Such approaches have the potential to enhance patient quality of life without imposing heavy financial demands, supporting a more equitable and sustainable model for managing sickle cell disease [ 71 ]. A research study was conducted to investigate the relationship between adhesion molecules, the gut microbiota, and hydroxyurea treatment in Angolan children with sickle cell anemia. Following administration of hydroxyurea, four adhesion molecules—sE‐selectin, ADAMTS13, sICAM‐1, and sVCAM‐1—showed a significant decrease. Positive correlations were identified between neutrophil counts and both sICAM‐1 and sP‐selectin, as well as between platelets and sP‐selectin. Similarly, leukocyte levels were positively associated with sICAM‐1 and sVCAM‐1. The majority of bacterial taxa exhibiting significant correlations belonged to the order Clostridiales . Within the Clostridium genus, groups g19, g21, and g34 demonstrated negative correlations with fetal hemoglobin (HbF) levels; groups g19, g21, and g24 showed positive correlations with leukocyte counts; group g19 correlated positively with neutrophils and sVCAM‐1; and group g34 was positively associated with both E‐selectin and P‐selectin. The opportunistic pathogen Serratia was positively linked to elevated levels of sE‐selectin and sICAM‐1. Furthermore, an inverse relationship was found between sP‐selectin and Bifidobacterium [ 70 ]. Another investigation assessed the diversity of gut microbiota in children and adolescents with sickle cell disease compared to healthy controls, aiming also to understand the clinical significance of microbiome composition. The patient group exhibited significantly elevated levels of white blood cells (WBCs), HGB, immature granulocytes, and C‐reactive protein (CRP). Analysis of the microbiome identified three distinct clusters among participants: one cluster consisting of controls and two clusters categorized within the sickle cell disease group, labeled as patient G1 and G2. Compared to controls, individuals with sickle cell disease showed a higher abundance of Bacteroides species, while Dialester and Prevotella species were less abundant. Additionally, the patient G2 subgroup demonstrated a greater presence of Bacteroides and a reduced presence of Prevotella relative to patient G1. This study revealed notable differences in microbiome composition between sickle cell disease patients and healthy individuals, as well as two distinct microbiota profiles within the patient population. However, these microbial variations among the patients did not appear to influence clinical outcomes such as vaso‐occlusive crisis or acute chest syndrome [ 72 ].

Microbiome and Immune Thrombocytopenia

Immune thrombocytopenia is an autoimmune disorder primarily driven by platelet‐targeting autoantibodies. It is marked by widespread hemorrhages and scattered petechiae and ecchymoses on both the skin and mucous membranes, accompanied by a reduced platelet count. The disease's underlying mechanisms are complex, but most cases result from increased platelet destruction mediated by humoral immune responses. In individuals with immune thrombocytopenia, plasma cells generate a substantial quantity of IgG autoantibodies that attach to Fcγ receptors on macrophages in the spleen [ 73 ]. This interaction facilitates the elimination of platelets coated with anti‐glycoprotein autoantibodies, ultimately leading to the development of immune thrombocytopenia. Emerging evidence suggests that the gut microbiota may be an influential factor in the onset of immune thrombocytopenia. Nevertheless, the precise role of gut microbial populations and their metabolites in this condition remains poorly understood, with existing research largely confined to fundamental experimental studies. As a result, the clinical application of gut microbiota modulation in treating immune thrombocytopenia is still distant [ 73 ]. A recent two‐step, two‐sample Mendelian randomization analysis employing an inverse variance‐weighted method investigated the causal involvement of gut microbiota in immune thrombocytopenia and explored the mediating effects of inflammatory cytokines on this association. The study identified 11 gut microbial species positively correlated and 12 species negatively correlated with immune thrombocytopenia risk among the 473 species evaluated. Of the 91 inflammatory cytokines screened, five—CXCL10, CXCL5, IL‐12RA, TRAIL, and VEGF‐A—demonstrated a causal link to immune thrombocytopenia. Mediation analysis indicated that the gut microbe UBA1066 contributed to immune thrombocytopenia development through its effect on CXCL10, with a mediation impact accounting for 0.118932, or 9.95% of the total effect. Similarly, the genus Treponema was found to promote immune thrombocytopenia via VEGF‐A mediation, with an effect size of 0.045873 representing 4.28% of the total effect. Additionally, Haloplasma influenced immune thrombocytopenia occurrence through CXCL5, which had a mediating effect of 0.038409 and a mediation ratio of 16.79%. This research uncovers a causal link between gut microbiota composition and susceptibility to immune thrombocytopenia, highlighting three inflammatory cytokines as key mediators in this relationship [ 74 ]. Another investigation examined the associations among gut microbiota, fatty acid metabolism, and cytokine profiles in immune thrombocytopenia. The findings demonstrated a link between microbial composition and fatty acid metabolism in immune thrombocytopenia patients. It is suggested that gut microbiota may contribute to immune thrombocytopenia development by influencing cytokine production and disrupting fatty acid metabolic pathways. At the genus level, Bacteroides , Phascolarctobacterium , and Lactobacillus were found to be more abundant in individuals with immune thrombocytopenia, whereas Ruminococcaceae UCG‐002 , Eubacterium coprostanoligenes , Megamonas , and Lachnospiraceae NC2004 were diminished. On the phylum scale, Proteobacteria and Chloroflexi showed increased relative abundance in immune thrombocytopenia cases, while Firmicutes , Actinobacteria , and the Firmicutes to Bacteroidetes ratio decreased. Plasma concentrations of metabolites such as 5‐hydroxyeicosatetraenoic acid (5‐HETE), 6‐trans‐12‐epi‐leukotriene B4 (6 t,12e‐LTB4), and resolvin D2 (RvD2) were elevated, whereas stachydrine, dowicide A, and dodecanoylcarnitine levels were reduced in patients with immune thrombocytopenia. Moreover, RvD2 displayed a positive correlation with the order Bacteroidetes VC2.1 Bac22 ; 5‐HETE correlated positively with the genus Azospirillum ; and 6 t,12e‐LTB4 showed a positive association with the genus Cupriavidus . Additionally, stachydrine was positively linked to the family Planococcaceae , dowicide A to class MVP‐15 , and dodecanoylcarnitine to the order WCHB1‐41 . Elevated plasma levels of IL‐6 and TNF‐α were also observed in immune thrombocytopenia patients [ 75 ].

