Causal Relationship Between Gut Microbiota and Leukemia: Future Perspectives.

Key Summary Points

Why carry out this study ? Conventional treatments for leukemia have limitations. The gut microbiota is closely associated with multiple diseases, but its relationship with leukemia is unclear, and there is a need for research. This study was carried out to explore the relationship between the gut microbiota and leukemia, and how to utilize this relationship to provide new strategies for the treatment and management of leukemia. What was learned from the study? There is a close connection between the gut microbiota and the occurrence, development, treatment effect, and complications of leukemia. Even if some results are inconsistent with the initial hypothesis, they provide new directions and ideas for future research. Whether the results are negative, neutral, or affirmative, they all contribute to further optimizing the research and treatment strategies for leukemia. For example, a deeper exploration of the mechanism of the gut microbiota in leukemia treatment can promote the development of personalized treatment regimens.

Introduction

Acute leukemia (AL) is a common blood cancer and is characterized by a malignant tumor of the hematopoietic system. According to the literature, the malignant features of leukemia include uncontrolled proliferation of leukemic cells, invasion of normal tissues and organs, and the possibility of metastasis, which is often assessed by various aspects such as cell morphology and genetic characteristics [ 1 – 3 ]. According to Global Cancer Statistics 2020, leukemia has a mortality rate of 3.1% [ 4 ]. Among youth and young adults, highly malignant acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) are two common types of leukemia [ 5 ]. Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries [ 6 , 7 ], and chronic myeloid leukemia (CML), a myeloproliferative neoplasm caused by the fusion gene BCR:ABL1, accounts for 15% of all newly diagnosed adult leukemia cases [ 8 , 9 ]. A comprehensive set of international standardized expert consensus guidelines has been established for the routine management of leukemia [ 2 , 10 ]. However, given the complexity, heterogeneity, and individual variability of different types of leukemia, the therapeutic effects remain limited to some extent. Therefore, it is important to further investigate the pathogenesis of leukemia and to explore new treatment strategies.

Within the larger community of microorganisms, the relationship between the gut microbiota and leukemia has long been established. The homeostasis of the gut microbiota is influenced by a variety of factors, both genetic and environmental [ 11 ]. It begins to colonize the neonate gut after birth and remains present throughout life [ 12 – 15 ]. However, disturbances in the gut microbiota directly or indirectly affect both healthy and diseased individuals [ 16 – 19 ]. In addition to leukemia, they has been associated with a variety of diseases [ 20 – 23 ], including respiratory diseases, central nervous system diseases, and tumors. Studies focusing on the gut microbiota to explore causal relationships with different types of leukemia may open up new avenues and options for the diagnosis and treatment of the disease. Emerging lines of inquiry may focus on the development of potential new strategies for the prevention and/or treatment of leukemia. This review focuses on recent studies of the gut microbiota and leukemia to explore the causal relationship and provide potential options for clinical treatment.

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Gut Microflora and Leukemia Causality

The intestinal microbiota, as a complex microbial system, consists of many species of microbial communities that exhibit certain similar characteristics. Among them, the genus Anabaena and phylum Actinobacteria are overwhelmingly dominant in terms of numbers [ 24 , 25 ]. The number of microorganisms in the leukemia community is very high [ 18 , 19 ]. However, different types of leukemia may also affect the composition of the intestinal flora [ 26 , 27 ] (Table 1 ). For example, Streptococcus spp. are most common in leukemia, while the families Lachnospiraceae and Ruminococcaceae are less common [ 28 ]. The gut microbiota is involved in the development and maturation of the immune system and in the regulation of immune responses and pathogen resistance, among other functions [ 29 ]. It was reported that the short-chain fatty acids (SCFAs) secreted by Escherichia coli obtained from healthy populations effectively inhibited the proliferation of tumor cells and exerted anti-cancer and anti-inflammatory effects [ 30 ]. In addition to protective mechanisms, analysis of macrogenomic samples from patients with different cancers has shown that the gut microbiota can be used as a diagnostic bacterial marker for a variety of diseases [ 31 ]. Table 1 The composition of the gut microbiota in different types of leukemia Types of leukemia Gut microorganisms ALL Bacteroidetes, Firmicutes, Prevotella , Megamonas CLL Ruminococcaceae , Lachnospiraceae , Bacteroidetes, Firmicutes AML Acidobacteria, Firmicutes , Actinobacteria , Faecalibacterium CML Acidobacteria, Actinobacteria, Streptococcus ALL acute lymphoblastic leukemia; CLL chronic lymphocytic leukemia; AML acute myeloid leukemia; CML chronic myeloid leukemia

