Гут Микробиота и аутоиммунные заболевания: терапевтический потенциал пробиотики.

Introduction

The gut microbiota plays a fundamental role in maintaining the body’s homeostasis by participating in various physiological processes, including digestion, metabolism, immune system regulation, and protection against pathogens. An increasing body of evidence indicates that disturbances in the gut microbiota referred to as dysbiosis may contribute to the development of numerous diseases, both metabolic and immunological in nature [ 1 ]. Intestinal dysbiosis is associated, among other things, with disrupted metabolic processes and impaired gut barrier function. Animal model experiments have demonstrated that an improperly composed gut microbiota can lead to excessive production of lipopolysaccharides (LPS) components of the cell wall of Gram-negative bacteria. High concentrations of LPS in the gastrointestinal tract promote chronic inflammation, damage to the intestinal mucosa, and loss of integrity in the tight junctions between intestinal epithelial cells, ultimately resulting in increased intestinal permeability (commonly referred to as “leaky gut”) [ 2 ].

The gut microbiota plays a fundamental role in the development and regulation of the host immune system. Through continuous interaction with gut-associated lymphoid tissue, commensal microorganisms contribute to immune homeostasis by modulating both innate and adaptive immune responses. Disruption of this balance (dysbiosis) has been linked to increased intestinal permeability, aberrant antigen presentation, and altered differentiation of immune cell subsets, including Th17 and regulatory T cells. These changes can promote chronic inflammation and loss of self-tolerance, thereby contributing to the onset and progression of autoimmune diseases. Increasing evidence highlights that microbiota–immune system crosstalk is involved in conditions such as rheumatoid arthritis, type 1 diabetes, multiple sclerosis, and inflammatory bowel diseases, suggesting that targeting the gut microbiome may offer novel therapeutic strategies [ 3 ].

In response to these disturbances, probiotic interventions have attracted growing interest due to their ability to beneficially modulate the composition of the gut microbiota, restore microbial balance, and improve intestinal barrier integrity [ 4 ]. Studies suggest that probiotics may reduce the translocation of LPS into the bloodstream, thereby decreasing inflammation and enhancing immune system function [ 4 , 5 ]. The relationship between gut microbiota and immune-mediated diseases is currently the subject of intense research. It has been shown that alterations in gut microbial composition may play a role in the pathogenesis of disorders such as autoimmune hepatitis (AH), rheumatoid arthritis (RA) [ 6 ], type 1 diabetes (T1D) [ 3 , 7 ], multiple sclerosis (MS) [ 8 ].

Moreover, recent studies suggest that gut microbiota may also influence neuropsychological functions, giving rise to the concept of the gut-brain axis. Dysregulation of this axis may be associated with the development of depression, anxiety, and even neurodegenerative diseases such as Parkinson’s disease [ 9 , 10 ].