Microbiome and Congenital Neutropenia

Severe congenital neutropenia (SCN) is an uncommon inherited disorder typically identified within the first few months of life, characterized by persistent low neutrophil counts and frequent severe infections. Its estimated prevalence ranges from approximately 3 to 8.5 cases per million people. Alterations in neutrophil homeostasis are believed to impact periodontal health, making individuals with SCN a valuable population for studying the causes of oral dysbiosis linked to periodontal diseases. Currently, there is limited, mainly cross‐sectional data available regarding the oral microbiota of SCN patients, such as findings related to saliva or subgingival communities, but comprehensive assessments at the ecosystem level remain lacking [ 76 ]. In this context, one study examined oral ecosystem dysbiosis in patients with SCN. At baseline, the clinical signs, immune responses, and microbial profiles indicated an imbalance in the oral ecology of these patients. Compared to SCN patients, control subjects exhibited significantly greater species richness in saliva both initially and after 6 months of follow‐up. The normalized sequencing dataset included 346 operational taxonomic units distributed across 16 phyla and 150 genera or higher taxonomic groups. The phylum Firmicutes dominated the sample, constituting 38% of all sequences, followed by Bacteroidetes (20%), Proteobacteria (18%), Fusobacteria (14%), Actinobacteria (9%), TM7 (0.6%), and Spirochaetae (0.1%), cumulatively representing 99.9% of the total reads. Among genera, Streptococcus was the most abundant, accounting for 21% of sequences, with Prevotella (13%), Veillonella (10%), Leptotrichia (9.7%), Neisseria (7%), Fusobacterium (4%), Actinomyces (4%), Haemophilus (4%), and Rothia (3.4%) following. Patients with SCN demonstrated significantly increased bleeding on probing percentages, elevated gingival crevicular fluid volumes, heightened cytokine concentrations, and a high bacterial load paired with reduced salivary bacterial diversity. Furthermore, the relationships between microbiome characteristics and immune parameters in SCN individuals differed notably from those observed in healthy controls [ 76 ]. Another study examined the host proteome and metaproteome in saliva and gingival crevicular fluid from SCN patients undergoing granulocyte colony‐stimulating factor treatment. Individuals with SCN exhibited a distinctive proteomic profile characterized by decreased levels of AMPs alongside increased complement proteins, which may contribute to their heightened vulnerability to infections. The dominant bacterial genera identified included Streptococcus , Veillonella , Selenomonas , Corynebacterium , Porphyromonas , and Prevotella . Compared to healthy subjects, SCN patients showed lowered AMP concentrations and elevated complement protein levels. Following an oral hygiene intervention, improvements in oral epithelial health were observed, accompanied by reductions in both AMPs and complement proteins [ 77 ].

Microbiome and Thrombosis

LPS, found in the outer membrane of gram‐negative bacteria, serves as a critical connection between gut microbiota and the state of hypercoagulability [ 5 ]. Various genetic predispositions and environmental influences, including diets high in fat, can cause dysbiosis characterized by the overgrowth of Enterobacterales and a reduction in microbial diversity. This imbalance leads to elevated LPS production within the intestinal lumen. When the intestinal epithelial barrier becomes compromised, LPS can infiltrate the hepatic portal vein and subsequently enter systemic circulation. This process contributes to several complications: (i) LPS activates TLR4 on endothelial cells, triggering the release of von Willebrand factor (VWF), Factor VIII, and P‐Selectin from Weibel‐Palade bodies; (ii) the activation of TLR2 on endothelial cells by LPS increases VWF levels, promotes platelet adhesion, and facilitates arterial thrombosis; (iii) LPS stimulation of TLR4 on platelets causes degranulation of alpha and dense granules, secretion of pro‐inflammatory cytokines and VWF, enhancement of thrombin activity, elevation of tissue factor in the extrinsic coagulation pathway, an increase in plasminogen activator inhibitor type 1 (PAI‐1)—which inhibits fibrinolysis—accompanied by decreases in tissue‐type plasminogen activator (TPA)—a protease that initiates clot breakdown—and in tissue factor pathway inhibitor (TFPI)—an anticoagulant protein; and (iv) LPS interaction with TLR2 on platelets triggers granule release, promotes platelet‐leukocyte aggregation, and results in platelet activation [ 78 ]. TLRs also mediate the expression of endothelial adhesion molecules—including ICAM‐1—binding to neutrophils, increased neutrophil extracellular trap (NET) formation, platelet–neutrophil interactions, and immunothrombosis, which can ultimately activate the contact activation (intrinsic) pathway and contribute to platelet aggregation. NETs also precipitate serine proteases—which in turn inactivate important anticoagulants such as TFPI and thrombomodulin; as a result, excessive coagulation occurs. NETs also trigger the intrinsic pathway by activating Factor XII and binding to VWF to facilitate platelet recruitment and activation [ 78 ]. On the other hand, although atherosclerosis is often multifactorial in origin, there is growing evidence that the gut microbiota is associated with the development of this disease through increased metabolism of dietary phosphatidylcholines to a compound called TMAO, thereby increasing the burden of coronary atherosclerotic plaques. TMAO increases the deposition of foam cell macrophages on fatty deposits—especially cholesterol—in the blood vessel wall, which drives one of the early steps in the development of atherosclerosis [ 5 , 78 ]. Western diet is rich in choline, phosphatidylcholine and carnitine, which can cause dysbiosis in the direction of increase of Firmicutes and Proteobacteria phyla. Choline and other compounds present in this type of diet are metabolized to trimethylamine (TMA) by the TMA lyase enzyme of altered gut microbiota. TMA then enters hepatic portal circulation where it is converted to TMAO by flavin monooxygenase (FMO)—especially FMO3—and is finally released into systemic circulation. Upon entering systemic circulation, TMAO does not directly stimulate platelets. However, it increases Ca 2+ release, activation of platelet agonists and consequently platelet hyperreactivity and increases foam cell macrophage deposition in early stages of atherosclerosis [ 78 ]. SCFAs are derived from the fermentation of indigestible dietary fiber by gut microbiota. Although high levels of these fatty acids are thought to have beneficial anti‐inflammatory effects, uncontrolled levels may be a risk factor for cardiovascular disease due to the role SCFAs play in regulating blood pressure [ 5 , 78 ]. Bile acids are synthesized in the liver from cholesterol and are essential for the excretion of cholesterol from the feces. The enzyme bile salt hydrolase (BSH)—which is produced by the gut microbiota—is involved in this process by deconjugating bile acids bound to glycine and taurine, resulting in the release of free bile acids. Therefore, any dysbiosis in the gut microbiota, by affecting this enzyme, can reduce the synthesis of bile acids and lead to reduced cholesterol excretion, increased cholesterol accumulation and ultimately increased risk of cardiovascular diseases [ 78 ]. A study explored the possibility of targeting the gut microbiota as an innovative approach to prevent thrombosis, highlighting berberine, a natural compound recognized for its cardiovascular benefits. The findings revealed that berberine reduces thrombosis by modifying the composition of the gut microbiota and its associated metabolic products. Specifically, berberine decreases the production of phenylacetylglycine—a coproduct generated by the host and gut microbiota that promotes thrombosis—by enhancing the breakdown of phenylacetic acid. This work emphasizes the importance of phenylacetylglycine as a risk factor for thrombosis, demonstrated by the fact that administering phenylacetylglycine intraperitoneally negates the protective effect of berberine. Furthermore, experiments involving fecal microbiota transplantation confirmed the essential role the gut microbiota plays in thrombus development [ 79 ]. A Mendelian randomization analysis investigated the relationships between gut microbiota, plasma metabolites, and venous thromboembolism. The study identified sixteen gut microbiota taxa—such as protective groups like Firmicutes and Clostridia , alongside risk‐related taxa including Bacteroidetes and Desulfovibrionaceae —and forty metabolites that exhibited causal links to venous thromboembolism, deep vein thrombosis, and pulmonary embolism. Further reverse Mendelian randomization analyses revealed eleven alterations in gut microbiota that occurred as a consequence of thrombosis. The study found no evidence of pleiotropy or heterogeneity. Additionally, ten metabolite‐mediated pathways, including arginine biosynthesis, connected the gut microbiota to thrombosis, highlighting gut microbiota‐metabolite interactions as promising biomarkers for assessing thrombotic risk and prognosis [ 80 ]. Another study examined the characteristics of gut and circulating microbiota in patients suffering from liver cirrhosis with portal vein thrombosis. While no differences in α‐diversity of gut microbiota were observed between groups, β‐diversity varied notably. Patients with portal vein thrombosis exhibited an increase in Gram‐negative bacteria—including Escherichia ‐ Shigella —alongside a reduction in SCFA‐producing bacterial taxa. Compared to microbiota from peripheral veins, the portal vein microbiota in cirrhotic patients with portal vein thrombosis showed significant distinctions in both α‐ and β‐diversity, with an enrichment of the genus Massilia . Among the tested microbiome sites, the portal vein microbiota demonstrated the highest diagnostic effectiveness for portal vein thrombosis presence. The group with thrombotic portal vein thrombosis displayed a greater number of genera shared between portal vein and feces compared with the nonthrombotic portal vein thrombosis group. Taxa shared among the portal vein, peripheral vein, and feces were predominantly LPS‐producing Gram‐negative genera such as Escherichia ‐ Shigella and Klebsiella . Most bacterial genera detected in the portal vein showed significant positive correlations with LPS levels and Factor VIII there. Genera like Faecalibacterium , the Eubacterium hallii group, Ruminococcus , Agathobacter , Bacteroides , and Romboutsia were significantly inversely correlated with Child‐Pugh scores. Likewise, Faecalibacterium , Eubacterium hallii group, Alistipes , Ruminococcus , Agathobacter , Bacteroides , Blautia , and Subdoligranulum exhibited notable negative associations with MELD scores. Additionally, Ruminococcus and Agathobacter were significantly negatively correlated with D‐Dimer levels, whereas Subdoligranulum demonstrated positive correlations with both LPS and Factor VIII within the portal vein [ 81 ].

