Modulating the Gut Microbiome as a Therapeutic Approach in Multiple Sclerosis: Implications for Gut‐Brain Interactions and Immune Pathways: A Narrative Review

The human GIT harbors a diverse community of microorganisms, including bacteria, viruses, fungi, and archaea, which vary in composition by anatomical location. Collectively known as the gut microbiome, these trillions of microbes are predominantly concentrated in the colon, and their combined genetic material outnumbers human genes by more than 100‐fold. Increasingly, the gut microbiome is recognized for its crucial roles in metabolism, immune defense, and even behavior. Its composition is dynamic and influenced by factors such as age, diet, medications, and anatomical position within the GIT (Reynders, 2021). Functionally, the gut microbiota metabolizes complex carbohydrates and proteins, synthesizes essential vitamins (e.g., B and K), and produces a wide array of metabolic byproducts, such as short‐chain fatty acids (SCFAs) (Figure1), that mediate communication between epithelial and immune cells (Zhang, 2023).

At the broader taxonomic level, the healthy adult gut microbiome is dominated by the phyla Firmicutes and Bacteroidetes, which together account for the majority of bacterial species in the colon. Smaller but functionally important proportions of Actinobacteria and Proteobacteria are also consistently present. These phylum‐level patterns provide the ecological framework for understanding dysbiosis, as shifts in the relative abundance of these groups form the basis of many microbiome alterations described in autoimmune and neuroinflammatory conditions, including MS (Tsogka et al., 2023; Hasaniani et al., 2024; Zhu et al., 2021).

The stomach and duodenum have acidic and bile‐rich environments, which result in relatively low microbial populations. The dominant microbes in these areas include Lactobacillus, Streptococcus, and certain yeast species. These microorganisms play a crucial role in the early stages of digestion and offer an initial line of defense against ingested pathogens (Cao, 2024).

As we move into the jejunum and ileum, the diversity of microbes increases. Here, we find facultative anaerobes such as Streptococcus, Lactobacillus, Clostridium, Prevotella, and Fusobacterium. These organisms help with nutrient absorption and prevent pathogen colonization through a process known as competitive exclusion (Lozupone et al., 2012).

The colon, particularly the cecum and large intestine, has the highest microbial density and diversity, containing up to 10¹² colony‐forming units per gram of content. Dominant microbial groups include Bacteroides, Bifidobacterium, Clostridia (especially Faecalibacterium prausnitzii and Roseburia), Akkermansia muciniphila, methanogenic archaea, fungi, and bacteriophages. These microbes ferment non‐digestible polysaccharides, producing SCFAs such as butyrate, acetate, and propionate. These SCFAs serve as energy sources for colonocytes, regulate immune responses, and help maintain the integrity of the gut barrier (Koh et al., 2016).

For example, F. prausnitzii and Roseburia have shown anti‐inflammatory properties by promoting the differentiation of regulatory T cells (Tregs) and suppressing pro‐inflammatory pathways, such as the activation of nuclear factor kappa B (NF‐κB) (Machiels et al., 2014; Sokol et al., 2008). Although Akkermansia muciniphila degrades mucin, this process promotes compensatory mucin production by the host, thereby maintaining the integrity of the mucus layer. Additionally, its metabolites enhance the expression of epithelial tight junction proteins, collectively contributing to the preservation of intestinal barrier function (Derrien et al., 2004).

In addition to providing metabolic support, the microbiota plays a significant role in regulating host immunity by interacting with gut‐associated lymphoid tissues (GALT). This interaction influences T‐cell polarization and shapes both innate and adaptive immune responses (Belkaid and Hand, 2014). Dysbiosis, which is characterized by a decrease in beneficial commensal bacteria, an overgrowth of harmful microbes, or a reduction in microbial diversity, has been associated with various disorders, including inflammatory bowel disease (IBD), metabolic syndrome, and neuroinflammatory conditions (Peterson et al., 2008). Furthermore, early‐life microbiome colonization is crucial for immune tolerance; disruptions during infancy have been linked to increased lifetime risk of autoimmune diseases, including MS. To put these descriptions into established reference frameworks, the microbial composition reviewed here reflects the seminal findings obtained from the NIH‐funded Human Microbiome Project (HMP), which represented the first large‐scale standardized microbial genomic catalog of healthy individuals across multiple body sites (The Human Microbiome Project (HMP) Consortium 2012). Subsequent integrative analyses, including the comprehensive overview by Gilbert et al., better outline how interindividual and functional diversity shape the stability and resilience of microbial ecosystems (2016). These landmark references provide foundational context for understanding the alterations in microbiomes as observed in MS across diverse cohorts.

