Many studies have discussed the altered gut microbiota regarding abundance and structural composition, and sequencing-based analyses have revealed a different composition of the gut microbiota in MS patients (Table 1).

This paper summarizes 24 studies on MS involving a total of 1,075 MS patients and 947 healthy controls (HC; Cantarel et al., 2015; Miyake et al., 2015; Chen et al., 2016; Jangi et al., 2016; Tremlett et al., 2016; Cekanaviciute et al., 2017; Cosorich et al., 2017; Forbes et al., 2018; Kozhieva et al., 2019; Oezguen et al., 2019; Storm-Larsen et al., 2019; Ventura et al., 2019; Zeng et al., 2019; Choileáin et al., 2020; Ling et al., 2020; Reynders et al., 2020; Saresella et al., 2020; Takewaki et al., 2020; Castillo-Álvarez et al., 2021; Cox et al., 2021; Galluzzo et al., 2021; Cantoni et al., 2022; Mekky et al., 2022; Vacaras et al., 2023). Although the differences in gut microbiota properties between the MS and HC groups were not found to be statistically significant in animal and human studies on MS. However, the relative abundance of Akkermansia, Christensenellaceae, Desulfovibrionales, Ruminococcus, and Streptococcus in the MS group was significantly higher than in (HC) group. One study found that Akkermansia isolated from MS patients reduced RORγt⁺ and IL-17 γδT cells to improve experimental autoimmune encephalomyelitis (EAE; Cox et al., 2021) Conversely, Akkermansia muciniphila may contribute to exacerbation of chronic inflammation and exacerbation of MS symptoms either directly by shifting the immune response to the Th1 phenotype or indirectly by interacting with other bacteria and reducing the ability to differentiate against Treg (Cekanaviciute et al., 2018). Christensenellaceae is influenced by the genetic composition of the host in the gut microbiome (Goodrich et al., 2014) and is a potential indicator of the risk of mortality in neurocritical care patients (Xu et al., 2019). Ruminococcus is a genus that produces abundant propionic and butyric acids and can participate in the digestion of food and the reduction of inflammatory factors with the maintenance of intestinal barrier function (Crost et al., 2023). Both Clostridium butyricum and norfloxacin treatment reduced the abundance of Desulfovibrionales and Ruminococcus, which inhibited the Th17 cell response promoted Treg differentiation, and attenuated the severity of EAE in mice through mitogen-activated kinase (MAPK) signaling (Chen et al., 2019). Streptococcus abundance has been shown to positively correlate with the proportion of Th17 cells and negatively correlate with Tregs and is therefore hypothesized to be a potential key factor in the development and/or relapse of MS disease (Zeng et al., 2019).

In contrast, the relative abundance of Bacteroidaceae, Lachnospiraceae, Prevotella, and Roseburia was significantly lower in the MS group than in the HC group. Studies on the diet of EAE mice found that intermittent fasting (IF) increased intestinal Bacteroidaceae abundance, decreased IL-17 cell production, increased Tregs differentiation, and ameliorated the clinical course and pathology of EAE (Cignarella et al., 2018). Lachnospiraceae were shown to impair oligodendrocyte differentiation in cultured cells and were associated with impaired myelin formation in mice (Katz Sand et al., 2019). Iljazovic et al. found that Prevotella colonization led to changes in the metabolism of the gut microbiota, which reduced the production of IL-18, thereby exacerbating intestinal inflammation and leading to systemic autoimmunity (Iljazovic et al., 2021). In a mouse model, Prevotella histicola reduces pro-inflammatory Th1 and Th17 cells in the CNS by inducing the number of CD4⁺FoxP3⁺ regulatory T-cells thereby reducing the severity of EAE (Shahi et al., 2019). Roseburia spp. plays an important role in the regulation of barrier homeostasis, immune cells, and cytokine release through its metabolite, butyrate. Thus, Roseburia also plays an important role in alleviating inflammation in autoimmune diseases (Nie et al., 2021).

The controversy over the abundance of Blautia, Dorea, Faecalibacterium, Methanobrevibacter, Parabacteroides, and Ruminococcaceae in MS and HC groups is consistent with the findings of a systematic review and review, probably due to significant differences in disease severity and duration, as well as differences in changes in gut microbiota (Ordoñez-Rodriguez et al., 2023).