Microbiome and Blood Malignancies

Microbiome and Lymphoma

Lymphomas slightly reduce the proportion of gut microbiota (Table 2 ); however, they are mainly associated with increased abundance of E. coli and Clostridium butyricum , especially in Hodgkin lymphoma (HL) [ 82 ]. E. coli produces colibactin and cytolethal distending toxins (CDTs), which are linked to DNA breakage in epithelial cells, increased incidence of genetic mutations, and contribute to tumor formation. E. coli also plays an important role in lymphoproliferative disorders—disorders associated with increased proliferation of erythroid lineage cells—and infections through initial colonization of the GI mucosa, where it can contribute to chronic inflammation. This inflammation may be sustained due to strategies by which these bacteria evade host immune responses, including blocking TLR‐4 signaling, inhibiting NF‐kB activity, and suppressing the production of pro‐inflammatory cytokines in cells [ 83 , 84 , 85 ]. C. butyricum also produces butyrate and through this can inhibit the activity of the host's histone deacetylases 6 & 9, leading to increased acetylation of the FOXP3 gene promoter, resulting in an increase in the number of Treg cells and inhibition of immune responses in the host [ 86 , 87 ].

Mendelian randomization (MR) studies have emerged as a powerful approach to infer causality in microbiome‐disease associations. As described in a recent review that investigated causal relationships between gut microbiota and cancers. MR uses genetic variants as instrumental variables to assess whether an exposure (e.g., specific microbial taxa) has a causal effect on an outcome (e.g., lymphoma), overcoming many limitations of observational studies by reducing confounding and reverse causation. In hematology, MR studies have identified potential causal relationships between specific bacterial taxa and disorders including aplastic anemia, immune thrombocytopenia, and venous thromboembolism. These findings, while requiring experimental validation, provide important direction for prioritizing mechanistic investigations and identifying targets for therapeutic intervention [ 44 , 88 , 89 , 90 , 91 ].

Mucosa‐Associated Lymphoid Tissue ( MALT ) Lymphoma

In this category of cancer, it is believed that a clone of malignant B cells emerges due to sustained lymphoid proliferation prompted by an antigenic trigger. This neoplastic clone, which arises from memory B cells located in the marginal zone of lymphoid follicles, progressively supplants normal cells and eventually causes the formation of lymphoma [ 92 ]. A thorough examination of the gastric microbiota demonstrated notable alterations in the bacterial communities present in the gastric mucosa of patients diagnosed with gastric MALT lymphoma. The association between H. pylori infection and gastric MALT lymphoma has been identified; this bacterium probably causes excessive proliferation of B lymphocytes, their clonal expansion, and ultimately the development of MALT lymphoma through local inflammation and persistent antigenic stimulation [ 92 , 93 ]. This lymphoma occurs in association with H. pylori infection in about 90% of cases, and it has even been seen that in about 80% of patients, eradication of this infection leads to complete recovery of gastric MALT lymphoma [ 93 , 94 , 95 ]. Therefore, antibiotic management of H. pylori infection can lead to the cure of most gastric MALT lymphoma in the early stages [ 95 , 96 ]. In addition to H. pylori , Helicobacter heilmannii can also cause MALT lymphoma [ 97 ]. A study examining the gastric microbiota of patients with gastric MALT lymphoma in relation to H. pylori infection found no significant differences in microbial diversity or bacterial composition between gastric MALT lymphoma patients and controls when H. pylori status was considered. Analysis of differential taxa revealed distinct microbial shifts linked to H. pylori ‐negative gastric MALT lymphoma: levels of Actinobacillus , Lactobacillus , and Chryseobacterium were elevated in these patients, whereas Veillonella , Atopobium , Leptotrichia , Catonella , Filifactor , and Escherichia ‐ Shigella were more abundant in the control group. Among patients with gastric MALT lymphoma remission, Haemophilus and Moraxella genera were found at significantly higher levels compared to those with refractory disease, while Atopobium and Actinomyces were notably increased in refractory cases [ 98 ]. Another study conducted a metagenomic analysis to compare the fungal microbiome of patients with conjunctival MALT lymphoma to that of healthy individuals. The detailed investigation revealed fungal dysbiosis and significant alterations in β‐diversity within the conjunctival region of MALT lymphoma patients. Using hierarchical clustering based on Malassezia abundance, participants were grouped into three distinct clusters: cluster I with Malassezia levels exceeding 70%, cluster II with levels between 25% and 70%, and cluster III with less than 25%. The majority of patients belonged to cluster I, while most healthy controls were classified in cluster III, highlighting a significant difference. Additionally, tear mucin levels were found to be notably reduced in patients with conjunctival MALT lymphoma compared to the healthy control group [ 99 ].

The causal relationship between H. pylori infection and gastric MALT lymphoma represents the best‐established example of microbial causation in hematologic malignancies. As noted in a recent review, a causal link between H. pylori infection and gastric MALT lymphoma was noted, with eradication leading to remission in approximately 80% of cases. The strength of this evidence derives from multiple sources: epidemiologic studies showing a consistent association, mechanistic studies demonstrating antigen‐driven B‐cell proliferation, and most importantly, interventional studies showing that antibiotic therapy alone can induce durable remissions. This causal framework has important implications for other hematologic disorders where microbial associations have been identified but causation remains unproven. The H. pylori paradigm suggests that establishing causation requires: (1) demonstration that the microorganism precedes disease onset, (2) identification of plausible biologic mechanisms, and (3) evidence that microbial eradication modifies disease course [ 44 ].

Diffuse Large B‐Cell Lymphoma ( DLBCL )

DLBCL represents the most prevalent subtype of adult Non‐Hodgkin lymphoma (NHL), accounting for over 60% of all adult NHL diagnoses in China. Despite improvements in remission rates through current treatments, approximately one‐third of patients fail to respond favorably [ 82 ]. In 2016, Kuo et al. from Taiwan linked the expression of cytotoxin‐associated gene A (Cag A) protein and CagA signaling molecules—phosphorylated‐SHP2 and phosphorylated‐ERK—in malignant B cells to H. pylori infection and stated that the likely path to treating DLBCL, especially in the early stages, is to eradicate this infection [ 100 ]. In one study, the fecal microbiota composition of 25 untreated DLBCL patients was compared with that of 26 healthy controls using 16S rRNA gene sequencing. Analysis of α‐diversity revealed no significant differences in species richness or abundance between the groups. However, β‐diversity analysis demonstrated a notable distinction in microbial community structure. The gut microbiota of DLBCL patients exhibited a progressive evolutionary pattern, notably from the phylum Proteobacteria to the genus Escherichia ‐ Shigella , which was significantly more abundant than in controls. At the genus level, Allisonella , Lachnospira , and Roseburia were also found at higher levels in the DLBCL group compared to healthy individuals. Functional predictions conducted with PICRUSt indicated that pathways related to thiamine metabolism and the biosynthesis of phenylalanine, tyrosine, and tryptophan were markedly reduced in patients with DLBCL. Overall, these findings provide clear evidence that the gut microbiota undergoes significant alterations in individuals with DLBCL [ 82 ]. Another study explored how the composition of the gut microbiota relates to chemotherapy effectiveness in DLBCL. The findings indicated that patients with DLBCL at the time of diagnosis exhibit altered gut microbiota profiles, including a pronounced increase in the abundance of the phylum Proteobacteria (class Gammaproteobacteria , order Enterobacteriales , family Enterobacteriaceae , genus Escherichia ‐ Shigella , and species E. coli ). Genetic analyses revealed a high prevalence of genes linked to virulence factors. Additionally, the baseline gut microbiota was found to correlate with clinical outcomes. Notably, the presence of Lactobacillus fermentum was associated with improved responses to treatment [ 101 ].