The aforementioned systemic and immune effects are directly relevant to MS, where altered SCFA and tryptophan derivative levels and impaired immune regulation have been implicated in neuroinflammation. Therefore, understanding the distribution and function of gut microbes in different regions of the GIT is essential for uncovering their impact on host health and disease.

The gut‐brain axis is a bidirectional communication network that involves gut microbes and their metabolites, the enteric nervous system (ENS), the autonomic nervous system (ANS), neuroendocrine signaling, and the CNS (Table1). Recent evidence suggests that dysbiosis plays a role in the pathogenesis of both GIT diseases such as IBD and irritable bowel syndrome (IBS) and neurological or psychiatric conditions including anxiety, depression, autism spectrum disorder (ASD), Alzheimer's disease (AD), MS, and Parkinson's disease (PD) (Cryan et al., 2019; Yoo et al., 2020).

Communication between the gut and brain occurs through multiple pathways. The vagus nerve and spinal ANS provide direct neural signaling routes. The ENS, a complex intrinsic network within the GIT, also contributes significantly to gut‐brain communication. Specific gut bacteria have been shown to influence brain activity by stimulating vagal afferent neurons, thereby forming a direct neural bridge between the microbiota and the CNS. Studies investigating the gut‐brain axis have demonstrated a critical role for the gut microbiota in orchestrating brain development and behavior (Cryan et al., 2019; Yoo et al., 2020; Sorboni et al., 2022). The immune system is emerging as an essential regulator of these interactions (Sorboni et al., 2022).

These processes, though listed as categories, not only interact extensively but also at the level of the peripheral immune system. The regulation of neurotransmitter production and microbial downstream activity affects the differentiation of immune cells and the secretion of cytokines, and immune‐derived mediators provide feedback to the regulation of the nervous and endocrine systems. In multiple sclerosis, the activation of the peripheral immune system serves as an important link between the dysfunctioning gastrointestinal tract microbiota and the central nervous system.

Beyond its neurological influence, the gut microbiome plays a fundamental role in modulating host immunity. It interacts with both the innate and adaptive immune systems, helping maintain intestinal homeostasis and suppressing inflammation. Through the production of SCFAs and other metabolites, the microbiota promotes the development of regulatory T cells (Tregs), strengthens the intestinal barrier, and regulates immune cell signalling. Gut epithelial cells, in turn, secrete mucus and antimicrobial peptides to separate the microbiota from host tissues and maintain barrier integrity. Disruption of these interactions can lead to increased gut permeability and the proliferation of pathogenic, gram‐negative bacteria, ultimately compromising immune tolerance and increasing the risk of infection (Rooks and Garrett, 2016; iMSMS Consortium 2022).

Recent research established the dramatic change in the gut microbiota of individuals suffering from MS, which shows a likely pathophysiologic link between the disease and the gut. Literature described a very dramatic change in the structure of the microbiota with an increase of certain bacteria such as Akkermansia muciniphila and a reduction of beneficial groups such as Faecalibacterium prausnitzii (Jangi et al., 2016; Lin et al., 2024). More recently, meta‐analyses further identify consistent reductions in Prevotella spp., members of the Clostridium groups IV and XIVa, the Eubacterium hallii group, Ruminococcus 2, and Lachnospira/Blautia (of the Lachnospiraceae family), which represent important butyrate producers, whereas Actinomyces species and Alistipes species, are found to be increased in MS patients according to a consensus identified using MS cohorts (De Gennaro, 2025; Shahi, 2023; Del Negro et al., 2023). These microbiota changes have been linked to regulatory and inflammatory mechanisms; an example is that Methanobrevibacter has been linked to disruptions in metabolic activity in MS patients. In addition, modulation of the gut microbiota by the environment or medications, such as food, has been postulated to have significant influence on MS evolution, and regulation of gut metabolites such as SCFAs has been implicated in the modulation of inflammation. Gut microbiota alterations predispose not just to inflammatory responses but also to treatment responses, and pointing towards implicating the gut‐brain axis as a potential therapeutic target in MS (De Gennaro, 2025; Shahi, 2023; Del Negro et al., 2023).