Probiotics Modulate Gut Microbiota and Immune Responses in Autoimmune Diseases

The human gastrointestinal tract is home to an immense number of microorganisms estimated at between 10 and 11 trillion bacteria meaning that bacterial cells outnumber human cells in the body [ 11 ]. The gut microbiota not only plays a role in digestion and metabolism but also participates in the regulation of many key physiological processes, including the immune response. It is primarily composed of four dominant bacterial phyla: Actinobacteria , Firmicutes , Proteobacteria , and Bacteroidetes . The relative abundance of these groups can vary significantly between individuals, influenced by numerous factors such as genetics, age, sex, lifestyle, health status, and most importantly diet [ 12 ]. A growing body of scientific research indicates that the gut microbiome is an active participant in modulating the host’s immune response. Notably, it influences the immune system through the activation of Toll-like receptors (TLRs), which function as sensors detecting the presence of microorganisms [ 13 ]. TLRs are responsible for recognizing so-called microbe-associated molecular patterns (MAMPs), pathogen-associated molecular patterns (PAMPs), as well as endogenous molecules released during tissue damage (DAMPs) [ 14 , 15 ]. In humans, ten types of TLRs have been described, each recognizing specific ligands ranging from viral proteins to components of bacterial cell walls or molecules derived from the host organism itself [ 13 ]. Upon activation, most TLRs except for TLR3 transmit signals via the MyD88 (Myeloid Differentiation Primary Response 88) adaptor protein-dependent pathway [ 16 , 17 ]. Activation of the MyD88 pathway leads to the stimulation of the transcription factor NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), which initiates the expression of genes encoding proinflammatory cytokines such as TNF-α, IL-1β, and IL-6. These cytokines are key mediators of the inflammatory response, responsible for the activation and recruitment of immune cells at sites of infection or tissue damage [ 16 ]. In addition to its role in innate immunity, TLR signaling is also crucial for the adaptive immune response. TLRs are present, for example, on the surface of macrophages and dendritic cells, where their activation enhances the expression of MHC class II molecules, facilitating more effective antigen presentation to CD4 + helper T cells [ 18 ]. This, in turn, leads to the coordination of the adaptive immune response, which can result in pathogen elimination or in cases of immune dysregulation contribute to the development of autoimmunity. In this context, increasing attention has been given to probiotics live microorganisms which, when administered in adequate amounts, confer health benefits to the host. According to the definition proposed by the World Health Organization (WHO), probiotics are capable of modulating the composition of the gut microbiota, thereby improving the immunological, metabolic, and barrier functions of the gastrointestinal tract. In recent years, researchers have been actively investigating the potential of probiotics as an adjunct therapy in autoimmune diseases. It is hypothesized that by modulating the gut microbiome and influencing inflammatory pathways, probiotics may alleviate the symptoms of diseases such as rheumatoid arthritis, inflammatory bowel disease, and MS [ 19 , 20 ]. These immunological mechanisms are particularly relevant in the context of autoimmune diseases, where dysregulation of gut microbiota and immune responses plays a key role in disease development.

The intestinal microbiota plays a crucial role in shaping immune responses, and its imbalance referred to as dysbiosis has been associated with various autoimmune diseases, including RA, MS, T1D [ 21 , 22 ]. Probiotic interventions that restore microbial balance have been associated with beneficial effects in some studies; however, their clinical efficacy remains uncertain. One of the most important mechanisms by which probiotics influence gut microbiota is their ability to compete with pathogenic microorganisms for resources in the gut, thereby inhibiting the growth of harmful bacteria. Probiotics, particularly those belonging to the genera Lactobacillus and Bifidobacterium , promote the growth of beneficial bacteria that support intestinal barrier function and prevent the translocation of pathogens into the bloodstream [ 23 ].

Probiotics can also enhance the production of short-chain fatty acids (SCFAs), such as butyrate, propionate, and acetate, which exhibit anti-inflammatory and immunomodulatory properties. SCFAs strengthen the function of regulatory T cells (Tregs), which suppress excessive immune responses and reduce inflammation [ 24 ]. Intestinal dysbiosis is increasingly recognized as a risk factor in the development of autoimmune diseases. In patients with conditions such as RA or MS, reduced levels of anti-inflammatory bacteria like Faecalibacterium prausnitzii and increased abundance of pro-inflammatory species such as Prevotella copri (in RA) have been observed [ 25 ]. A clear example of this mechanism is the dysbiosis-related increase in Prevotella copri in the intestines of RA patients, which may contribute to disease progression by activating the immune system and inducing proinflammatory cytokine production [ 25 ]. Probiotics may help restore microbial balance in the gut, thereby reducing the intensity of inflammatory processes associated with these diseases. Animal studies and some clinical trials suggest that probiotic supplementation may have beneficial effects on autoimmune conditions; however, the available evidence remains limited and heterogeneous. Probiotic supplementation in RA patients resulted in a reduction in inflammatory markers and improvement in clinical symptoms [ 26 ]. Similarly, a study by Zamani et al. [ 27 ] showed that patients who received Lactobacillus casei for eight weeks experienced a significant decrease in C-reactive protein (CRP) levels, indicating reduced systemic inflammation. Research has also shown that probiotics may help restore immune balance in diseases such as MS, in which gut microbiota alterations can exacerbate inflammation in the central nervous system [ 28 ]. Probiotics have been found to reduce the number of Th17 lymphocytes—cells involved in MS pathogenesis—and promote the activity of Tregs, which have anti-inflammatory effects and suppress autoreactive T cells [ 28 ].