Based on these results, it is suggested that interventions or changes in gut microbiota can alter susceptibility to inflammatory demyelination in MS in humans or animals and that gut microbiota can be an important hub for regulating and synchronizing many of the changes associated with the pathophysiology of MS.

Bidirectional interactions involving endocrine, neuroimmune, and chemical interactions between the gut microbiota and the central nervous system form the MGB (Ullah et al., 2023). Gut microbiota metabolites are involved in the maintenance of homeostasis in the body and influence the development of MS through the MGB (Table 2), and the following description highlights the most important metabolites of the gut microbiota that have recently been involved in the progression of MS.

EAE and cuprizone (CPZ) is a commonly used animal model for MS (Ji et al., 2024). Regulatory T cells (Tregs) interacting with B cells and CNS glial cells are key factors in MS and EAE neurodegeneration (Brummer et al., 2022). Among them, helper T cells (Th)1 and Th17 cells are the main coordinators of pathogenic inflammatory processes in MS (Kamali et al., 2019). During pro-inflammatory cytokine production, self-antigen presentation to T cells acts as a pathogenic B-cell effector in MS. In EAE, antigen presentation by B cells is sufficient to cause disease by predominantly reactivating Th1 and Th17 cells (Thomann et al., 2023).

Altered gut microbiota in MS patients can be attributed to T-cell dysfunction (Hussman et al., 2016). Recent studies have shown that gut microbiota metabolites such as short-chain fatty acids (SCFAs), secondary bile acids, and tryptophan (Trp) can act as immunomodulators of regulatory T cells and T helper cells (Calvo-Barreiro et al., 2023), Important regulators of brain and neuronal activity that can influence MS progression (Tan et al., 2023).

SCFAs composed of acetic acid, propionic acid, and butyric acid act as a link between the gut microbiota and the immune system and can protect against many autoimmune diseases by regulating T cell differentiation (Liu et al., 2024). Reinforcement of the blood–brain barrier (BBB) by SCFAs suppresses experimental CNS inflammation (Kim, 2023). Previous studies have shown lower levels of SCFAs in the feces of MS patients (Cantoni et al., 2022), SCFAs positively correlate with Treg levels (Zeng et al., 2019). SCFAs increase the number of regulatory T cells (Park et al., 2019), and decrease clinical activity in MS patients (Park et al., 2019). Lower levels of acetic acid in feces and plasma were observed in MS patients in Park et al. (2019) and Zeng et al. (2019). In a study by Pérez et al. acetate levels were found to be negatively correlated with CD4+ Treg cells and positively correlated with CD8+ Treg cells (Pérez-Pérez et al., 2020). Not only that, MS patients had lower levels of propionic acid in feces and plasma (Park et al., 2019; Zeng et al., 2019; Duscha et al., 2020; Takewaki et al., 2020; Trend et al., 2021), but MS patients continued to have a significant increase in T-cell counts and a decrease in Th1 and Th17 cell counts after 2 weeks of propionic acid ingestion. Propionic acid ingestion for 3 years reduced MS annual relapses and stabilized the disease (Duscha et al., 2020). Similarly, fecal and plasma levels of butyric acid have been found to be reduced in MS patients in several studies (Park et al., 2019; Zeng et al., 2019; Ling et al., 2020; Saresella et al., 2020; Takewaki et al., 2020), and Clostridium butyricum treatment decreased Th17 responses and increased Treg responses in EAE mice (Chen et al., 2019). And elevated fecal and plasma caproic acid (Saresella et al., 2020). Caproic acid was positively correlated with CD4+/ nterferon-γ (IFNγ) + T cells, and the butyric acid/caproic acid ratio was positively correlated with CD4+/CD25high/Foxp3+ and negatively correlated with CD4+/IFNγ+ T lymphocytes (Saresella et al., 2020). However, there is disagreement about acetic and butyric acid levels in MS, and Pérez et al. examined SCFA levels in plasma from Spanish patients and found a significant increase in acetic acid levels (Pérez-Pérez et al., 2020). Olsson et al. studied 58 patients and found a significant elevation of butyric acid in their plasma (Olsson et al., 2021).