In order to investigate the causal association between gut microbiota and leukemia, in recent years a large number of extensive studies have examined the gut microbiota in children with ALL, including the application of survival prediction based on the variability in gut microbiota, and the assessment of the risk of infection during chemotherapy for childhood ALL [ 32 – 35 ]. This article attempts to summarize some of the studies on gut microbiota and childhood ALL (Table 2 ). Studies have shown that before the treatment of ALL in children, variations in their intestinal microflora are observed, and bacteria with protective mechanisms, such as Enterococcus faecalis and Bacteroides , show a decrease or even absence, while the overproliferation of enterococci exacerbates intestinal damage and inflammatory response. Such specific changes are strongly associated with the course of childhood ALL. In the case of ALL, some studies have used mice to construct an animal model of pregenetic B-cell ALL (pB-ALL), and the results have shown that the lack of a commensal microbiota, rather than a characteristic microbiota, promotes leukemia development [ 36 ]. Differential microbiota colonization may also be associated with infant leukemia development, as reported by the Children's Oncology Group [ 37 ]. These findings confirm the interaction between the gut microbiota and AL occurrence and development. However, the relevant literature shows inconsistent results for alterations in specific microbiota genera [ 28 , 38 ]. For example, the relative abundance of Edwardsiella tarda and Prevotella maculosa was positively correlated with interleukin 10 levels [ 39 – 41 ]. This reveals the inconsistency in recent studies in terms of the depth of sequencing of gut microorganisms and issues with small sample sizes of individual studies; thus, more standardized, large-scale deep sequencing samples are needed for future analyses. Table 2 Correlation between gut microbiota and pediatric leukemia Research target Year/area Methodologies Conclusion References Pediatric ALL 2020/Denmark 16srRNA sequencing There is a strong relationship between microbiologically specific changes and the course of the disease, and the butyrate-producing gut microbiota may decrease, while loss of bacterial alpha diversity and enterococcal overgrowth exacerbate intestinal damage and inflammatory responses during chemotherapy [ 33 ] Pediatric ALL 2016/USA 16srRNA sequencing Antibiotics disrupt the gut microbiota, and the composition of the gut microbiota can be used as an indicator of a patient's response to different chemotherapies [ 142 ] Children with ALL 2018/USA 16srRNA sequencing Gut microbiota can be used as an infection risk grading tool in ALL diagnosis [ 35 ] Children with ALL 2019/USA 16srRNA sequencing Decreased microbiota diversity in patients with ALL exposed to antibiotics [ 143 ] Pediatric ALL 2020/China 16srRNA sequencing The main gut microbiota was significantly different in the children, but the chemotherapeutic drugs did not significantly affect the gut microbiota [ 144 ] Children with ALL 2020/Malaysia 16srRNA sequencing Gut microbiota is dysregulated in the gut of children with ALL and is restored by remission or cessation of chemotherapy [ 145 ] Children with ALL 2020/China 16srRNA sequencing real-time fluorescent PCR Differences in the gut microbiota between children with ALL and healthy individuals, and microbial ecological dysregulation in patients with ALL, with Clostridium difficile being clearly demonstrated [ 146 ] Patients < 19 years old with ALL 2020/USA 16srRNA sequencing Protective Enterococcus faecalis bacteria depleted in children with ALL [ 32 ] Children with ALL 2021/China 16srRNA sequencing Strong association between chemotherapy-induced pneumonia and alterations in the gut microbiota in children with ALL [ 97 ] ALL acute lymphoblastic leukemia

In patients with CLL, it was found that the gut microbiota was most enriched in species of Bacteroidaceae , Clostridiaceae , Prevotellaceae , and Actinetobacteraceae species, whereas those of the families Lachnospiraceae and Ruminococcaceae exhibited depletion [ 42 ]. Compared to healthy individuals, patients with CLL have reduced diversity and variability of bacterial phyla of the gut microbiota, as evidenced by an increased abundance of thick-walled phyla and a decreased abundance of Anaplasma [ 43 ].

Previous studies have shown that the gut flora of AML is disrupted during induction chemotherapy (IC). The baseline diversity of the gut microbiome has been associated with the risk of infection during IC in AML, and assessing the diversity of the gut microbiota during IC may reduce the complications of AML infections [ 44 , 45 ]. Interestingly, after cessation of chemotherapy, the microbiota produced new communities that were highly distinct from baseline and showed persistent alterations, whereas the abundance of Bacteroides immitis remained low [ 46 ]. Pötgens et al. reported that intensive treatment of AML temporarily impaired gut barrier function and induced long-lasting changes in the composition and metabolic activity of the gut microbiota, which correlate with the characteristics of cachexia [ 47 ].

It has been shown that Actinobacteria, Acidobacteria, and Chloroflexota are present in high abundance in the gut microbiota of patients with CML, while Mycoplasmatota (formerly Tenericutes) had relatively low abundance. Yu et al. performed a comparison study of the gut microbiota of patients with myeloid leukemia (ML) and controls using 16S rRNA analysis and found that Streptococcus spp. exhibited increased abundance in the microbiome of both patients with AML and CML [ 48 ]. However, lactic acid, as a major compound produced by Streptococci during sugar fermentation, may have an impact on the progression of CML [ 49 ]. An increase in streptococcal abundance might have a detrimental effect on leukemia; however, Actinomycetes abundance could potentially help to reduce adverse reactions. Studies have shown that bacteria of the phylum Actinobacteria may be beneficial for patients with AL, exhibiting antioxidant activity [ 50 , 51 ].