In the context of T1D an autoimmune disease that leads to the destruction of pancreatic beta cells—probiotics also show therapeutic potential. Animal models and preliminary clinical studies suggest that probiotics may reduce pancreatic inflammation and improve beta cell function by modulating the immune response. Studies indicate that probiotics can influence gut microbiota by reducing pathogenic bacteria and enhancing SCFA production, which in turn contributes to decreased systemic inflammation [ 29 ].

However, despite these promising findings, the use of probiotics in the treatment of autoimmune diseases still requires further research. While early results are encouraging, some studies emphasize the need for careful selection of probiotic strains with specific therapeutic effects. Additionally, the efficacy of probiotic therapy may depend on the individual’s gut microbiota composition, highlighting the importance of personalized approaches to treatment.

The Role of Gut Microbiota and Probiotics in the Pathogenesis and Treatment of Autoimmune Diseases

The gut microbiota plays a crucial role in the development and progression of autoimmune diseases through its interactions with the host immune system. Dysbiosis may lead to disruption of intestinal barrier integrity, increased permeability, and activation of pro-inflammatory immune responses. These processes contribute to immune dysregulation and may promote the onset and progression of autoimmune disorders [ 30 ].

In recent years, increasing attention has been given to the use of probiotics as modulators of gut microbiota and immune responses. The following subsections summarize current knowledge on selected autoimmune diseases, focusing on both disease pathogenesis and the effects of probiotic interventions (Fig.  1 ; Table  1 ) [ 30 – 32 ].

Probiotics modulate the gut-microbiota-immune axis, inhibiting autoimmune diseases

Table 1 Probiotics in autoimmune disease Study type Main findings Ref
Autoimmune hepatitis (AIH)
In vivo (mouse) Reduced Th1/Th17, increased Tregs, improved gut barrier [ 33 ] Clinical Increased gut permeability, reduced ZO-1/occludin [ 38 ]
Type 1 diabetes (T1D)
In vivo (NOD mice) Reduced incidence, increased IL-10 [ 46 ] In vivo Butyrate-producing bacteria reduced inflammation [ 47 ] Clinical (cohort) Early probiotics reduced autoimmunity risk [ 29 ] Clinical (RCT) Improved metabolic parameters [ 55 ] Clinical (RCT) No significant HbA1c effect [ 56 ]
Rheumatoid arthritis (RA)
Clinical Reduced inflammatory markers [ 26 ] Clinical (RCT) Reduced CRP, improved symptoms [ 27 ] Case report FMT improved symptoms [ 71 ]
Multiple sclerosis (MS)
Clinical Dysbiosis linked to immune changes [ 28 ] Clinical (RCT) Reduced inflammation, ↑ Treg markers [ 80 ] Clinical (RCT) Improved metabolic/mental parameters [ 81 ] Clinical (RCT) Reduced fatigue and oxidative stress [ 82 ] Case report FMT improved symptoms [84]

Probiotics in autoimmune disease

The Role of Probiotics in Modulating Gut Microbiota and Immune Response in Autoimmune Hepatitis

Autoimmune hepatitis (AIH) is a chronic liver disease characterized by elevated levels of immunoglobulin G (IgG) and increased activity of liver enzymes such as transaminases [ 30 , 31 ]. The standard treatment for AIH involves the use of glucocorticosteroids, often combined with azathioprine. These therapies effectively alleviate symptoms and slow disease progression; however, their long-term use is associated with numerous side effects, which in some cases can even exacerbate AIH [ 32 , 33 ]. To better understand AIH pathogenesis, a mouse model of autoimmune hepatitis was developed using HLA-DR3 + transgenic mice immunized with DNA plasmids encoding the human fusion protein CYP2D6/FTCD. This model has expanded knowledge about the relationship between AIH and gut microbiota composition [ 34 ]. Despite extensive research, the immunopathogenesis of AIH remains largely unclear. Observations suggest that hepatocyte damage primarily results from the activation of a Th1-type immune response (T helper type 1 cells) [ 35 ].