In addition, MS disease‐modifying drugs (DMTs) have also been found to alter microbiota composition, and treated individuals were observed to be distinct in microbial networks, indicating that therapeutic maneuvers on the microbiome can modulate immune processes (Brown et al., 2021). This evidence is indicative of the dualistic function of the gut microbiome to induce and, perhaps, inhibit MS pathogenesis by modulating unique therapeutic strategies.

While EAE studies provide mechanistic insights, the growing body of human cohort studies, including that by Chen et al. (2016) and Cekanaviciute et al. (2017), validates that MS‐associated microbial dysbiosis has direct immunological consequences observable in patient‐derived samples. Landmark human cohort studies further support these findings. In a seminal case‐control study, Chen et al. (2016) were able to show that MS patients had reduced butyrate‐producing taxa and altered microbial functional pathways impacting dendritic cell maturation. Similarly, Cekanaviciute et al. (2017) demonstrated that fecal microbiota from MS patients induced a pro‐inflammatory phenotype following transplantation into germ‐free mice, providing causative evidence that MS‐associated human microbial communities modulate host immunity (Lin et al., 2024). Recent systematic reviews and meta‐analyses that integrated data across multiple MS cohorts consistently show depletion of SCFAs‐producing Clostridiales, Prevotella, and Faecalibacterium, with increased Akkermansia and Methanobrevibacter, reinforcing the reproducibility of these microbial signatures in humans (Tsogka et al., 2023; Rumah et al., 2013).

The link established by microbes in MS had been observed even before modern methods for the investigation of the current status of the microbiome were discovered. It should be noticed that the epsilon‐toxin produced by the bacterium Clostridium perfringens has been identified to cross the blood‐brain barrier, thereby reacting with myelin and oligodendrocytes. For this reason, it is established that the titer of antibodies produced against epsilon‐toxin is high in MS patients (Gil et al., 2015; Schrijver, 2001).

In parallel, it was demonstrated that bacterial peptidoglycans are also found in active lesions of MS patients. This is taken as direct histopathological proof of the presence of bacterial antigens in the CNS. Also, the presence of bacterial peptidoglycans is known to trigger the activation of innate immune receptors like NOD‐ and Toll‐like receptors. The results make it clear that bacterial antigen translocation could be an important factor in the triggering of the immune response in the CNS in MS (Thirion et al., 2023).

It has been discovered that MS patients characteristically show specific patterns in the gut microbiota, which vary from the general population. Repeated changes observed are increased prevalence of specific bacteria such as Akkermansia muciniphila and Methanobrevibacter, which contribute to immune modulation and inflammation. At the same time, decreases in anti‐inflammatory bacteria like Faecalibacterium prausnitzii and Butyricimonas have also been seen that may be attributed for the pro‐inflammatory milieu seen with MS (Jangi et al., 2016; Lin et al., 2024). Recent evidence suggests differences in microbiome composition according to MS subtype. In Relapsing‐Remitting Multiple Sclerosis (RRMS), there tends to be Akkermansia enrichment and Prevotella depletion. In secondary progressive MS (SPMS), there's less microbial diversity with greater losses in SCFAs producers. In Primary Progressive Multiple Sclerosis (PPMS), there are specific differences like increased abundance of Clostridium bolteae, Ruthenibacterium lactatiformans, fewer Lachnospiraceae, and Blautia species. These differences are evident in one study (Reynders, 2021). Region, diet, and ethnicity are additional variably expressed modifiers (Zhang, 2023; Cao, 2024). In addition, it has been seen that the gut microbiota profile in MS has been associated with differences in gene expression in the dendritic cell development pathway and interferon signaling (Lin et al., 2024). Diverse microbial communities also are associated with MS DMTs in patients, indicating that therapy can reestablish microbial homeostasis to some degree (Jangi et al., 2016). Further research is needed to further define the role for these microbe alterations in MS pathogenesis and disease progression and in therapeutic intervention (Chen et al., 2016; Rumah et al., 2013). Although there are encouraging results, there are methodological issues in studying microbiome‐MS. They are largely cross‐sectional with small numbers. Clearly, there are confounding variables like diet, antibiotics, or disease‐modifying antirheumatic drugs which greatly influence microbial community diversity. Besides, there are issues related to differences in sequencing depth or platform and analysis pipelines. More longitudinal and multi‐omics analyses are thus warranted to provide clarification into mechanisms that are potentially therapeutic (Jangi et al., 2016; Lin et al., 2024; De Gennaro, 2025; Shahi, 2023; Del Negro et al., 2023; Brown et al., 2021; Chen et al., 2016; Cekanaviciute et al., 2017; Lin et al., 2024; Rumah et al., 2013).