In children with ALL, diversity and variability in the gut microbiota prior to treatment correlate with disease duration, and factors such as the lack of a commensal microbiota promote progression, whereas in patients with CLL, decreased diversity and variability is found in the bacterial phyla of the gut microbiota. In patients with AML, the gut flora is disrupted during chemotherapy, and intensive treatment impairs gut function and leads to lasting changes. In patients with CML, changes are found in the abundance of some of the bacterial phyla of the gut microbiota, as evidenced by changes in the abundance of Streptococcus and Actinomyces . To date, studies on gut microbiota and cancer have shown a causal relationship between them [ 52 ].

Gut Microbiota and Other Diseases

In addition to leukemia, we have identified associations between the gut microbiota and several other diseases, both oncological and non-oncological. Seventeen strong associations have been demonstrated between genetic susceptibility of the gut microbiome and cancer, which include cancer pathogenesis and progression through regulation of tumor immune surveillance [ 53 , 54 ]. For example, in colorectal cancer (CRC), the gut microbiota metabolites deoxycholic acid (DCA) and lithocholic acid (LCA) may contribute to CRC development through modulation of cell signaling cascades and membrane perturbation effects [ 55 , 56 ]. In lung cancer, the gut microbiota promotes lung cancer development and progression through regulation of metabolic pathways, suppression of immune cell function, and production of pro-inflammatory factors [ 57 ].

The gut microbiota plays a key role in diseases such as cardiovascular disease, atherosclerosis, hypertension, diabetes mellitus, and inflammatory bowel disease (IBD) [ 58 – 62 ]. It influences the course of disease by participating in and regulating numerous metabolic processes in the host, including energy homeostasis, glucose metabolism, and lipid metabolism [ 63 ]. For example, in IBD, imbalances in microbial homeostasis contribute to the development of IBD by increasing the risk of host immune responses [ 64 ]. In the case of hypertension, it triggers an imbalance in the intestinal flora as well as intestinal barrier dysfunction, as evidenced by an increase in harmful bacteria, hydrogen sulfide, and lipopolysaccharides (LPS), a decrease in beneficial bacteria and SCFAs, a decrease in intestinal tight junction proteins, and an increase in intestinal permeability [ 65 ]. The gut microbiota has been the subject of targeted therapies against dyslipidemia-related diseases [ 66 ]. This is sufficient to confirm the importance of the gut microbiota in therapy.

In conclusion, the gut microbiota is not only associated with leukemia, but also causally involved in both neoplastic and non-neoplastic diseases, either directly or indirectly influencing the course of the disease. Insights gained show that the homeostasis of the gut microbiota and the metabolites of the flora should not be underestimated in the treatment of leukemia.

Gut Microbiota and Metabolites

Bacterial metabolites of the intestinal microbiota including SCFAs, acetate (C2), propionate (C3), and butyrate (C4)—particularly SCFAs and butyrate—are produced by thick-walled intestinal bacteria [ 67 ]. Butyrate demonstrates a localized protective effect on the intestinal barrier, exerts a protective effect on the immune system through macrophage activation and regulatory T-cell development, and also plays a key role in controlling inflammation [ 67 , 68 ]. In addition, butyrate affects gene expression through the inhibition of histone deacetylase (HDAC) and activation of histone demethylase LSD1 [ 69 ]. Research has shown that AML contributes to the development of intestinal dysbiosis. It has been suggested that AML leads to impaired intestinal integrity, reduced barrier function, butyrate deficiency, and elevated blood LPS levels, which in turn accelerates the progression of AML. In contrast, increased production of SCFAs (especially butyrate) and activation of G protein-coupled receptors (GPRs) such as GPR43 and GPR109A, which regulate peripheral blood LPS concentrations by affecting the intestinal barrier, may slow the progression of AML [ 70 ]. Lactic acidosis has been reported in patients during the development of leukemia [ 71 – 73 ]. The Warburg effect has been associated with many malignancies, of which hematologic malignancies, such as leukemia, are the most common [ 74 , 75 ]. Activation of G protein-coupled receptor 81 (GPR81) by lactate or shuttling to the membrane via the monocarboxylate transporter protein (MCT) controls immune evasion and chemotherapeutic drug resistance [ 76 , 77 ] (Fig. 1 ). These findings confirm the association of gut microbiota metabolites with immune regulation in patients with leukemia. However, the modes and mechanisms of regulation are still unclear. Fig. 1 Butyrate in short-chain fatty acids plays multiple physiological roles by regulating gene expression in intestinal cells through inhibition of HDAC and other pathways. Butyrate induces regulatory T cells (Treg) expressing the transcription factor Foxp3 via DC, and propionate activates with GPRs to inhibit HDAC and indirectly produce IL-10. Cytokine activation of the IL-25 receptor upregulates the expression of Th-2-related cytokines, which indirectly promotes the differentiation and expansion of Th-2 cells. The lactate–GPR81–Wnt/ß–catenin axis regulates jejunal stem cell function and promotes proliferation of intestinal epithelial cells and RX3CP1-mediated phagocytosis for tissue repair and regeneration. CSFAs short-chain fatty acids; GPRs G protein-coupled receptors; GPR109a G protein-coupled receptor 109a; GPR81 G protein-coupled receptor 81; GPR31 G protein-coupled receptor 31; Wnt3 a member of the Wnt family of proteins involved in the classical Wnt/ß-catenin signaling pathway; HDAC histone deacetylases; IL-10 interleukin 10; IL-25 interleukin 25; Th-2 type 2 helper T cells; DC dendritic cells; Foxp3+Treg regulatory T cells (Treg) expressing the transcription factor Foxp3