Liu and colleagues employed a C57BL/6 mouse model where AIH was induced by administering liver antigens combined with complete Freund’s adjuvant (S100/CFA) [ 34 , 36 ]. In their experiment, probiotic therapy involved oral administration of a mixture of 15 probiotic strains, including Bifidobacterium lactis HN019, Bifidobacterium bifidum BB06, Bifidobacterium animalis BB-12, Bifidobacterium breve BI-07, Lactobacillus rhamnosus GG, Lactobacillus casei LC11, Lactobacillus helveticus R52, Lactobacillus paracasei Lpc-37, Lactobacillus plantarum R1012, Lactobacillus reuteri HA188, Lactobacillus rhamnosus R11, Lactobacillus acidophilus NCFM, and Streptococcus thermophilus St21. Macroscopic examination revealed that livers from control mice exhibited a smooth, pink surface, whereas those from mice with induced AIH displayed a distinctly granular and swollen texture. Importantly, the livers of probiotic-treated mice resembled those of the control group, suggesting a protective effect. Probiotic therapy significantly reduced the differentiation of Th1 and Th17 cells while increasing the number of regulatory T cells (Tregs). Post-treatment, there was a decrease in the expression of pro-inflammatory cytokines IL-17 A and IFN-γ, alongside an increase in the anti-inflammatory cytokine TGF-β. Western blot analysis of signaling proteins showed that mice with induced AIH exhibited elevated expression of TLR4, NF-κB p65, and P-IκB/IκB, whereas probiotic treatment substantially lowered these protein levels compared to untreated AIH mice. Additionally, S100/CFA administration increased intestinal permeability, supporting the hypothesis of the gut barrier’s role in AIH pathogenesis. In the probiotic group, a lower Firmicutes/Bacteroidetes ratio was observed, alongside a reduction in taxa such as Deferribacteres , Saccharibacteria , and Proteobacteria , with a concurrent increase in Actinobacteria and Verrucomicrobia abundance [ 34 ]. It is important to note that a high proportion of Firmicutes is associated with increased risk of fatty liver and inflammation [ 37 ]. The probiotic-treated mice showed increased levels of beneficial bacterial genera such as Bifidobacterium , Bacteroides , Lactobacillus , Anaerostipes , Faecalibacterium and Blautia , while potentially pathogenic microbes like Helicobacter , and Staphylococcus decreased. Blautia and Anaerostipes produce acetic and butyric acids, respectively, both SCFAs with documented anti-inflammatory effects that play a vital role in maintaining intestinal epithelial integrity [ 34 ]. An independent study by Lin et al. in 2015 examined 24 patients diagnosed with AIH and 8 healthy controls. Histological analysis revealed that AIH patients had shortened, sparsely distributed intestinal villi with irregular structure, and disrupted tight junctions between epithelial cells. Additionally, inflammatory cell infiltrates and other morphological changes were observed in the lamina propria. Levels of tight junction proteins such as zonulin-1 (ZO-1) and occludin were significantly reduced in AIH patients, indicating gut barrier dysfunction and its possible involvement in disease pathogenesis [ 38 ].

The Role of Gut Microbiota and Probiotics in the Pathogenesis and Treatment of T1D

T1D is an autoimmune disease characterized by the destruction of pancreatic β-cells, leading to an absolute deficiency of insulin. In recent years, scientific research has increasingly focused on the role of the gut microbiota and the potential impact of probiotics on the development and treatment of this disease [ 39 ]. Patients with T1D exhibit an abnormal composition of gut microbiota, including a reduced Firmicutes to Bacteroides ratio and decreased microbial diversity. These changes are observed both in children with diabetes and in individuals with autoantibodies [ 40 ]. Characteristic alterations also include a reduction in butyrate-producing bacteria such as Clostridium clusters IV and XIVa [ 41 ], as well as decreased numbers of Bifidobacterium and mucin-degrading bacteria like Prevotella and Akkermansia [ 42 ]. Moreover, evidence suggests a link between colonization by Candida albicans and the development of T1D, indicating a possible role of the gut microbiota in disease pathogenesis [ 43 ].