There is a two‐way relationship between the gut microbiome and the gut immunity. The microbiome regulates the development and function of gut immunity, and on the other hand, the innate and adaptive immunity of the gut influences the composition of the microbiome. Depletion of SCFAs‐producing bacteria leads to lower butyrate circulation, hampering Tregs' differentiation but favoring pro‐inflammatory T helper 17 (Th17) responses. Also, elevated Akkermansia muciniphila leads to mucin depletion in the gut mucus layer, increasing microbial translocation and activation of antigen‐presenting cells. In addition, microbial metabolism of tryptophan contributes to differences in aryl‐hydrocarbon receptor (AhR) signaling pathways. In turn, these differences regulate microglial activation or neuroinflammation within the CNS (Miyauchi et al., 2020). For instance, Th17 cells are currently widely recognized as key influencers in MS pathophysiology. Increased Th17 cells in the gut have been linked to increased disease activity and altered gut microorganisms in MS. The microbiome sends specific signals that trigger myelin oligodendrocyte glycoprotein (MOG)‐specific Th17 cells in the gut. An experiment conducted on mice colonized by two strains of bacterial families from the small intestine, namely the Erysipelotrichaceae family and Lactobacillus reuteri, has shown them to develop worse experimental EAE in comparison to bacteria‐free mice. The Erysipelotrichaceae assists in enhancing the Th17 cell activity, whereas Lactobacillus reuteri makes proteins that possibly mimic MOGs. Thus, the combined effect of both these strains of bacteria could be involved in the development of MS (Wilson et al., 2022). Myelin basic protein (MBP)‐specific Th17 cells as well as neutrophilic infiltration of the intestine play a similar role (Sterlin et al., 2021). Neutrophils act via the Toll‐like receptor (TLR) pathway for differentiation of Th17 cells by neutrophil extracellular traps (NET) (Kadowaki et al., 2019). All these mechanisms lead us to believe that the gut is a prime site for the encephalitogenic T17 cell's differentiation, while the microbiome plays a crucial role in forming a link between them and the CNS (Miyauchi et al., 2020). Severe MS is associated with dramatically decreased responses of intestinal immunoglobulin A (IgA) (den Besten et al., 2013). C‐C chemokine receptor type 9 (CCR9⁺) memory T cells, typically regulatory in a healthy population, become pro‐inflammatory in MS, especially in SPMS (Miyauchi et al., 2020; den Besten et al., 2013). This was via the increased production of interleukin (IL)‐17A and interferon‐gamma (IFN‐γ) in such patients. Therefore, an imbalance between the commensals of the gut promotes immune dysfunction and increase the risk of MS (Miyauchi et al., 2020).

SCFAs, such as acetate, butyrate, and propionate, are produced by fermentation of dietary fibers and resistant starch by the intestinal microbiome (Montgomery et al., 2024). Certain SCFAs are known to be produced by particular bacterial strains. Butyrate is produced mainly by Clostridium clusters IV and XIVa, Eubacterium, Ruminococcus, and Faecalibacterium, whereas the Bacteroidota phylum produces acetate and propionate (Silva et al., 2020). SCFAs are an energy source for both the body and gut microbiota. They have the ability to cross the BBB, allowing widespread anti‐inflammatory effects, influencing immune and CNS function. Immunologically, they promote Treg differentiation, and interleukin‐10 (IL‐10) production and suppress pro‐inflammatory responses from T cells, macrophages, and neutrophils. They act on BBB cells, microglia, astrocytes, and oligodendrocytes, modulating neuroinflammation and barrier integrity (Ntranos et al., 2021; Jensen et al., 2021).