Gut Microflora and Leukemia Therapy

Chemotherapy, infection prevention, and drug control remain the mainstay of treatment associated with AL. Chemotherapy is a systemic cancer treatment utilizing cytotoxic drugs that significantly improves the overall survival of patients [ 78 ]. The relationship between chemotherapeutic agents and the gut microbiota is interactive during treatment. Chemotherapeutic agents may cause imbalances by altering the gut microbial ecology or causing damage to the gut epithelium. Similarly, imbalances in the gut microbiota may affect the absorption and metabolism of chemotherapeutic agents, resulting in increased toxicity and decreased efficacy [ 16 ]. Recent studies on the course of leukemia treatment with regard to the gut microbiota are summarized in Table 3 . Table 3 Recent studies on the relationship between gut microbiota and leukemia Research target Year/country Methodologies Conclusion References ALL 2019/USA 16S qPCR Loss of intestinal lymphoid tissue leading to bacterial ectasia in ALL [ 98 ] AML 2020/USA 97srrRNA analysis Gut microbiota biomarkers are predictive of infection risk during induction chemotherapy in patients with AML [ 44 ] AL 2021/China 3srRNA sequencing Changes in fecal butyric acid-producing cocci, anaplasmosis, and butyric acid-producing bacteria following chemotherapy [ 93 ] ALL 2021/USA 10S rRNA sequencing Differential gut microbiota in patients with ALL compared to healthy individuals after long-term treatment [ 147 ] Multiple blood disorders 2022/China 16S rRNA sequencing Dynamic changes in the gut microbiome are significantly associated with treatment response and cytokine release syndrome during CAR-T therapy for hematologic malignancies (B-ALL, B-NHL, and MM) [ 121 ] ALL 2022/China 16S rDNA sequencing Diversity of intestinal flora is reduced in children with ALL, and the abundance of intestinal flora is significantly reduced after chemotherapy, as are beneficial bacteria [ 96 ] ALL acute lymphoblastic leukemia; AML acute myeloid leukemia; AL acute leukemia; CAR-T chimeric antigen receptor T cell; B-ALL B-cell acute lymphoblastic leukemia; MM multiple myeloma; B-NHL B-cell non-Hodgkin lymphoma; qPCR quantitative real-time polymerase chain reaction

In pharmacological microbiology, certain intestinal microbiota can alter the structure of a drug through enzymatic action, thereby altering the bioavailability, bioactivity, or toxicity of the drug, which in turn affects the individual's response to the drug [ 79 ]. Changes in the gut microbiota of patients with AL can also directly affect the body's absorption and response [ 16 ].

Methotrexate (MTX) is an important antitumor drug widely used for the treatment of leukemia by inhibiting folate metabolism in tumor cells, which can cause significant damage to the intestinal tract [ 80 , 81 ]. In addition, the damage caused by MTX to intestinal epithelial cells induces a series of inflammatory responses. Animal experiments have shown that MTX-treated mice display reduced intestinal microbial diversity and changes in the composition of the intestinal microbiota with Bacteroides fragilis , and there is a tendency for B. fragilis to proliferate at a reduced rate as the density of M1 macrophages increases [ 82 ].

Cyclophosphamide (CTX) has potent anticancer activity and can be effective in the treatment of AML. Viaud et al. investigated the role of gut microbiota in CTX therapy using mouse models [ 83 ], and noted that CTX causes damage to the intestinal epithelial barrier, which is manifested by discontinuity of the epithelial barrier, shortening of villi, and mesenchymal edema [ 83 ]. They also found that treatment with CTX had a significant impact on the intestinal epithelial barrier. In addition, in mice treated with CTX, commensal bacteria from the gut microbiota (e.g., Lactobacillus johnsonii , Lactobacillus rhamnosus , and E. faecalis ) were detected in lymphoid organs such as mesenteric lymph nodes and spleen due to the impairment of the intestinal barrier. This suggests that a significant translocation of the gut microbiota occurred [ 83 ]. It was also reported that CTX treatment induced selective translocation of the gut microbiota, resulting in reduced abundance of Lactobacillus and Enterococcus in the small intestine of mice [ 50 ].

Bortezomib has been shown to be effective in relapsed T-cell acute lymphoblastic leukemia (T-ALL) [ 84 ], while Fusobacterium citriodora is associated with multiple myeloma (MM) relapse and induces bortezomib resistance [ 85 ]. Of interest, other novel drugs targeting leukemia cells, such as the FLT3 inhibitor gilteritinib, have shown promising efficacy in treating relapsed or refractory AML harboring FLT3 mutations [ 86 ]. Venetoclax, a BCL-2 inhibitor, and inotuzumab ozogamicin, an antibody–drug coupling agent, are currently missing from studies on the association with gut microbes.