Studies using animal models, such as Non-Obese Diabetic (NOD) mice and Biobreeding Diabetes-Prone (BB-DP) rats, have shown that alterations in the gut flora significantly influence diabetes onset. Antibiotic administration, including vancomycin, modifies the microbiota, which in some studies increased diabetes incidence [ 44 ], while others suggested protective effects [ 45 ]. Probiotic supplementation, for example with the VSL#3 mixture administered to young NOD mice, significantly reduced diabetes incidence [ 46 ]. Administration of Clostridium butyricum increased the Firmicutes to Bacteroides ratio and the number of butyrate-producing bacteria, leading to a decreased frequency of diabetes [ 47 ]. In BB-DP rats, Lactobacillus johnsonii isolated from diabetes-resistant animals delayed or inhibited disease onset [ 48 ]. Microbiota transplantation from NOD mice deficient in the MyD88 gene reduced diabetes incidence in wild-type NOD mice, while microbiota transfer from NOD mice to diabetes-resistant NOR mice induced insulitis [ 49 , 50 ]. These findings highlight the significant role of gut microbiota in T1D pathogenesis. Cohort studies in humans indicate that microbiota changes may precede disease development, suggesting a causal role in T1D pathogenesis [ 51 , 52 ]. Breastfeeding stabilizes infant gut flora, potentially reducing T1D risk [ 53 ]. Probiotic interventions, particularly in early life, show protective effects—supplementation within the first month of life reduced the risk of β-cell autoimmunity in genetically predisposed children [ 29 ]. In individuals with established T1D, probiotics may improve metabolic parameters and reduce inflammatory markers [ 54 , 55 ], although findings remain inconclusive [ 56 ]. The pathogenesis of T1D involves the innate immune system, which is modulated by the gut microbiota. TLRs and their adaptors such as MyD88 and TRIF regulate immune responses and affect microbiota composition, influencing disease development [ 57 , 58 ]. TLR4 expression modulates the balance between Bacteroidetes and Firmicutes , determining diabetes risk [ 59 ]. Similarly, NOD-like receptors (NLRs) in pancreatic lymph nodes play a critical role—their activation promotes T1D, whereas deficiency or antibiotic therapy is protective [ 60 ]. Microbiota also modulates antigen-presenting cells (APCs), such as macrophages and dendritic cells, influencing the activation of cytotoxic CD8 + T cells, with epigenetic effects transmissible across generations. Furthermore, microbiota affects adaptive immune responses, including CD4+, CD8+, MAIT, and iNKT cells. An imbalance in Th1/Th2 responses and a deficiency of regulatory T cells (Tregs) are strongly linked to β-cell destruction [ 61 ]. Certain bacteria, such as Bacteroides fragilis and Faecalibacterium prausnitzii , induce Tregs differentiation through butyrate production, supporting immune tolerance [ 62 ]. Th17 cells, involved in inflammation, can also be modulated by specific microbes, affecting T1D progression [ 63 ]. Changes in microbiota influence CD8 + T cell activation and accelerate disease progression, as well as impact MAIT and iNKT cells, which play essential roles in maintaining gut integrity and immune regulation [ 64 , 65 , 66 , 67 ].

In summary, probiotics have shown beneficial effects in experimental and some clinical studies in type 1 diabetes; however, their clinical applicability remains uncertain. Their actions include balancing Th1/Th2 responses, supporting Treg function, promoting short-chain fatty acid production, and modulating activity of Th17, CD8 + , MAIT, and iNKT cells. Despite promising results, further research is needed to fully understand the immunological mechanisms and clinical benefits of probiotic therapies in T1D.

Rheumatoid Arthritis and the Role of Gut Microbiota and Probiotics in Disease Pathogenesis and Therapy

RA is a chronic autoimmune disease characterized primarily by persistent inflammation leading to progressive joint damage and numerous systemic complications. It affects approximately 1% of the population and occurs more frequently in women than in men [ 68 ]. The disease course involves an aberrant immune response, including excessive activation of T and B lymphocytes and the production of pro-inflammatory cytokines such as TNF-α and IL-6. As a result, the body attacks its own tissues, including joints, causing chronic inflammation, pain, and structural joint damage. Recent research highlights the gut microbiome—the complex community of microorganisms residing in the gastrointestinal tract—as a key regulator of immune responses and a significant factor in the development of autoimmune diseases, including RA. Dysbiosis, or imbalance of the gut microbiota, may contribute to exacerbated inflammatory processes and autoimmune disease progression. In RA, dysbiosis manifests as a reduced abundance of anti-inflammatory bacteria such as Faecalibacterium prausnitzii and an overgrowth of pro-inflammatory bacteria, including Prevotella copri [ 25 ]. These alterations damage the intestinal barrier, leading to increased gut permeability and translocation of pathogens and LPS into the bloodstream. Consequently, LPS can trigger inflammatory responses that amplify systemic inflammation and contribute to RA development or exacerbation of symptoms [ 69 ].