Adolescent/Young Adult Hodgkin Lymphoma ( AYAHL )

This type of lymphoma is attributed to reduced exposure to microbes—significantly reduced fecal‐oral exposure—during childhood. The expansion of intestinal microorganisms during childhood causes a shift in immune responses from Th2 to Th1; therefore, the reduction in diversity of intestinal microorganisms due to low exposure during childhood will cause a deviation of immune responses, failure to induce a shift from Th2 to Th1 and subsequently suppression of Th1 activities and an increase in Th2 responses. These events, in turn, increase the concentration of Th2 cytokines—IL‐4, IL‐5, and IL‐13—and IgE—induced by IL‐4, as well as a decrease in the number of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, which are crucial in antitumor activities. Thus, it is likely that the decrease in diversity of intestinal microorganisms is influential in the incidence of AYAHL [ 102 ]. One study involving twins investigated the diversity of fecal microbiota in survivors of AYAHL. In the initial analysis, all α‐diversity indices were higher in the unaffected twin controls compared to the AYAHL survivors. Additionally, AYAHL cases showed a lower number of unique operational taxonomic units relative to their cotwin controls; however, this difference was not statistically significant when focusing only on abundant operational taxonomic units. These findings suggest that survivors of AYAHL may have a reduced presence of rare gut microbial species [ 103 ]. In a separate study, an average of 219,373 sequencing reads per sample were obtained, ranging from 64,742 to 391,120 reads. No significant differences were observed in α‐diversity metrics between AYAHL survivors and their unaffected twins, although for each metric, the unaffected twin consistently exhibited higher diversity scores than the corresponding HL survivor. β‐diversity analyses showed no significant differences between the groups. Significant variations in the relative abundance of several bacterial genera—including Streptococcus , Sellimonas , Candidatus Stoquefichus , unclassified S24‐7 , Faeclitalea , Veillonella , Faecalibacterium , and the [ Eubacterium ] oxidoreducens group—were found between survivors and their unaffected twin controls. Notably, Faecalibacterium and the [ Eubacterium ] oxidoreducens group were more prevalent in survivors, whereas the remaining genera were more abundant in the unaffected twins [ 104 ].

Cutaneous T‐Cell and B‐Cell Non‐Hodgkin Lymphoma

Skin cancer significantly affects individuals' quality of life, and its incidence is increasing worldwide. Recent studies highlight the crucial influence of disruptions in the skin microbial community in promoting chronic inflammation, evading immune responses, and initiating skin cancer. Normally, certain bacteria like Staphylococcus epidermidis are the dominant members of the skin microbiota. Conversely, bacteria such as Staphylococcus aureus are rarely found on the skin of healthy individuals. A disturbance in the balance between beneficial and harmful bacteria may contribute to the development of various skin disorders or systemic diseases, including cancer. Cutaneous lymphoma, a form of skin cancer, is divided into cutaneous T‐cell lymphoma and cutaneous B‐cell lymphoma. Increasing evidence indicates that changes in the skin microbiota might play a role in the onset or progression of cutaneous lymphomas [ 105 ]. Reports of the presence of DNA of Borrelia burgdorferi in malignant lymphomas have suggested that infection with this bacterium may be a factor in the development of NHL; even cutaneous B‐cell Non‐Hodgkin lymphoma has been reported in individuals seropositive for antibodies against B. burgdorferi . It is believed that this bacterium exerts its tumorigenic mechanisms through abnormal replication of B‐lymphocyte DNA resulting from increased growth of these lymphocytes, oxidative stress, and activation of oncogenes [ 102 , 106 , 107 ]. Nguyen et al. investigated the gut microbiota of patients with cutaneous T‐cell lymphoma undergoing narrowband ultraviolet B therapy, uncovering changes linked to disease treatment. Protective commensal bacteria such as Lactobacillaceae and Erysipelatoclostridiaceae were found to be significantly reduced in cutaneous T‐cell lymphoma patients compared to healthy controls. Following treatment, the gut microbiota of these patients showed a decline in phylogenetic diversity and a lower relative abundance of the pro‐inflammatory family Sutterellaceae . Additionally, Sutterellaceae levels were notably higher in patients whose condition worsened, while Eggerthellaceae and Erysipelotrichaceae tended to increase in those who showed improvement. Lastly, functional predictions using PICRUSt2, based on variations in bacterial sequence abundance, consistently revealed changes in inositol degradation pathways, which are crucial for host immune regulation, including inositol phospholipid signaling that influences T‐cell survival and proliferation [ 108 ]. A study investigated how modulation of the skin microbiota in cutaneous T‐cell lymphoma affects tumor growth and survival in the murine EL4 model. Treatment with a triple antibiotic regimen significantly delayed tumor onset, thereby extending the survival of the mice. When combined with phototherapeutic agents—PUVA, UVB, or no phototherapy—antibiotic intervention markedly reduced tumor growth. β‐diversity indices calculated using the Bray–Curtis model demonstrated a significant shift in the microbial community following antibiotic treatment. Modulating the skin microbiota through antibiotics led to an increase in commensal Clostridium species, such as Lachnospiraceae sp., Ruminococcaceae sp., and Blautia sp., alongside a notable decrease in facultative pathogens including Corynebacterium sp., Pelomonas sp., Streptococcus sp., Pseudomonas sp., and Cutibacterium sp. Interestingly, there was a significant reduction in the frequency of S. aureus , while the overall detection frequency of the Staphylococcus genus increased, suggesting that antibiotic treatment helped restore microbial balance by promoting nonpathogenic Staphylococcus populations. These results indicate that topical antibiotic modulation of the microbiome contributes to microbial equilibrium restoration, decreases pathogenic microbes, reduces chronic inflammation, delays tumor progression, and improves survival in this cutaneous T‐cell lymphoma model [ 109 ].

Microbiome and Leukemia

Acute Lymphoblastic Leukemia ( ALL )

ALL is the most common onco‐hematological pathology in children (Table 3 ). There may be a relationship between the onset of this leukemia and the mode of birth: that is when infants are exposed to the vaginal microbiota of the mother. The interaction between the immune system and exposure to microbes—during fetal life, natural childbirth or breastfeeding—and the consequent colonization of these microorganisms in the body of infants may increase the risk of leukemia during this period [ 5 ]. Studies also indicate dysbiosis and reduced microbial diversity in adults with ALL; a decrease in the relative abundance of Edwardsiella tarda and Prevotella maculosa has been observed in ALL patients, and it has also been associated with a decrease in IL‐10 levels—as an immune system inhibitory cytokine [ 110 , 111 , 112 ]. Other studies have reported a decrease in the abundance of Faecalibacterium among ALL patients and have associated it with increased levels of IL‐6 and CRP [ 113 ]. Megamonas is also found in abundance in the gut microbiota of these patients and is directly related to the levels of pro‐inflammatory cytokines such as IL‐6 [ 103 , 114 , 115 , 116 , 117 , 118 ]. A decrease in the abundance of Firmicutes is another change in the composition of the microbiome of individuals with ALL [ 119 ]. The Firmicutes phylum is a major butyrate producer—like the genus Streptococcus —and has anticancer activities [ 119 , 120 ]. Butyrate may be important in repairing damage to the intestinal epithelial barrier and subsequently preventing the leakage of LPS into the bloodstream, potentially playing a protective role against leukemia progression [ 121 ].