Both MTX and CTX cause damage to the intestinal mucosa, resulting in increased intestinal permeability, which in turn leads to dysbiosis of the gut microbiota, resulting in altered blood flow and exacerbating the progression of leukemia. However, there is a lack of research on novel drugs targeting leukemia cells and the gut microbiota. Therefore, the effects of chemotherapeutic agents on the ecological stability of the gut still require extensive research, and the potential effects of different chemotherapeutic agents need to be taken into account in clinical treatment.

Association Between Gut Microbiota and Leukemia Complications

The gut microbiota and the host exist in dynamic equilibrium, and when this equilibrium is disrupted, it can lead to the onset or progression of host disease and complications. Studies have shown that complications after chemotherapy are associated with alterations in the gut microbiota and affect the prognosis of patients with leukemia. Major complications from chemotherapy include gastrointestinal dysfunction, neutropenia, infection, and organ toxicity. Typically, the earliest and only infectious complication in patients with AL is neutropenic fever (febrile neutropenia, FN). In some studies, Gram-negative bacteria are the main cause of infections in hematologic patients with NF tumors, and multidrug resistance has emerged among these pathogens [ 87 ]. Carbapenem resistance has been found in more than 50% of the major pathogens isolated from neutropenic patients (i.e., E. coli , Pseudomonas aeruginosa , and Klebsiella pneumoniae ), and up to 50% of Enterobacteriaceae isolates in some European countries [ 88 , 89 ].

It was found that the gut microbiota of patients with NF is highly diverse, and patients with AML presenting with NF for the first time postoperatively had a significantly reduced gut flora, which remained unchanged despite bone marrow recovery or remission [ 90 ]. Among the common complications in patients with hematologic malignancies receiving chemotherapy, NF is associated with high morbidity and mortality [ 35 ]. It is particularly important to prevent the possible development of NF in patients with leukemia during chemotherapy in which antibiotics are applied. Antibiotics can cause damage to the intestinal mucosa, leading to dysbiosis of the intestinal microbiota and impairment of the intestinal barrier. This is similar to recurrent Clostridium difficile infection, where the gut microbiota response to antibiotics depends on the baseline microbiota [ 91 ]. Disturbances in gut microbiota-to-host interactions during periods of antibiotic use can lead to infections and immune dysregulation [ 92 ]. There is also significant variability in the gut microbiota of patients with leukemia in chemotherapy remission without prophylactic antimicrobial agents or NFs [ 93 ], such as fecal butyric acid-producing cocci, fecal mimics, and butyric acid-producing bacteria.

However, dysbiosis of the gastrointestinal microbiota may result during intensive chemotherapy through direct damage to the gut and indirect effects on the immune system, and therapeutic or prophylactic antibiotics used during chemotherapy may also affect the gut microbiota. In addition, instability of the gut ecology during repeated treatment may lead to dysbiosis of the gut microbiota [ 94 ]. Therefore, the use of antibiotics during chemotherapy is essential. A previous study showed that ciprofloxacin prevented NF, was well tolerated, and had no serious side effects [ 95 ]. However, the durability of the protective effect of antibiotics remains to be investigated.

Association Between Gut Microbiota and Infection Risk

Disruption of the gut microbiota results in the incursion of pathogenic bacteria such as E. coli , Akkermansia muciniphila , and B. fragilis , and induces inflammation. A previous study revealed a significant difference in the gastrointestinal microbiota between children with ALL and healthy controls, as analyzed by 16S rRNA gene sequencing, and this difference was observed both before and after chemotherapy, which significantly reduced the diversity of the gut microbiota and some probiotic strains [ 33 , 96 ]. This can increase the risk of bloodstream infections and even some complications in patients. It has been shown that altered gut microbiota induces pneumonia related to pediatric ALL [ 97 ]. The gut microbiota of children with ALL receiving chemotherapy is dominated by Enterococcaceae and Streptococcaceae, which predicts the development of infections during the subsequent treatment phase [ 35 ]. For example, in mouse models of ALL, severe damage to gut-associated lymphoid tissues led to lymphocytopenia and ultimately to bloodstream infections [ 98 ]. In contrast, bloodstream infections are also caused by an imbalance in the intestinal flora, resulting in damage to the intestinal mucosal and epithelial barriers. Part of the intestinal flora then enters the bloodstream or local lymph nodes, leading to an inflammatory immune response through metabolic disturbance, immune cell activation, and alterations in key intracellular signaling pathways, which may play a role in tumor development [ 90 ].