The results of recent animal studies have shown that the gut metabolite bile acids, taurine deoxycholic acid (TUDCA), has a good therapeutic advantage in neurological disorders due to its neuroprotective properties, nontoxic nature, and ability to cross the blood–brain barrier (Grant and DeMorrow, 2020). Bhargava et al. performed cellular experiments and found that bile acid receptor expression was enhanced in immune and neuroglial cells from MS patients, and supplementation of cells and mice with TUDCA revealed that TUDCA alleviated symptoms in MS patients by modulating the bile acid receptor G protein-coupled bile acid receptor 1 (GPBAR1; Bhargava et al., 2020). TUDCA was found to inhibit inflammatory responses in C57BL/6 mice by suppressing astrocyte hyperactivation in the cerebral cortex of EAE mice through the G-protein coupled bile acid receptor Gpbar1/ threonine kinase/ I (TGR5/AKT/NF-KB) signaling pathway (Xu et al., 2023). Another study also found that TUDCA supplementation increased circulating levels of several bile acids, affected peripheral immune phenotypes, and altered gut microbiota (Ladakis et al., 2024). In a mouse model of EAE, agonism of GPBAR1 was found to reduce the number of monocytes and T cells in the CNS and to reduce monocyte and microglia activation in the CNS as well as monocyte activation in the periphery, and a reduction in the severity of the disease in EAE was found to be detected by clinical scores (Lewis et al., 2014).

In addition to SCFA and bile acids, elevated gut metabolite Trp is associated with multiple sclerosis compared to healthy controls (Nourbakhsh et al., 2018). EAE animal studies found that the number of IL-17- and IFNγ-producing CD4+ T cells was reduced at low tryptophan levels, whereas colonization of Lactobacillus reueriat high tryptophan levels increased the number and frequency of TCRγδ cells and increased IL-17 production, suggesting that Lactobacillus reueritryptophan metabolism promotes host susceptibility to CNS autoimmunity (Montgomery et al., 2022). Metabolism of the canine uridine pathway is an important pathway for Trp involvement in the regulation of immunity, neurological function, and intestinal homeostasis (Platten et al., 2019), Includes kynurenine (KA) and quinolinic acid (QA) as neuroactive kynurenine pathway metabolites with neuroprotective and neurotoxic properties respectively (Zheng et al., 2022). A study in Italy found that urinary kynurenine concentrations in MS patients were significantly lower than in the HC group (Gaetani et al., 2020). T-cell suppression mediated by IDO-1 in MS patients leads to MS progression through the production of excitotoxic QA (and increased QA/KA ratio) by infiltrating macrophages (Lim et al., 2017).

Other gut metabolites such as changes in the metabolism of aromatic amino acids (AAA) in MS patients, the AAA-derived lactate metabolite ILA reduces pro-inflammatory cytokine interleukin-6(IL-6) and IL-1β production and ameliorates worsening MS severity (Fitzgerald et al., 2021). Lipopolysaccharide (LPS) catabolism was higher in MS participants compared to HC group (Mirza et al., 2022). In EAE mice, LPS-induced dendritic cell (DC) apoptosis inhibits Th17 and IFN-γ cell activity and blocks myelin oligodendrocyte glycoprotein (MOG)-triggered CD4+ T-cell activation in vivo, thereby inhibiting the development of EAE (Zhou et al., 2014).

In summary, there is growing evidence that gut microbiota and their metabolites can communicate with the host via T cells and that T cell-mediated immune pathways play a large role in controlling the host immune system and inflammation. We believe that changes in metabolites from gut microbiota may be a key way to understand how gut microbiota and MS “talk to each other.” However, there is still much uncertainty about this issue.

Recent evidence from microbiology suggests that mitochondria originate with the phylum α-Ascomycetes and that there is a close connection between gut microbiota and mitochondria, despite the different roles of mitochondria and gut microbiota (Bajpai et al., 2018; Murphy and O’Neill, 2024). Bidirectional communication exists between gut microbiota and mitochondria, and gut microbiota has become a dynamic central regulator of mitochondrial function whereas mitochondria are the most responsive organelles to microbial signaling (Jackson and Theiss, 2020).