One key mechanism by which gut microbiota influences RA pathogenesis is the activation of TLRs by bacterial LPS. TLR activation induces overproduction of pro-inflammatory cytokines such as TNF-α and IL-6 and enhances Th17 lymphocyte activity, which plays a role in inflammatory responses, while decreasing regulatory T cell (Treg) numbers, further amplifying the autoimmune response [ 70 ]. Additionally, metabolites produced by the gut microbiota, such as SCFAs, particularly butyrate, exhibit anti-inflammatory properties. SCFAs regulate cytokine production, support intestinal barrier function, and reduce systemic inflammatory activity. Numerous animal and human studies confirm the beneficial effects of probiotics on RA progression. For example, Zhang et al. [ 71 ] described a case of an RA patient who experienced symptom reduction and decreased inflammatory markers following fecal microbiota transplantation (FMT). Other research, such as Zamani et al. [ 27 ], showed that eight-week supplementation with Lactobacillus casei significantly lowered CRP levels and improved clinical outcomes, especially by reducing the number of swollen and tender joints compared to placebo. Probiotics also contribute to the maintenance of intestinal barrier integrity by enhancing the expression of tight junction proteins such as ZO-1 and occludin. Improved gut barrier function reduces intestinal permeability and limits the translocation of bacterial components such as lipopolysaccharides (LPS) into the bloodstream. This is particularly relevant in rheumatoid arthritis, where increased gut permeability and systemic exposure to microbial antigens may contribute to chronic inflammation and disease progression [ 72 ].

Probiotics may serve as supportive adjuncts to pharmacological therapy in RA; however, the available clinical evidence remains limited and inconsistent. Clinical trials demonstrate that supplementation with Lactobacillus plantarum and Lactobacillus acidophilus reduces TNF-α and IL-6 levels and improves clinical symptoms in RA patients [ 27 ].

Research into the gut microbiota and its impact on RA pathogenesis opens new therapeutic possibilities that may lead to the development of more effective treatments for this chronic disease. Gut dysbiosis likely plays a key role in RA development by intensifying inflammatory responses and damaging the intestinal barrier, exacerbating disease symptoms. The use of probiotics, and advanced treatments such as FMT may reduce inflammation, improve gut barrier function, and modulate immune responses. Although findings are promising, further advanced clinical studies are needed to develop targeted and effective microbiota-based therapeutic strategies for RA management.

However, the current body of clinical evidence remains limited and heterogeneous. Many studies are characterized by small sample sizes, short duration, and variability in probiotic strains and study design, which makes it difficult to draw definitive conclusions regarding their efficacy in RA. Therefore, the benefits reported should be interpreted with caution.

Multiple Sclerosis: The Role of Gut Microbiota and Probiotics in Pathogenesis and Therapeutic Approaches

MS is a chronic, progressive autoimmune disease of the central nervous system (CNS) characterized by damage to the myelin sheath, which subsequently leads to axonal injury and neurodegeneration. It is marked by the development of demyelination, resulting in impaired nerve conduction and a variety of neurological symptoms. In the pathogenesis of MS, abnormal activation of the immune system plays a key role, particularly CD4⁺ T lymphocytes, including Th1 and Th17 subpopulations, which secrete pro-inflammatory cytokines such as IFN-γ, IL-17, and TNF-α. These cytokines facilitate the infiltration of immune cells across the blood-brain barrier, leading to myelin sheath damage and exacerbation of inflammation in the CNS [ 73 , 74 ]. In recent years, there has been growing interest in the relationship between gut health and MS progression, linked to the discovery of the gut-brain axis. The integrity and function of the intestinal barrier significantly influence immune regulation and inflammation, while disturbances in the gut microbiota may contribute to the development and exacerbation of MS. Damage to the intestinal barrier, often referred to as “leaky gut” exposes the immune system to bacterial antigens, including LPS, which in turn activate systemic inflammation. This process may promote microglial activation and demyelination in the CNS, worsening MS symptoms [ 75 , 76 ]. The gut microbiota plays a fundamental role in modulating immune responses. Patients with MS exhibit dysbiosis—an imbalance in gut microbiota—characterized by a reduced abundance of anti-inflammatory bacteria such as Faecalibacterium prausnitzii and Bifidobacterium spp., alongside an increased presence of pro-inflammatory bacteria, including Akkermansia muciniphila and Methanobrevibacter [ 28 ].