Curcumin treatment in leukemia improves intestinal integrity and modulates the gut microbiota response to cytarabine, and inhibits inflammation and improves chemotherapy resistance in patients with AL [ 99 ]. In a 16S rRNA-based analysis of patient feces in a study of 97 patients with AML, the alpha diversity of the gut microbiota at baseline predicted the risk of infection during chemotherapy [ 44 ]. Immunocompromised patients with leukemia are at increased risk for infection, especially related to multidrug resistance. Intestinal decontamination (ID) and selective intestinal decontamination (SID) aim to remove potentially pathogenic microorganisms from the gastrointestinal tract, especially Gram-negative aerobic bacilli, and thereby prevent infectious complications [ 100 ]. Early studies have shown that SID significantly reduces the colonization of Gram-negative aerobic bacteria and Candida in the gut, which in turn reduces the risk of infection [ 101 ]. In the case of ID of multidrug-resistant Klebsiella pneumoniae in immunocompromised patients with leukemia after recurrent infections, it was shown that follow-up monitoring of stool cultures for MDR and carbapenem-resistant Klebsiella pneumoniae at 36 and 58 days after bowel decontamination was negative, and the patient's hematopoietic stem cell transplantation (HSCT) was successful without recurrence of leukemia [ 102 ]. However, studies of the effects of SID on the gut flora have shown an increase in the level of aminoglycoside resistance genes in commensal microorganisms [ 103 , 104 ], and widespread use is bound to increase antibiotic resistance and alter the structure of pathogenic microorganisms [ 105 ]. Nevertheless, most studies conducted to date have found that SID is effective in reducing Gram-negative infections. Therefore, by analyzing the characteristics of the patient's flora to determine whether the patient is exposed to further infections and taking appropriate prophylactic measures, the rational use of SID may prevent risk of infection and reduce patient morbidity and mortality.

Gut Microbiota and Hematopoietic Stem Cell Transplantation

It has been shown that recurrent C. difficile infection in patients with leukemia undergoing HSCT leads to dysbiosis of the intestinal microflora, which can be corrected by fecal microbiota transplantation (FMT), a safe and effective method for treating C. difficile infection after HSCT [ 106 ]. HSCT is an effective treatment for patients with relapsed or refractory ALL. Previous studies have shown that changes in intestinal flora after HSCT are strongly associated with major complications such as graft-versus-host disease (GvHD), infection, and relapse. Recent studies have found that certain gut bacteria are associated with the outcome of allogeneic HSCT (allo-HSCT) transplantation, and disruption of the normal structure of the gut microbiota is associated with the risk of GvHD [ 107 , 108 ].

GvHD is a pro-inflammatory syndrome induced by donor T cells and includes both acute (aGvHD) and chronic (cGvHD) types [ 109 ]. Studies have shown that severe GvHD is associated with increased abundance of Enterobacteriaceae , while C. difficile is associated with an anti-inflammatory response [ 110 ]. In allo-HSCT, GvHD causes mucosal damage in the gastrointestinal tract, which in turn leads to intestinal microecological disorders and a decrease in flora. According to the literature, the progression of GvHD promotes the damage to intestinal stem cells, which ultimately leads to intestinal mucosal damage [ 111 ]. Mucosal damage and intestinal dysbiosis increase the incidence of GvHD and associated mortality, which is significantly corrected with the restoration of the intestinal flora [ 112 ]. Sofi et al. demonstrated that stabilization of the intestinal microflora could reduce the incidence of GvHD by stabilizing the intestinal ecosystem with B. fragilis [ 113 ].

Taur et al. investigated the effect of gut diversity on post-transplant mortality, suggesting that the gut flora are a key factor in the success or failure of allo-HSCT [ 114 ]. In a cohort study of 80 patients with leukemia undergoing HSCT, lower gut flora diversity was associated with higher mortality, suggesting that microbial diversity is an important predictor of mortality [ 114 ]. In addition, alpha diversity of the intestinal flora was associated with mobility characteristics in pediatric patients with ALL treated with HSCT and undergoing an exercise training program [ 115 ]. Furthermore, the relationship between gene therapy and clinical outcomes is the strongest evidence for adult allo-HSCT [ 38 ]. HSCT-related events and patient immunity are associated with specific alterations in the gut microbiome [ 116 ]. For example, the genus Bifidobacterium , a beneficial bacterium that produces butyric acid, was significantly reduced in patients prior to receiving allo-HSCT, and these bacteria have been reported to attenuate the worsening of intestinal inflammation [ 117 ]. In a small-sample prospective study evaluating changes in the gut microbiome of patients with MM in the first year after autologous HSCT, a reduction in gut microbial alpha diversity at the time of cell implantation was associated with autologous HSCT tolerance [ 118 ]. In addition, fecal microbiota diversity in patients with lymphoma, MM, and amyloidosis treated with autologous HSCT was lower early before transplantation and further decreased during transplantation. For patients with MM and a relatively high level of diversity, the risk of disease progression or death during neutrophil transplantation is lower [ 116 , 119 ]. A study including 13 patients with AL treated with HSCT showed that the gut microbiota plays an important role in the regulation of muscle metabolism [ 120 ]. Therefore, the diversity or composition of the gut microbiota or specific species may serve as potential biomarkers for predicting and preventing complications after allogeneic or autologous HSCT and prolonging the duration of transplantation.