Acute Myelogenous Leukemia ( AML )

AML is the most common form of acute leukemia in adults, with its incidence increasing significantly with age; the median age at diagnosis typically falls between 65 and 72 years in Western countries. According to a registry study, the global age‐standardized incidence rate of leukemia is 46.4 per million annually among children aged 0–14 years and 28.5 per million among adolescents aged 15–19 years. In the United States, around 20,050 people of all ages were diagnosed with AML in 2022, leading to 11,540 deaths attributable to the disease [ 122 ]. Sung et al. reported that gram‐positive cocci and mainly heterogeneous Viridans streptococci were the most common microorganisms isolated from patients with AML [ 123 ]. Leukotoxin A (LtxA), produced by a type of oral microbiota called Aggregatibacter actinomycetemcomitans , is effective in preventing the development and progression of AML by reacting with lymphocyte function antigen‐1 (LFA‐1) present on the surface of susceptible leukocytes. In these patients, it has been shown that the LtxA protein destroys malignant and leukemic cells both in vivo and in vitro, but in contrast, healthy cells are resistant to its cytotoxicity. Therefore, any dysbiosis that reduces the abundance of this oral microbiota and consequently reduces the toxin produced by it may be effective in AML [ 124 ]. LukS‐PV is a subunit of the Panton‐Valentine Leukocidin (PVL) toxin secreted by S. aureus . This exotoxin causes lysis of human neutrophils, monocytes, and macrophages and also plays a role in inhibiting proliferation and inducing apoptosis of leukemic cells [ 125 , 126 , 127 ]. This toxin is also important in inducing leukemic cell differentiation by stimulating the extracellular‐signal‐reduced kinase (ERK) and c‐JUN/c‐FOS signaling pathways [ 125 , 126 , 128 ]. Thus, any dysbiosis that reduces the abundance of S. aureus , as a microbiota of the upper respiratory tract, intestinal mucosa, and skin, may effectively reduce the toxin produced by it and the occurrence of AML. In addition, the researchers found that a reduction in the proportion of Faecalibacterium could contribute to the proliferation and invasion of tumor cells and the suppression of their apoptosis [ 121 , 129 ]. Most Faecalibacterium strains are associated with energy production for intestinal epithelial cells and synthesizing metabolites such as butyric acid, bioactive peptides, and anti‐inflammatory substances, thus contributing to intestinal health [ 130 ]. Studies have shown that the use of Actinobacteria may be beneficial in the treatment of patients with acute leukemia; several Actinobacteria metabolites, such as indolocarbazoles, isoprenoids, nonribosomal peptides, anthracyclines, macrolides, and enediynes, have antioxidant and antitumor properties. These metabolites have cytotoxic activity against cancer cell lines by reducing the activity of cyclooxygenases and lipoxygenases [ 131 , 132 ]. Cyclooxygenases are involved in prostaglandin synthesis and cause leukemic cell proliferation and production of ROS. At the same time, lipoxygenases catalyze the production of hydroxyl eicosatetraenoic acids and leukotrienes, which help suppress apoptosis and stimulate tumor cell proliferation [ 132 ].

Chronic Lymphoblastic Leukemia ( CLL )

CLL is among the most prevalent types of leukemia and primarily affects older adults. The disease often follows an indolent course that may not require immediate treatment but can also manifest as an aggressive form with rapid progression. Through the combined use of chemotherapy and monoclonal antibodies (chemoimmunotherapy), progression‐free survival exceeding 8 years has become achievable in certain subgroups of CLL patients with specific genetic markers [ 133 ]. Th17 cells play a prominent role in the intestinal immune microenvironment [ 10 ]. Huang et al. observed that Prevotella , as a microbiota of the human colon, causes the production of Th17 cells in the colon of mice and subsequently the production of cytokine IL‐17 in their serum, thus concluding that these cells have a potential role in the formation of the intestinal immune system and the occurrence of CLL [ 134 ]. However, the precise mechanisms through which Th17 cells may contribute to the progression of CLL have not yet been investigated. Another study has reported, at the genus level, an increased abundance of Bacteroides , Parabacteroides , Prevotella , and Acinetobacter , and at the phylum level, an increased abundance of Firmicutes , along with a decreased abundance of Bacteroidetes , in patients with CLL compared to healthy individuals [ 135 , 136 ]. In contrast, other studies have shown decreased Lachnospiraceae and Ruminococcaceae in CLL patients [ 137 , 138 ]. Lachnospiraceae play a role in hematopoietic repair by providing resistance to high doses of ionizing radiation—a factor in the development of CLL—and in the repair of the host digestive system by producing butyrate [ 139 ]. Ruminococcaceae also produce butyrate and several types of SCFA, and its deficiency has been associated with the disruption of several signaling pathways [ 140 ]. However, the exact role of Ruminococcaceae in the recovery of patients with leukemia remains unknown; however, it is possible that these bacteria and their metabolites could improve the diagnosis and treatment of several types of cancer.

Chronic Myelogenous Leukemia ( CML )

CML is a cancer primarily affecting adults. In 2024, the estimated number of new CML cases and deaths in the United States are 9280 and 1280, respectively. This malignancy is one of the cancers showing notable improvements in survival rates, likely due to advances in treatment strategies, especially the introduction of targeted therapies [ 141 ]. According to research, in CML patients, the Actinobacteria , Acidobacteria , and Chloroflexi phyla are more abundant, and in contrast, the Tenericutes phylum is reduced in these patients [ 142 ]. Faitová et al., using shotgun DNA sequencing of fecal samples, found that CLL patients exhibiting diminished microbiome diversity alongside an increased abundance of bacteria linked to poor health had more advanced or aggressive disease stages. Moreover, reduced microbiome diversity—with a predominance of the genera Mucispirillum and Parabacteroides —was also detected in mice kept in environments with lower hygiene standards. In summary, taxonomic analyses of the microbiome were utilized to establish a relationship between gut microbiota diversity and both clinical progression of CLL in humans and disease development in mice. These novel insights lay the groundwork for further studies aimed at uncovering the pathological and mechanistic contributions of gut microbiota to CLL pathogenesis [ 143 ]. An analysis of the gut microbiota composition revealed two distinct patient groups (cluster 1, N = 10; cluster 2, N = 23), with 13 patients remaining unclassified in any cluster. Patients categorized in cluster 1 exhibited higher abundances of Firmicutes , Tenericutes , and Verrucomicrobia . In addition, they were undergoing fewer concomitant treatments compared to those in cluster 2, which was marked by an increased presence of Bacteroidetes and a greater frequency of side effects. Upon evaluating all selected cell lines and comparing their distribution across clusters, it was observed that the percentage of CD8+ central memory T cells and mature NK cells was significantly elevated in cluster 1 [ 144 ]. In addition, studies have reported increased levels of Streptococcus in patients with CML [ 142 ]. In this case, Streptococcus has been associated with increased levels of the inflammatory cytokine IFN‐γ [ 145 ]. Streptococcus also produces lactic acid through the fermentation of sugars, which may have implications for the progression of CML [ 146 ].