Studies conducted in mice have shown that those colonized with SCFAs‐producing organisms or those directly treated with SCFAs have shown to reduce the severity of disease in the EAE model of MS. Lower SCFAs levels (especially butyrate) have been observed in feces, plasma, and serum of people with MS. Reductions correlate with increased intestinal permeability, decreased Tregs, and worsening Expanded Disability Status Scale (EDSS) disability scores. SCFAs‐producing taxa (e.g., Butyricimonas, Lachnospira, Bacteroides) have been found to be depleted in MS patients (Silva et al., 2020). A study using a daily propionate supplement showed a positive response from MS patients who adhered to the treatment for one whole year consistently (Ntranos et al., 2021). Findings also suggest that restoring SCFAs levels in MS patients is overall beneficial in reducing relapse rates, improving disease status, and reducing progression (Silva et al., 2020; Ntranos et al., 2021). Therefore, further studies are required to determine the exact mechanism in order to utilize this concept in the therapeutic management of MS.

Tryptophan, an essential amino acid, is metabolized by the gut microbiota into indole derivatives, tryptamine, and indole‐3‐acetate. Certain protective bacterial metabolites, such as indole‐3‐lactate and indole‐3‐propionate, are found to be decreased and correlate with lower disability in pediatric cohorts. Whereas indoxyl‐sulfate and p‐cresol‐sulfate, which are neurotoxic metabolites, are observed to be increased in relapsing‐remitting MS (RRMS) (Silva et al., 2020; Jensen et al., 2021; Ghimire et al., 2022). Isoflavones, found in soy, exhibit anti‐inflammatory effects. Gut microbes like Adlercreutzia equolifaciens metabolize them into S‐equol, a protective estrogen‐like compound. In EAE models, isoflavone‐rich diets reduced disease severity, but this effect required equol‐producing bacteria. Isoflavone‐driven changes in gut lipopolysaccharide (LPS) synthesis also promoted anti‐inflammatory macrophage responses (Wu et al., 2023; Campagnoli et al., 2024).

Secondary bile acids, modified by gut microbiota, are reduced in MS. These metabolites act on farnesoid X receptor (FXR) and G protein‐coupled bile acid receptor 1 (GPBAR1) receptors to suppress inflammation. Tauroursodeoxycholic acid (TUDCA), a secondary bile acid, improves EAE outcomes and is safe in people with MS, suggesting a therapeutic role (Silva et al., 2020). Akkermansia muciniphila is enriched in MS gut microbiota, but its effects are context dependent. This microbe degrades mucin and phytate, leading to propionate and myo‐inositol production, both linked to immune modulation in MS. It produces indoles and GABA, with evidence showing increased gamma‐aminobutyric acid levels and altered microbial gene expression in EAE models colonized with A. muciniphila. In some studies, A. muciniphila promotes EAE, while in others it correlates with vitamin K production and slower MS progression (Campagnoli et al., 2024; Li, 2022).

The BBB is the border of endothelial cells that allows very selective and permeable passage, which keeps the CNS safe from systemic immune challenges and toxins. The BBB needs to stay intact for normal functioning of the CNS. In MS, increased permeability of the BBB happens as an early pathologic event before immune cells enter and demyelination occurs. New findings have suggested that a healthy gut flora can influence in maintaining a proper functioning BBB and therefore mediate its role in MS through the gut‐brain axis. Different studies have proven unhealthy gut imbalances with changed diversity and composition have also badly impacted both structure and function of the BBB (Schumacher et al., 2024; Tankou et al., 2018; Liu et al., 2022).