Gut Microbiota and Immunotherapy

In recent years, the efficacy of chemotherapy and HSCT for the treatment of leukemia has improved significantly, but problems such as primary or secondary drug resistance, relapse after remission, and serious complications still exist. Novel cancer immunotherapies with high specificity and low toxicity have shown great potential in the treatment of refractory or relapsed leukemia. Currently, the major immunotherapies for the treatment of leukemia include chimeric antigen receptor (CAR) T-cell therapy, antibody–drug coupling (ADC), bispecific T-cell inducer (BiTE) therapy, immune checkpoint inhibitors (ICIs), natural killer (NK) cell therapy, and dendritic cell (DC) therapy. There is growing evidence that the microbiota may alter the response to cancer immunotherapy. A study of immunotherapy utilizing CAR T-cell therapy for relapsed/refractory MM ( n = 43), ALL ( n = 23), and non-Hodgkin lymphoma (NHL; n = 12) demonstrated a high success rate for the gut microbiota [ 121 ]. It was found that 20(S)-GRh20, which affects the immune system and gut microbiota, altered the composition of the gut microbiota by increasing the levels of tight junction proteins, antimicrobial peptides, and immunoglobulin A (IgA), promoted gut homeostasis, and ameliorated LPS-induced intestinal inflammatory responses in T-ALL mice [ 122 ]. ICIs prevent molecules such as CTLA4, PD-1/PD-L1, LAG-3, and TIM-3 from binding to their ligand receptors, activate the suppressed immune system, and promote the clearance of malignant cells [ 123 ]. The gut microbiota was shown in one study to have a significant impact on the gut microbiota. The composition of the gut microbiota (different Anabaena spp.) was found to affect the antitumor effects of CTLA-4 resistance in tumor-bearing mice in vivo, and the antitumor effect of CTLA-4 blockade was dependent on different Anabaena spp. [ 123 ]. It was shown in a mouse model of hepatocellular carcinoma that vancomycin-induced alterations in the gut microbiota may exert anticancer effects by increasing the number of hepatic NK T cells and decreasing the level of secondary bile acid metabolism [ 124 ]. Therefore, gut microbiota and flora interactions should be further explored in vitro and in vivo to improve the efficacy of immunotherapy.

Gut Microbiota and Fecal Microbiota Transplantation

FMT is a therapeutic approach in which a fecal suspension containing healthy donor microbiota is injected into the gastrointestinal tract of a recipient to improve the composition and function of the host's intestinal flora, which can be tailored to the individual patient [ 125 – 127 ]. Previous studies have confirmed the successful use of FMT to treat steroid-refractory aGvHD [ 128 , 129 ]. FMT has been reported to be more effective than various probiotics in repairing the intestinal flora in animal models using antibiotics [ 130 ]. In a clinical trial of four patients with AML undergoing allo-HSCT who developed refractory diarrhea due to intestinal infections or intestinal GVHD, FMT proved to be a successful and safe therapy [ 131 ]. In a study using mice as a model, antibiotic-induced intestinal bacterial imbalance promoted AML, whereas butyrate obtained from fecal transplants slowed the progression of AML and improved intestinal mucosal barrier function [ 70 ]. In a study of autologous fecal transplant therapy (aFMT) in 25 patients with AML treated with intensive chemotherapy and antibiotics, aFMT appeared to be safe and effective in restoring the gut microbiota [ 132 ]. In addition, FMT after HSCT promotes the reconstitution of gut flora structure and bacterial architecture with better efficacy [ 133 , 134 ]. The results of this study are summarized in Table 4 . As research progresses, studies have increasingly shown that dysbiosis of the gut flora plays an important role in several neurological disorders, including Parkinson's disease (PD) [ 21 ]. Furthermore, in a prospective study, 16 patients with PD were treated with FMT, and the balance of gut bacteria in these patients normalized [ 135 ]. Therefore, FMT can quickly and effectively restore the disrupted intestinal flora, and its efficacy has been confirmed in a large number of clinical studies.

Gut Microbiota and Probiotics/Prebiotics

Probiotics are active microorganisms that stabilize the intestinal ecosystem, promote nutrient absorption, protect the intestinal mucosal barrier, and modulate immunity. In a randomized controlled trial involving 60 children with AL receiving chemotherapy, patients in the probiotic group reported significantly fewer gastrointestinal side effects [ 136 ]. A systematic evaluation of probiotics has shown a significant reduction in gastrointestinal side effects as well, with a reduction in the frequency and severity of diarrhea in patients with cancer [ 137 ]. However, some studies have shown that probiotics are not effective for cancer complications such as diarrhea [ 138 ]. Therefore, treatment with probiotics cannot be generalized, and the mechanism of action may be related to the patient's tolerance level.

Prebiotics are found in certain foods, such as soybean extract, and have an indirect effect by altering the composition of the gut flora. For example, a soy–whey mixture significantly increased the diversity of the gut microbiota and was effective in improving muscle condition in AL survivors [ 120 ]. A study in mice with allogeneic bone marrow transplantation showed that the addition of a soy–whey protein mixture accelerated the recovery of hematopoietic function and the reconstitution of immune function [ 139 ]. In addition, polysaccharides and ginsenosides extracted from American ginseng were found to be protective against CTX therapy [ 140 ]. Enteral nutrition can rapidly restore the balance of gut microbiota after HSCT [ 80 ]. Therefore, moderate addition of prebiotics is another therapeutic approach to improve the structure of the intestinal flora.