Microbiome and Multiple Myeloma ( MM )

MM is a prevalent form of hematological cancer marked by the uncontrolled proliferation of plasma cells within the bone marrow (BM). It is classified among disorders called monoclonal gammopathies. MM develops progressively, typically following an initial asymptomatic phase referred to as monoclonal gammopathy of undetermined significance (MGUS), and frequently an intermediate phase known as smoldering multiple myeloma (SMM). About 15% of individuals with MGUS and 10% of those with SMM advance to MM within 5 years after their diagnosis [ 147 ]. A preclinical study has demonstrated that Prevotella heparinolytica promotes the differentiation of T helper cells toward the Th17 subset [ 148 ]. This cytokine may contribute to the development of MM through three proposed mechanisms: (i) Th17 cells initially colonize the gut and subsequently migrate to the bone marrow; elevated levels of IL‐17—a cytokine produced by Th17 cells—within the bone marrow facilitate the progression of MM; (ii) The transcription factor STAT3 is essential in naive B cells for inducing plasma cell differentiation as well as supporting the survival and expansion of effector B cells; IL‐17 enhances plasma cell formation by stimulating STAT3 phosphorylation; and (iii) Aberrant paracrine signaling is likely present between innate and adaptive immune systems, and the amplification of these signals by commensal bacteria may accelerate MM progression [ 5 ]. Additionally, Zhang et al. found that MM patients exhibit an altered gut microbiota composition and diversity compared to healthy controls: (i) At the phylum level, an increased abundance of Proteobacteria and a decreased presence of Actinobacteria were observed; (ii) At the genus level, there were elevated proportions of Bacteroides , Faecalibacterium , and Roseburia ; and (iii) Higher levels of Pseudomonas aeruginosa and Clostridium leptum were particularly noted in advanced disease stages [ 149 ]. While P. aeruginosa is recognized as an opportunistic pathogen, C. leptum is a member of the normal gut microbiota involved in butyrate production and glucose metabolism via the pyruvate and acetyl coenzyme A pathways in the intestine [ 150 ]. Nonetheless, further investigation is required to clarify the specific roles of these bacteria in MM pathogenesis.

Therapeutic Development

Allogeneic Hematopoietic Stem Cell Transplantation ( aHSCT )

HSCT is often used as a treatment strategy for patients with hematological disorders (Figure 4 ). In aHSCT, the risk of GVHD is high (30% to 70%), which can manifest as systemic and local complications [ 151 ]. GVHD is when the immune cells—usually T lymphocytes—found in the transplant donor tissue recognize the transplant recipient tissues as foreign and attack them. It occurs most frequently in organs where there is an interaction between the microbiota and specific epithelia—intestine, mouth, skin, eye, lung, and liver. The integrity of the microbiota‐epithelium barrier—especially the intestinal epithelium—plays an important role in both immune homeostasis and in preventing the occurrence of GVHD. Any damage to the intestinal epithelium and loss of the integrity of its mucosal lining causes the movement of the gut microbiota to extraintestinal locations—such as the blood, thus exposing the bacterial population of the gut microbiota, PAMPs—such as LPS—and damage‐associated molecular patterns (DAMPs) to antigen presenting cells (APCs), which leads to the activation of alloreactive T cells present in the transplant donor tissue, the creation of inflammatory conditions accompanied by the release of cytokines, and ultimately damage to the target organs and the occurrence of GVHD in the transplant recipient [ 5 ]. Jenq et al. found that reduced gut microbiota diversity may contribute to increased mortality from GVHD; they assessed the abundance of bacteria belonging to the genus Blautia according to clinical factors and found that reduced levels of these bacteria due to treatment with antibiotics that inhibit anaerobic bacteria—metronidazole, vancomycin, meropenem, etc.—or total parenteral nutrition (TPN) for a long time were associated with an increase in fatal GVHD. They concluded that increased abundance of commensal bacteria belonging to the genus Blautia is associated with improved effects of transplanted cells due to their beneficial anti‐inflammatory effects—including increased infiltration of Treg cells into the colon [ 14 ]. A first study to apply RATIO to a large patient cohort, combining microbial data from two different anatomical sites—saliva and stool—to predict time‐to‐event outcomes related to HSCT complications and to validate the microbial associations identified by the model. The greatest disruption in the oral and fecal microbiota occurred within the first 2 weeks following HSCT, with partial restoration observed thereafter. The analysis highlighted certain stool genera, such as Collinsella and Eggerthella , which were linked to a shorter duration until the onset of various complications [ 152 ]. Compared to timepoints, patients who developed acute GVHD exhibited a significant decrease in the abundance of the phylum Proteobacteria and the family Enterobacteriaceae , accompanied by a notable increase in Enterococcus species over time. In those who later developed chronic GVHD after aHSCT, there was a consistent decline over time in the abundance of the family Eurobacteriaceae and the genus Roseburia [ 153 ]. Accordingly, aHSCT improves hematological disorders by transplanting healthy stem cells, but success depends on preventing or managing GVHD. Maintaining a balanced gut microbiota that supports immune regulation (e.g., through Blautia and other beneficial bacteria) helps reduce GVHD risk and improves the effectiveness of the transplanted cells.

Clinical studies have now established that microbiome composition predicts outcomes in allogeneic HCT. As noted in a comprehensive review, microbiota composition can predict mortality in allogeneic hematopoietic cell transplantation. Peled and colleagues demonstrated that lower gut microbiome diversity at engraftment is associated with increased risk of transplantation‐related mortality, and specific microbial taxa correlate with different causes of death. This predictive capacity has important clinical implications, suggesting that microbiome assessment could inform risk stratification and guide preventive interventions. Furthermore, recent research has revealed complex interactions between medications and the microbiome in transplant recipients. A study published that nonantibiotic drugs, including proton pump inhibitors and analgesics, are associated with specific changes in gut microbiota composition and transitions between microbiome states. These findings highlight the need to consider the full medication regimen—not just antibiotics—when interpreting microbiome changes in transplant patients and designing interventions to preserve or restore microbial diversity [ 53 , 154 ].