Gut microbiota and their metabolites can regulate mitochondrial energy metabolism, ROS production, and immune-inflammatory responses by participating in the Borbolis et al. (2023) and Endres and Friedland (2023). Li et al. found that butyrate can induce mitochondrial autophagy through the activation of adenylate-activated protein kinase (AMPK), thereby attenuating hydrogen peroxide- (H₂O₂-)induced oxidative stress, intestinal epithelial barrier damage, and mitochondrial dysfunction (Li X. et al., 2022). Alterations in butyrate may affect glial cells, leading to mitochondrial dysfunction in microglia and oligodendrocytes, which up-regulates oxidants and reduces their ability to cope with oxidants, thereby inhibiting myelin synthesis in MS disease (Anderson et al., 2019). MS patients ingesting propionic acid for 2 weeks showed a significant increase in Treg cells and a significant decrease in Th1 and Th17 cells, restoring mitochondrial respiration in MS (Duscha et al., 2020). Therefore, it is hypothesized that propionic acid may ameliorate MS symptoms by modulating mitochondrial function in T cells. In studies of atherosclerotic disease, it has been found that short-chain fatty acids, trimethylamine, and bile acids can affect mitochondrial DNA (mtDNA) mutations, oxidative stress, and alterations in mitochondrial autophagy, thereby increasing inflammation, further disrupting intracellular homeostasis and innate immune homeostasis, and exacerbating atherosclerosis (Li et al., 2023). Dysbiosis of gut microbiota causes translocation of molecular patterns associated with pathogens of bacterial origin (bacterial metabolites, bacterial vesicles, and even bacteria) into neurons of the central nervous system, which affects neuronal function through mitochondrial autophagy and ultimately contributes to the development of Parkinson’s disease (Magalhães et al., 2023). Gut microbiota metabolism may lead to altered mitochondrial function or disturbances in mitochondrial quality control, which may alleviate or accelerate the progression of diabetic nephropathy (Ma et al., 2023).

Mitochondrial ROS production, kinetic disorganization, and respiration play important roles in the composition of the gut microbiota (Saint-Georges-Chaumet and Edeas, 2016). Cao et al. used Lactobacillus plantarum ZJUIDS14 to intervene in a Non-alcoholic Fatty Liver Disease (NAFLD) model mouse and found that the increase in the relative abundance of Roseburia in the feces of the model mice also increased Drp 1 and decreased the mitochondrial oxidative phosphorylation (OXPHOS) thereby improving mitochondrial function and ultimately attenuating high-fat diet-associated hepatic steatosis, and liver injury (Cao et al., 2022). Drp1 induces ROS accumulation in IECs potentially leading to aberrant composition of the anaplastic bacillus population and reduced production of SCFAs (Duan et al., 2020). In contrast, inhibition of Drp1 by P110 treatment reduced TNF-α or H2O2-induced mitochondrial damage and prevented demyelination in EAE-immunized mice (Luo et al., 2017). It was found that mtDNA defects as well as changes in mitochondrial structure and function can modulate gut microbiota to influence MS progression (Mahad et al., 2008). For example, other mouse strains carrying different mtDNA variants such as C57BL/6, ND6 P25L/(C57BL/6 J), and mt-129(C57BL/6 J) regulate the composition of the gut microbiota by altering the mitochondrial redox state and the associated ROS production (Yardeni et al., 2019). Similarly, mitochondria can produce ROS during OXPHOS respiration, and studies using mice carrying different mtDNA variants have found differences in the composition of gut microbiota due to reduced OXPHOS respiration and increased glycolysis (Hirose et al., 2017).

Thus, these results suggest that establishing the crosstalk between gut microbiota and mitochondria is critical to understanding the complex and evolving interactions between gut microbiota and mitochondria and the host. By targeting the crosstalk between gut microbiota and mitochondria, a range of diseases associated with disorders of gut microbiota and mitochondria can be treated more precisely (e.g., Figure 1).

As mentioned previously, although both mitochondrial dysfunction and alterations in gut microbiota have been associated with the pathogenesis of MS, it is uncertain whether the gut microbiota transmits signals to the mitochondria to contribute to the development of MS. Therefore, based on the current findings, we propose a potential mechanism by which gut microbiota-mitochondrial crosstalk plays an important role in the pathogenesis of MS (Figure 2). In this crosstalk with the degradation, digestion, and absorption of food by the gut microbiota, the use of probiotics, and fecal transplants, a variety of gut microbiota metabolites are produced in response to the gut microbiota and then enter the circulatory system. These gut microbiota metabolites, such as SCFAs cross the blood–brain barrier to reach the brain and interact with the brain’s mitochondria. Metabolites of gut microbiota may lead to altered mitochondrial function, which may alleviate or accelerate the progression of MS.