Discussion

In the coming years, the study of the relationship between the gut microbiota and leukemia is expected to achieve more in-depth and comprehensive results. With advances in technology, such as more advanced sequencing techniques and more precise analytical methods, we will be able to more clearly reveal the complex causal relationship between the gut microbiota and the development of leukemia.

On the therapeutic side, gut microbiota-based therapies such as FMT, probiotics, and prebiotics, which we summarized through ClinicalTrials.gov, are still relatively sparse in ongoing or completed studies in recent years (Table 4 ), but are expected to be further optimized and standardized. More large-scale, multicenter clinical trials will provide stronger evidence for the efficacy and safety of these therapies, leading to more personalized treatment options for patients with leukemia. Table 4 Current or completed studies on FMT Country/registration number Methodologies Research target Research purpose USA NCT03678493 FMT capsule/placebo AML allo-HSCT A randomized placebo-controlled clinical trial of FMT in patients with AML and allo-HSCT recipients France NCT04935684 FMT AL in remission MDS MPS HL NHL Myeloma CLL To evaluate the efficacy of FMT in preventing complications of allo-HSCT, particularly GvHD France NCT02928523 aFMT Leukemia, myeloid, acute aFMT for the prevention of dysbiosis complications in patients with AML receiving intensive therapy: feasibility and safety South Korea NCT01751997 Family mismatch/haploid donor with matched unrelated donor AML To compare the clinical outcomes of transplants from family-mismatched/haploidentical donors (FMT) with transplants from 8/8-matched unrelated donors (MUT), which are a current gold standard donor when lacking human leukocyte antigen (HLA)-matched-siblings UK NCT06355583 IMT ALL ALAL CML CMML MDS AML Testing the ability of patients with blood cancer scheduled for stem cell transplantation to restore their gut microbiota to healthier levels Bratislava NCT05939791 Dairy probiotics ( Lactobacillus casei ) ALL, pediatric Comparison of gut microbiome structure in children shortly after treatment for ALL (1–3 years after cancer treatment) and healthy controls USA NCT04629430 Prebiotic MM AML ALL NHL HL HD MF MDS MNP SCD MCL To determine whether HSCT recipients can consistently eat a prebiotic-rich diet FMT fecal microbiota transplantation; aFMT autologous fecal transplant therapy; IMT intestinal microbiota transplantation; HSCT hematopoietic stem cell transplant; GvHD graft-versus-host disease; allo-HSCT allogeneic hematopoietic stem cell transplantation; ALL acute lymphoblastic leukemia; CLL chronic lymphocytic leukemia; AML acute myeloid leukemia; AL acute leukemia; CML chronic myeloid leukemia; MDS myelodysplastic syndromes; MPS myeloproliferative syndrome; HL Hodgkin lymphoma; NHL non-Hodgkin lymphoma; ALAL acute leukemia of ambiguous lineage; CMML chronic myelomonocytic leukemia; MM multiple myeloma; HD Hodgkin disease; MNP myeloproliferative neoplasm; MF myelofibrosis; SCD sickle cell disease; MCL mantle cell lymphoma

With regard to the role of the gut microbiota in leukemia complications, future studies will focus on clarifying the specific mechanisms and regulatory pathways, leading to the development of more targeted preventive and therapeutic strategies to reduce the incidence and severity of complications.

In the field of immunotherapy, the importance of the gut microbiota is already being demonstrated [ 141 ]. By gaining a deeper understanding of how the gut microbiota affects the immune system's response to leukemia, it is expected that combination therapies will be developed to improve the efficacy of immunotherapy. In addition, with a deeper understanding of the interaction between the gut microbiota and leukemia, interdisciplinary collaborations will become closer, including experts in microbiology, immunology, oncology, and other fields working together to promote the translation of basic research into clinical applications. This will bring new breakthroughs in the treatment of leukemia and improve the survival rate and quality of life for patients.

Conclusion

In conclusion, in this study, the intestinal flora were explored in depth and found to be strongly associated with tumorigenesis, tumor growth, HSCT, and chemotherapy efficacy. Thus, modulation of the gut flora supplemented with appropriate interventions is expected to revolutionize the treatment and management of leukemia in the future.

Acknowledgements

We thank Editage ( www.editage.com ) for their editing support on this manuscript. Thanks to FigDraw for providing a platform to create medical illustrations.

Author Contributions

Zexin Wang and Qiang Yang wrote and structured the paper; Zexin Wang analyzed literature data and wrote the paper; Lingling Gan and Miao Liu reviewed the literature. All authors have read and agreed to the published version of the manuscript.

Funding

No funding or sponsorship was received for this study or publication of this article. The Rapid Service Fee was funded by the authors.

Data Availability

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

Declarations

Conflict of Interest

Qiang Yang, Zexin Wang, Miao Liu, and Lingling Gan declare that they have no competing interests. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

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