Probiotics

The Food and Agriculture Organization of the United Nations (FAO) and the World Health Organization (WHO) define probiotics as follows: Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. Restoration of a healthy microbiome and subsequent improvement of hematological diseases may be possible with the development of specific probiotics. Probiotics enhance innate immune responses by increasing NK cell cytotoxicity and stimulating phagocytes. In addition, probiotics enhance adaptive immune responses by increasing the production of IgM and IgA immunoglobulins [ 102 ]. Among the most famous probiotics in this field, we can mention Bifidobacteria and Lactobacillus . These bacteria induce the secretion of elements that play a role in the subsidence of inflammation by reducing the production of the cytokine IL‐8—a factor that induces the migration of neutrophils to the site of inflammation, reducing the concentration of the cytokine IFN‐γ—a factor that promotes recruitment of macrophages, and reducing the expression of NF‐κB‐dependent genes [ 155 , 156 ]. In a study, potential probiotic strains were isolated from dairy products and their effects on the gut immune system were evaluated. The tested probiotics included a commercial strain, Lactobacillus acidophilus ‐14, as well as laboratory‐isolated strains Pro‐3 ( Weissella confusa MZ735961 ) and Pro‐4 ( Lactiplantibacillus plantarum MZ727611 ). While expected levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), IL‐6, and bilirubin were observed in both male and female subjects, a slight elevation in AST and creatinine was noted in females receiving probiotic treatment compared to their male counterparts. Male groups showed notable fluctuations in mean corpuscular hemoglobin concentration (MCHC), whereas female groups exhibited negligible changes. Morphological assessments revealed no signs of damage to the liver, thymus, or colon tissues. Furthermore, rats administered with the potential probiotics demonstrated significant improvements in colon wall thickness, external muscle layer, crypt depth, and mucosal integrity. The supplementation appeared to activate the immune system and potentially protect the intestinal mucosa by enhancing immune response and improving intestinal function, including nutrient absorption and increasing goblet cell numbers. Based on these findings, L. plantarum presents itself as a promising, cost‐effective, and low‐risk therapeutic option for managing functional gastrointestinal disorders [ 157 ]. In another investigation, the cell‐free culture supernatants (CFCS) from 24 different probiotic strains were screened for their antitumor activity against MM cells. Among these, the CFCS derived from C. butyricum showed the strongest ability to decrease the viability of MM cells. Subsequent fractionation of this CFCS using reverse‐phase and gel filtration chromatography identified butyrate as highly concentrated in the fraction exhibiting antitumor activity, a finding confirmed by gas chromatography–mass spectrometry analysis. Butyrate was found to reduce MM cell viability in a dose‐dependent fashion and displayed significantly greater cytotoxicity toward RPMI‐8226 MM cells compared to peripheral blood mononuclear cells (PBMCs) obtained from healthy donors. In an RPMI‐8226 xenograft mouse model, butyrate substantially suppressed tumor growth. Analysis of the cell cycle revealed that butyrate treatment caused G1 phase arrest and an increase in sub‐G1 phase cells, indicating DNA fragmentation. Western blot results showed accumulation of cleaved poly ADP‐ribose polymerase (PARP) following butyrate exposure. Moreover, flow cytometry demonstrated an increased population of annexin V‐positive MM cells, consistent with apoptosis induction. When combined with the proteasome inhibitor bortezomib, butyrate exhibited synergistic antitumor effects. These results suggest that bioactive compounds produced by probiotics, such as butyrate, could potentially augment the treatment of hematologic cancers like MM [ 158 ]. These findings are particularly relevant for multiple myeloma patients, where modulation of microbiota‐derived metabolites may enhance responses to standard therapies such as proteasome inhibitors and reduce disease progression.

A Lactic Acid Bacteria (LAB) strain isolated from chili pickle was identified as Pediococcus acidilactici MTCC5101 through 16S rRNA gene sequencing. This study aimed to evaluate the probiotic properties of P. acidilactici MTCC5101 and assess its ability to colonize the human GI tract. Additionally, a pilot preclinical trial was conducted involving 30 young anemic women to examine the effect of P. acidilactici MTCC5101, in combination with another probiotic, Bacillus coagulans MTCC492, on the absorption of therapeutic iron salts in the human GI system. An in vitro adhesion assay using Caco‐2 cells confirmed the strain's ability to adhere to intestinal epithelial cells. Molecular identification of the strain in fecal samples from the volunteers after oral administration for 4 weeks corroborated these results, demonstrating successful colonization of the GI tract. HGB measurements from the 4‐week pilot trial revealed that supplementation with iron salts alongside the probiotic mixture significantly enhanced iron absorption compared to two other groups. Specifically, Group III exhibited an average HGB increase of 2.25 ± 0.6 mg/dL, whereas Group I and Group II showed increases of 1.56 ± 0.9 mg/dL and 1.65 ± 0.4 mg/dL, respectively. These findings support the probiotic efficacy of both P. acidilactici MTCC5101 and B. coagulans MTCC492, highlighting their potential applications in the food industry [ 159 ]. Although this study was conducted in nonmalignant anemia, it highlights a mechanism that may be relevant in hematologic malignancy patients, in whom anemia is a common complication of both disease and treatment. Therefore, probiotics may help improve outcomes in hematologic malignancy patients—particularly those undergoing chemotherapy or hematopoietic stem cell transplantation—by restoring gut microbial balance, reducing infection risk, enhancing immune reconstitution, and potentially mitigating treatment‐related toxicities such as mucositis and graft‐versus‐host disease.

Prebiotics

Prebiotics are dietary supplements and fibers that can help nourish and grow the gut microbiota population. The advantages of this therapeutic strategy include their ability to stimulate multiple beneficial gut bacterial populations—significantly increasing the abundance of butyrate and SCFA‐producing species, cost‐effectiveness, easy storage (probiotics may need to be refrigerated), and simple administration [ 160 ]. Seven studies were analysed, including a total of eight randomized controlled trials, focusing primarily on iron deficiency anemia and anemia related to chronic kidney disease, with 632 patients involved. The results indicated that probiotics, prebiotics, or synbiotics significantly increased HGB levels in anemic patients, although there was considerable variability among studies. In two randomized controlled trials with 120 participants, the probiotic group showed notable improvements in serum iron levels, accompanied by moderate variability. Another two trials involving 192 participants found no significant differences in serum ferritin levels between groups, with high variability present. Subgroup analysis demonstrated that probiotics raised HGB levels in both renal anemia and iron deficiency anemia, and this effect was consistent across different dosages. The synbiotic group consistently showed positive results, whereas the prebiotic group did not display significant benefits and exhibited very high variability [ 161 ]. A study explored the therapeutic effects of Bacteroides ovatus (BO) alone and in combination with the MIL‐101 (CuFe) nanozyme on iron deficiency anemia. Findings revealed that BO notably boosted intestinal iron uptake by increasing the expression of duodenal iron transporters ZIP14 and ferroportin (Fpn). Additionally, BO enhanced iron transport and storage by upregulating hepatic proteins, including transferrin receptor 1 (TFR1) and the ferritin subunits FTH and FTL. The expression of hepatic hepcidin was also markedly reduced by BO, helping to preserve Fpn functionality. The synthesized MIL‐101 (CuFe) nanozyme demonstrated prebiotic effects by significantly stimulating BO growth, with an increase exceeding threefold. When combined, BO and MIL‐101 (CuFe) created the CuFeBO “nanozyme‐synbiotics,” which effectively mitigated iron deficiency anemia through a synergistic improvement of iron absorption (via Fpn), transport (via TFR1), and storage (via FTH/L). Overall, this research clarifies how BO and the CuFeBO nanozyme‐synbiotic work together to combat iron deficiency anemia by precisely targeting multiple aspects of iron metabolism [ 162 ]. Liu et al. developed oral colon‐retentive inulin gels as prebiotic that help protect against radiation‐induced damage to the hematopoietic and GI systems by enhancing gut homeostasis. The hematopoietic system showed strong protection, with effective recovery of blood cells and increased cell proliferation in the femur and spleen. Administration of oral inulin gels led to higher relative levels of important commensal bacteria, including Lachnospiraceae , Akkermansia , Blautia , as well as increased production SCFA metabolites. Additionally, there was an upregulation of anti‐inflammatory cytokines IL‐22 and IL‐10 within intestinal cells, along with altered expression of tight junction proteins claudin‐1 and occludin in the gut lining. In a mouse model of colorectal cancer subjected to 10‐Gy abdominal radiation, treatment with oral inulin gels enhanced the effectiveness of radiotherapy while reducing radiation‐induced injury. Overall, these findings indicate that oral inulin gels act as a bioactive agent against damage caused by ionizing radiation [ 163 ]. These findings suggest potential applications in patients receiving radiotherapy or conditioning regimens for hematopoietic stem cell transplantation. A study demonstrated that pectin—as prebiotic—complexed with iron through ultrasonic extraction and a 20‐min de‐esterification process (referred to as DU20‐Fe) exhibited the strongest antioxidant properties. DU20‐Fe was then selected for in vivo testing using a mouse model of iron deficiency anemia. The results showed that DU20‐Fe significantly increased red blood cell (RBC) count, mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH) in the anemic mice. Additionally, liver tissue analysis revealed that DU20‐Fe successfully reduced liver damage caused by iron deficiency anemia in the mice [ 164 ]. Hence, prebiotics may contribute to improved outcomes in hematologic malignancy patients by modulating the gut microbiota to enhance hematopoietic recovery, reduce inflammation, protect against treatment‐related toxicity (e.g., radiation or chemotherapy‐induced injury), and improve anemia‐related parameters.