In germ‐free mice, lower expression of tight junction proteins (such as occludin and claudin‐5) and higher permeability of the BBB were reversed by colonization with conventional microbiota (Schumacher et al., 2024). SCFAs result from healthy metabolic interactions between bacteria and provide energy for epithelial cells (Schumacher et al., 2024). In MS, dysbiosis was found to reduce microbial‐derived SCFAs necessary for both preservation of BBB tight junctions and suppression of neuroinflammation in EAE models. Specific bacterial components can activate microglia and astrocytes indirectly through modulation of peripheral immune tone, which, in turn, further degrades the BBB, thereby facilitating the entry of autoreactive T cells into the CNS (Tankou et al., 2018; Liu et al., 2022).

The gut flora also helps with overall body inflammation, which is very important in disrupting the BBB. Dysbiosis leading to translocation of bacterial products like LPS into the bloodstream turns on toll‐like receptor pathways on endothelial lining and immune cells. This causes the body to make pro‐inflammatory cytokines like IL‐1β and tumor necrosis factor‐alpha and worsens BBB permeability (Jia et al., 2021). Therefore, balancing microbes by using probiotics, prebiotics, and changing diet adds hope for better gut and BBB health. These treatments alter specific microbe metabolites, lower systemic inflammation, and likely restore barrier integrity, all key to slowing down MS (Borody et al., 2022).

Probiotics are live microbial entities that display specific effects across strains related to host immunity and metabolism. In MS patients, Lactobacillus casei Shirota has shown reductions in pro‐inflammatory cytokines, and Bifidobacterium infantis has shown increased secretion of IL‐10 and Tregs, whereas Clostridium butyricum has shown increased secretion of SCFAs, which work cumulatively to down‐regulate Th17‐induced inflammation in MS patients. The probiotics used in MS trials include VSL#3, which consists of a combination of Lactobacillus, Bifidobacterium, and Streptococcus strains, and LBS, an eight‐strain high‐dose blend (Silva et al., 2020; Ntranos et al., 2021; Jensen et al., 2021; Ghimire et al., 2022; Wu et al., 2023). Meta‐analyses support their role in preventing and managing gastrointestinal (GI) disorders, such as antibiotic‐associated diarrhea and IBS, although efficacy varies by strain and host factors (Sadowsky et al., 2021).

Prebiotics are nondigestible fibers, such as inulin, fructooligosaccharides (FOS), and galactooligosaccharides (GOS), that selectively stimulate the growth of beneficial gut microbes. Other prebiotic substrates like resistant starches, pectin, polyphenols, mannose, or human oligosaccharides in breast milk could further improve the growth of SCFAs‐producing microbes like Faecalibacterium prausnitzii or Roseburia species and anti‐inflammatory immune functions involving increased secretion of IL‐10 (Browne et al., 2021). They enhance mineral absorption, promote SCFAs production, and demonstrate immunomodulatory and anti‐pathogenic effects (Browne et al., 2021). While traditional strains, such as Lactobacillus, Bifidobacterium, and Saccharomyces boulardii, are widely used, newer strains, including Roseburia spp., Akkermansia muciniphila, Faecalibacterium prausnitzii, and Propionibacterium spp., are emerging for their anti‐inflammatory and mucosal protective roles. Beyond glucans and fructans, compounds like pectin, resistant starch, polyphenols, mannose, and human milk oligosaccharides are also being recognized for prebiotic potential (Sadowsky et al., 2021; Browne et al., 2021; Hui et al., 2019).

Synbiotics, which combine probiotics and prebiotics, offer synergistic benefits by enhancing microbial colonization, immune function, and gut homeostasis. At a mechanism level, synbiotics function through SCFAs (butyrate and propionate), improvement in gut barrier function, Treg and IL‐10 induction, and inhibition of Th17/IFN‐γ. Serum propionate has been shown to correlate with elevated frequencies of regulatory B cells and lower levels of inflammatory cytokines in MS patients (Hui et al., 2019). Both probiotics and prebiotics primarily act through their effects on gut microbiota, offering metabolic and immunological advantages (Hui et al., 2019) (Figure2).