Interestingly, Akkermansia muciniphila , a mucin-degrading bacterium commonly associated with beneficial metabolic and anti-inflammatory effects, appears to exhibit a context-dependent role in multiple sclerosis. While under physiological conditions it contributes to maintaining gut barrier integrity and immune homeostasis, its increased abundance in MS patients has been linked to enhanced pro-inflammatory immune responses [ 28 ]. Recent studies suggest that Akkermansia muciniphila may promote the activation of Th1 and Th17 lymphocytes, which are central drivers of MS pathogenesis. Additionally, elevated levels of anti- Akkermansia IgG antibodies have been detected in the cerebrospinal fluid of MS patients, indicating that immune recognition of this bacterium may contribute to autoimmune processes within the central nervous system [ 28 ]. These findings highlight the dual and context-dependent nature of Akkermansia muciniphila and underscore the complexity of microbiota–immune system interactions in MS. This paradoxical behavior suggests that the effects of Akkermansia muciniphila may depend on host-specific factors, disease stage, and interactions with other microbial communities.

One of the mechanisms through which gut microbiota influences inflammation and immune responses is the production of SCFAs, such as butyrate and propionate. SCFAs have potent immunomodulatory properties: they support regulatory T cell (Treg) function, inhibit differentiation of Th1 and Th17 lymphocytes, and enhance intestinal barrier integrity, thereby reducing systemic inflammatory responses [ 77 , 78 ]. In terms of MS treatment, Probiotics have shown promising effects in some studies; however, evidence remains limited and further research is required. Selected probiotic strains, especially from the genera Lactobacillus , Bifidobacterium , and Prevotella , have demonstrated the ability to restore gut microbiota balance, strengthen the intestinal barrier, and promote immune tolerance. The strain Prevotella histicola has shown immunoregulatory effects in animal models, inhibiting Th1 and Th17 activation and stimulating Treg cells [ 28 ]. Other strains, such as Lactobacillus reuteri , exhibit biphasic effects depending on the specific strain, they can act both pro- and anti-inflammatory highlighting their therapeutic potential in MS [ 79 ]. The efficacy of probiotic interventions in MS has also been confirmed in clinical studies. For example, Rahimlou et al. [ 80 ] reported that a 12-week supplementation with a multi-strain probiotic reduced inflammatory markers such as CRP, TNF-α, and IFN-γ, while increasing expression of genes related to Treg function (FOXP3) and the cytokine TGF-β. Studies by Kouchaki et al. [ 81 ] documented improvements in lipid profiles, mental health status, and reductions in inflammatory markers following probiotic supplementation. Additionally, Aghamohammadi et al. [ 82 ] demonstrated that administration of Saccharomyces boulardii improved antioxidant status and reduced clinical symptoms such as fatigue and pain. Another intriguing and promising, though still experimental, therapeutic strategy is FMT. Preliminary findings suggest that FMT may improve gut microbiota diversity, increase SCFA levels, and reduce neurological symptoms associated with MS [ 83 ]. However, due to a lack of long-term data, further placebo-controlled clinical trials are necessary to assess the safety and long-term efficacy of this method.

In summary, the gut microbiota and its metabolites play a crucial role in MS pathogenesis by influencing immune responses, microbial balance, and intestinal barrier integrity. Probiotic interventions and fecal microbiota transplantation offer promising supportive treatments, particularly for modulating the immune system and alleviating chronic inflammation. Nonetheless, further research is essential to confirm the effectiveness of these therapies and to develop optimal microbiota-targeted treatment strategies for MS.