Fecal Microbiota Transplantation ( FMT )

FMT has emerged as a promising strategy to restore healthy gut microbiota in patients with hematologic disorders [ 102 ]. Recent clinical trials have provided important safety and efficacy data supporting its use in specific contexts.

Phase I/ II Trials in AML and Allo‐ HCT

The CIMON phase 1b trial evaluated MaaT033, an oral pooled allogeneic lyophilized fecal microbiotherapy, in patients with AML undergoing intensive chemotherapy. As reported by Malard et al., this phase 1b trial demonstrated that MaaT033 was well‐tolerated and effective in restoring gut microbiota after intensive chemotherapy in AML patients, with decreased inflammatory markers and increased SCFAs. The influence of gut microbiota on patient outcomes following aHSCT is now well recognized. Specifically, disruptions in the gut microbiota (dysbiosis) have been linked to the development of acute GVHD. Additionally, growing evidence points to the gut microbiota playing a role in outcomes after autologous hematopoietic cell transplantation and CAR T‐cell therapy. The gut bacterial community interacts closely with the immune system, impacting both immunological complications and the antitumor response to treatments. Consequently, FMT has been applied in patients with hematologic malignancies for various purposes, including treating Clostridioides difficile infection, eliminating multidrug‐resistant (MDR) bacteria, and managing steroid‐refractory acute GVHD. Moreover, prophylactic FMT aimed at restoring gut microbiota balance to enhance patient outcomes has been introduced in the context of aHSCT and is likely to be extended soon to patients undergoing autologous transplantation or CAR T‐cell therapy [ 165 , 166 ]. The MAST trial, currently underway, represents the next step in this research. The published protocol describes this phase IIa trial protocol describes the use of intestinal microbiota transplant prior to allogeneic stem cell transplant to restore microbiome diversity and potentially reduce complications. This randomized, double‐blind, placebo‐controlled trial will provide crucial evidence regarding whether pretransplant FMT can reduce the incidence and severity of graft‐versus‐host disease by preserving microbiome integrity during the peritransplant period [ 167 ].

FMT for Recurrent C. difficile in Hematology Patients

A systematic review of FMT in hematologic malignancy patients with recurrent C. difficile infection demonstrated promising outcomes. A total of ten studies, consisting of five case series and five case reports, were reviewed, encompassing 29 patients who underwent 38 FMT procedures. The follow‐up period ranged from 1 to 14 months. Among these patients, 17 were diagnosed with leukemia, 10 with lymphoma, and two each with MM and myelodysplastic syndrome. Seven patients had previously received hematopoietic stem cell transplants. The combined cure rate after a single FMT was 82%, with no observed heterogeneity across studies. The procedure was generally well‐tolerated, with only mild adverse events reported (transient abdominal pain, diarrhea, constipation, nausea). One death from cardiac arrest 5 days post‐FMT was deemed unrelated to the procedure. Although these findings—drawn from limited observational data—suggest that FMT is a desirable and effective treatment for recurrent C. difficile infection in patients with hematological malignancies, additional prospective clinical trials are necessary to confirm its safety and efficacy as a first‐line therapy in this group [ 168 ].

Third‐Party FMT in aHSCT and AM

Rashidi et al. conducted a randomized, double‐blind Phase II trial comparing FMT to placebo in patients undergoing aHSCT and those with AML. After FMT, unique donor bacterial sequences accounted for 25% to 30% of the fecal microbiota. FMT enhanced the recovery of microbiome diversity following antibiotic treatment, replenished several depleted obligate anaerobic commensal bacteria, and reduced the presence of overgrown genera such as Enterococcus, Streptococcus, Veillonella , and Dialister . Overall, in patients undergoing aHSCT and those with AML, third‐party FMT was well tolerated and helped improve intestinal dysbiosis [ 169 ]. However, FMT improves hematologic disorders by restoring a healthy gut microbiota composition, which in turn modulates immune responses, reduces infectious complications, and mitigates immunological side effects like acute GVHD. These effects collectively enhance patient recovery and treatment efficacy following HSCT and related therapies. However, while observational data are promising, further clinical trials are needed to validate FMT as a standard treatment approach in hematologic patients.

Conclusions and Perspectives

The human microbiome, particularly the gut microbiota, plays a fundamental and multifaceted role in hematopoiesis and the pathogenesis of diverse hematological disorders, ranging from aplastic anemia and anemia of chronic disease to various hematologic malignancies like lymphoma, leukemia, and MM. Emerging evidence underscores that microbial dysbiosis disrupts immune homeostasis, metabolite production, and hematopoietic signaling pathways, thereby influencing disease onset, progression, and responses to therapy. In hematologic disorders, shifts in specific microbial taxa—such as the decrease of beneficial butyrate‐producing bacteria and the proliferation of pro‐inflammatory or pathogenic species—are consistently linked with impaired immune regulation and hematopoietic dysfunction. Similarly, altered gut microbial metabolites, including SCFAs and microbial toxins, impact HSC differentiation and immune cell maturation, revealing intricate cross‐talk between microbes and host cellular processes. In malignancies, microbial influences contribute to oncogenesis, tumor microenvironment modulation, and treatment outcomes, suggesting the microbiome as a potential biomarker and therapeutic target. Therapeutically, interventions such as probiotics, prebiotics, and FMT demonstrate promising potential to restore microbial balance, mitigate disease‐associated dysbiosis, and enhance treatment efficacy. Particularly, maintaining or reestablishing a diverse and balanced microbiome appears crucial in preventing complications such as GVHD post‐HSCT and in improving hematological recovery. However, the therapeutic use of microbiome modulation remains in early stages, requiring rigorous clinical investigation to optimize strain selection, dosage, and timing. Looking forward, a deeper mechanistic understanding of microbiome‐hematopoiesis interactions is essential. Future research should prioritize longitudinal and functional studies to delineate causal relationships, microbial metabolite pathways, and host immune responses. Integrating multi‐omics approaches alongside clinical data will facilitate personalized microbiome‐based diagnostics and therapeutics in hematology. Furthermore, addressing environmental and lifestyle factors that shape the microbiome offers preventive avenues against hematologic diseases. Finally, harnessing the microbiome's regulatory capacity represents a novel frontier with transformative potential for hematological health. Bridging basic science and clinical application promises innovative strategies to improve patient outcomes, reduce disease burden, and advance precision medicine in hematology.

Ongoing research is exploring next‐generation microbiome therapeutics, including defined microbial consortia designed to restore specific functions and rationally designed combinations of prebiotics and probiotics (synbiotics). As noted in recent studies, therapeutic approaches aimed at restoring altered microbiome diversity may improve clinical outcomes of anti‐hematologic malignancy treatments. These approaches may offer advantages over FMT in terms of standardization, safety, and regulatory approval pathways. However, FMT currently remains the most potent intervention for rapidly restoring global microbiome diversity and function.

Author Contributions

M.H.‐B. and H.S.E.‐S. designed, supervised the project, and edited the final manuscript. M.T.M. and A.M. wrote different parts the manuscript. All authors have read and approved the final manuscript.

Funding

The authors have nothing to report.

Ethics Statement

The authors have nothing to report.

Consent

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Acknowledgments

This narrative review was entirely written by the authors. OpenAI's ChatGPT was used only as a language editing tool to improve grammar and clarity. No part of the scientific content or structure was generated by AI tools.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

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