Modulating the gut microbiome is now recognized as a promising therapeutic approach for various health conditions. FMT is one such approach, where stool from a healthy donor is transferred into the GIT of a patient to restore microbial balance. This technique introduces a diverse and balanced microbial consortium of bacteria, viruses, fungi, and archaea with the potential to reverse dysbiosis‐driven diseases (Hvas et al., 2019). Pilot trials in patients with RRMS show that FMT procedures are safe and that there are transient benefits to microbial composition and barrier function. The mechanisms involved are correcting microbial diversity, increasing SCFAs, fixing barrier function, and correcting immune function. These include fixing T‐reg functions and suppressing Th17. There are risks involved concerning infection transmission, donor variability, and regulatory challenges, and there are no proven benefits to neurological symptoms (Hvas et al., 2019; Zhang, 2022).

FMT has demonstrated high efficacy, particularly in treating recurrent Clostridioides difficile infections, with cure rates approaching 85%–90%, and is now recommended in clinical guidelines for patients with multiple relapses (Zhang, 2022; Sugihara and Kamada, 2021; Fu et al., 2022). Its use has also expanded to conditions such as inflammatory bowel disease (IBD), where some clinical trials suggest moderate improvement in symptoms (Liu et al., 2022).

In IBS, the role of FMT remains more controversial. While some randomized controlled trials have shown symptomatic improvement, others failed to demonstrate a benefit, leading to inconsistent overall findings (Cao, 2024; Straus Farber et al., 2024). Ongoing research continues to explore the mechanisms, optimal donor profiles, delivery methods, and long‐term safety of FMT in both GI and systemic diseases.

Food components provide substrates not only for human metabolism but also for the gut microbiota, which plays an essential role in modulating immune responses involved in MS. Gut microbes ferment dietary fibers into short‐chain fatty acids (SCFAs), such as butyrate and propionate, which enhance gut barrier integrity and exert anti‐inflammatory effects. These mechanisms may help protect against the development of MS (Choi et al., 2021; Ohlsson et al., 2023; Depommier et al., 2019). Diets high in fiber and rich in whole grains, legumes, fruits, and vegetables are associated with increased microbial diversity and elevated SCFA production, which may help maintain intestinal and systemic immune homeostasis. In MS, dietary trials that have been explored are keto diets, intermittent fasting (IF) regimens, or Mediterranean/MIND diets. These diets result in increased SCFAs producers, improved microbiota diversity, elevated barrier function, increased Tregs and IL‐10, and downregulated Th17 and IFN‐γ. Pilot trials suggest that keto diets are helpful in alleviating fatigue symptoms, IF diets can modulate immune status and Mediterranean/MIND diets are helpful in establishing anti‐inflammatory microbiota (Romano et al., 2021; Duan et al., 2022; Zmora et al., 2022). Conversely, Western dietary patterns characterized by high intake of saturated fats, refined sugars, and processed foods can reduce beneficial SCFA‐producing bacteria and promote pro‐inflammatory microbial profiles, potentially exacerbating neuroinflammation (Choi et al., 2021). Functional foods, including fermented products and polyphenol‐rich fruits, have also been shown to positively influence the gut microbiome by providing live beneficial microbes and prebiotic substrates, thereby supporting anti‐inflammatory microbial activity (Figure3). (Romano et al., 2021; Duan et al., 2022; Zmora et al., 2022; Logotheti et al., 2021).

Building upon the growing understanding of gut microbiota's role in MS, a wide range of microbiota‐based therapeutic approaches are under active investigation (Table2) (Blais et al., 2021; Tankou et al., 2018). These include conventional strategies such as probiotics, dietary modifications, IF, and FMT, each with varying levels of clinical validation. In a comprehensive systematic review, Tsogka et al. (2023) evaluated 13 studies involving 212 relapsing–remitting MS patients and 200 healthy controls. Their review encompassed interventions such as probiotic formulations like VSL#3 and LBS (a blend of Lactobacillus, Bifidobacterium, and Streptococcus), as well as dietary protocols, IF regimens, and case‐based reports on FMT. Mechanistically, these interventions were found to promote anti‐inflammatory cytokine profiles, modulate immune responses, and improve intestinal barrier function. Clinically, the studies reported reductions in relapse rates and EDSS scores, as well as improvements in fatigue, quality of life, and inflammatory markers, including IL‐4, IL‐6, and high‐sensitivity C‐reactive protein (hs‐CRP). Microbiome analyses further revealed reduced microbial diversity and metabolic pathway shifts favoring anti‐inflammatory functions, as observed through Kyoto Encyclopedia of Genes (KEGG) profiling. Blais et al. (2021) and Tankou et al. (2018) also reviewed human and animal studies involving strains such as VSL#3, Lactobacillus paracasei, Bifidobacterium animalis, Escherichia coli (E. Coli) Nissle 1917, and Prevotella histicola, supporting the therapeutic potential of commensal‐based probiotics. However, limited data on clinical endpoints and inconsistent microbiome data tempered the interpretability of their findings.