Conclusion

The current understanding of the gut microbiota’s role in autoimmune diseases such as RA and MS undeniably opens exciting new avenues for therapeutic intervention. The modulation of the immune system through probiotics, and even FMT has demonstrated promising results in reducing inflammation, restoring microbial balance, and alleviating clinical symptoms. However, despite these encouraging findings, several critical limitations and challenges temper the optimism surrounding probiotic therapy and related microbiota-targeted treatments. First and foremost, the complexity of autoimmune diseases themselves presents a major obstacle. Autoimmune conditions are multifactorial, involving intricate interactions between genetic predisposition, environmental triggers, immune dysregulation, and microbiome. Probiotics, while capable of influencing immune responses and gut barrier integrity, cannot address all underlying disease mechanisms. The heterogeneity among patients both in disease phenotype and gut microbial composition means that a “one-size-fits-all” probiotic treatment is unlikely to be universally effective. Personalized approaches remain underdeveloped, and currently available probiotic formulations lack sufficient precision in targeting specific immunological pathways relevant to each individual. Moreover, the methodological limitations of existing research must be critically acknowledged. Many studies to date have been conducted on small sample sizes or animal models, which, although valuable, do not fully replicate the complexity of human autoimmune diseases. Clinical trials often suffer from short durations, small cohorts, and lack of standardized probiotic strains and dosages, making it difficult to draw definitive conclusions or to compare results across studies. Publication bias towards positive outcomes further clouds the true efficacy of probiotics. Without large-scale, long-term, randomized controlled trials with rigorous controls, the current evidence remains preliminary. Safety considerations also impose significant constraints on the clinical use of probiotics in autoimmune diseases. While probiotics are generally safe for healthy individuals, their administration in immunocompromised patients—a large subset of those with autoimmune conditions raises concerns. There are documented cases of probiotic-related infections in such vulnerable populations, emphasizing the need for careful patient screening and risk assessment before recommending these therapies. Additionally, the potential for probiotics to alter the native gut microbiota in unpredictable ways is not yet fully understood and could, in some cases, exacerbate dysbiosis or promote resistance to beneficial microbes. Another critical limitation is the lack of regulatory oversight and standardization in probiotic production. Another important limitation is the lack of standardization in probiotic formulations, including differences in strains, dosages, and treatment duration, which complicates comparison between studies and limits reproducibility. Furthermore, the long-term effects of probiotic supplementation remain insufficiently understood, particularly in patients with chronic autoimmune diseases.

Variability in strains, viability, concentration, and quality control between commercial products undermines the reproducibility of therapeutic effects and challenges clinicians’ ability to prescribe evidence-based probiotic interventions confidently. Without strict regulatory frameworks, the risk of inconsistent product efficacy and safety increases, which can erode patient trust and impede integration into standard care. The long-term impact of probiotic supplementation also remains an open question. Autoimmune diseases are chronic conditions requiring sustained management, yet most probiotic studies focus on short-term outcomes. The consequences of prolonged probiotic use whether beneficial, neutral, or potentially harmful are inadequately studied. This gap in knowledge limits the ability to provide concrete recommendations for long-term therapy and raises concerns about unforeseen adverse effects on microbiome stability and immune function.

Finally, while microbiota-targeted therapies represent an innovative frontier, they should not be viewed as a panacea. Probiotics and FMT currently serve best as adjuncts rather than replacements for established immunomodulatory and disease-modifying treatments. Their integration into comprehensive treatment regimens demands a nuanced understanding of interactions with pharmacological agents, disease stage, and patient-specific factors.

In summary, despite the growing excitement and promising early results, probiotic therapy in autoimmune diseases faces considerable scientific, clinical, and regulatory challenges. The field demands more robust, high-quality research to unravel the complex host-microbiome interactions, to define precise therapeutic targets, and to develop standardized, safe, and effective probiotic products. Until then, probiotic use should be approached with cautious optimism—acknowledging its potential while recognizing its current limitations. Only through continued rigorous investigation can microbiota-based therapies fulfill their promise as a valuable component in the management of autoimmune diseases.

Acknowledgements

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Author contributions

AK: Writing, original draft, investigation, review & editing. AD: Writing, original draft, investigation.

Funding

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Data Availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

The authors declare no competing interests.

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References

Associated Data

Data Availability Statement

No datasets were generated or analysed during the current study.