Further mechanistic insights emerged from two pilot trials conducted by Tankou et al. (2018). In the first, administration of VSL#3 in MS patients resulted in immunomodulatory effects, including reduced intermediate monocytes and downregulation of cluster of differentiation 80 (CD80) and human leukocyte antigen—DR isotype (HLA‐DR) expression, although no clinical outcomes were assessed (Cignarella et al., 2018). Microbiome profiling in this study revealed increased abundance of Lactobacillus, Streptococcus, and Bifidobacterium. In their second trial, a different group of patients received a high‐dose LBS formulation (3600 billion CFU/day for two months), which led to decreased expression of pro‐inflammatory genes, lower monocyte counts, and no relapses during the study period (Birnie et al., 2020). This intervention also resulted in enrichment of beneficial bacteria and suppression of potentially pathogenic genera such as Blautia and Dorea, alongside altered alpha diversity. In a parallel preclinical and pilot human study, Cignarella et al. (2018) and Bonnechère et al. (2023) explored the impact of IF and FMT. In EAE mice, fasting increased gut microbial richness and activated antioxidant pathways, while modulating immune responses by reducing IL‐17–producing T cells and increasing regulatory T cells. In MS patients, IF similarly shifted immune and metabolic parameters, including changes in adipokines. FMT from fasted donors conferred disease protection in the animal model, highlighting the potential for targeted microbial transfer in therapeutic contexts.

While these findings provide strong biological plausibility and early clinical signals, recent efforts have turned toward personalized and next‐generation microbiome therapies. Newer methods involve postbiotics (SCFAs or tryptophan catabolites), genetically modified probiotics expressing IL‐10 or other immunomodulators, or artificial intelligence‐based personalized microbiome therapy performed using multi‐omics analysis. These are intended to specifically address immune system dysregulation in MS patients and improve treatment outcomes, but these are still in preliminary development phases (Romano et al., 2021, Duan et al., 2022, Zmora et al., 2022). Emerging strategies aim not only to correct dysbiosis but also to precisely modulate immune responses in MS. Novel probiotic candidates such as Akkermansia muciniphila and Faecalibacterium prausnitzii have attracted attention for their anti‐inflammatory properties and ability to restore gut barrier function (Depommier et al., 2019). Engineered bacterial strains, including modified E. coli Nissle capable of delivering IL‐10 directly in the gut, represent an innovative approach for targeted immunoregulation (Romano et al., 2021; Duan et al., 2022). These approaches are also being studied for their potential to enhance responses to immunotherapies, not only in MS but also in broader neurological and oncological settings. Importantly, not all microbiome‐modifying interventions have demonstrated clinical benefit in MS. Indeed, several probiotic randomized placebo‐controlled trials have demonstrated no significant improvement in relapse rates, Expanded Disability Status Scale (EDSS) progression, fatigue, and inflammatory markers in up to ∼40% of MS patients (Romano et al., 2021; Zmora et al., 2022; Logotheti et al., 2021). In some studies, probiotic supplementation induced changes in the microbiome composition; this did not translate into measurable clinical benefits. Dietary intervention and IF trials have demonstrated heterogeneous responses, with individuals failing to demonstrate alterations in immune parameters or symptom burden (Romano et al., 2021; Duan et al., 2022; Zmora et al., 2022). FMT pilot studies have, by and large, been safe but have not consistently improved neurological outcomes. These neutral or negative findings underscore the presence of variability in treatment response, strain‐specific differences, and the need for rigorously designed, adequately powered RCTs. The inclusion of both positive and negative results underlines the substantial uncertainty still present in the field and avoids a potential publication bias (Logotheti et al., 2021).