Mining the microbiota to identify gut commensals modulating neuroinflammation in a mouse model of multiple sclerosis

Abstract

Background The gut microbiome plays an important role in autoimmunity including multiple sclerosis and its mouse model called experimental autoimmune encephalomyelitis (EAE). Prior studies have demonstrated that the multiple sclerosis gut microbiota can contribute to disease, hence making it a potential therapeutic target. In addition, antibiotic treatment has been shown to ameliorate disease in the EAE mouse model of multiple sclerosis. Yet, to this date, the mechanisms mediating these antibiotic effects are not understood. Furthermore, there is no consensus on the gut-derived bacterial strains that drive neuroinflammation in multiple sclerosis. Results Here, we characterized the gut microbiome of untreated and vancomycin-treated EAE mice over time to identify bacteria with neuroimmunomodulatory potential. We observed alterations in the gut microbiota composition following EAE induction. We found that vancomycin treatment ameliorates EAE, and that this protective effect is mediated via the microbiota. Notably, we observed increased abundance of bacteria known to be strong inducers of regulatory T cells, including members of Clostridium clusters XIVa and XVIII in vancomycin-treated mice during the presymptomatic phase of EAE, as well as at disease peak. We identified 50 bacterial taxa that correlate with EAE severity. Interestingly, several of these taxa exist in the human gut, and some of them have been implicated in multiple sclerosis including Anaerotruncus colihominis, a butyrate producer, which had a positive correlation with disease severity. We found that Anaerotruncus colihominis ameliorates EAE, and this is associated with induction of RORγt+ regulatory T cells in the mesenteric lymph nodes. Conclusions We identified vancomycin as a potent modulator of the gut-brain axis by promoting the proliferation of bacterial species that induce regulatory T cells. In addition, our findings reveal 50 gut commensals as regulator of the gut-brain axis that can be used to further characterize pathogenic and beneficial host-microbiota interactions in multiple sclerosis patients. Our findings suggest that elevated Anaerotruncus colihominis in multiple sclerosis patients may represent a protective mechanism associated with recovery from the disease.

Decision Tree Ensembles Utilizing Multivariate Splits Are Effective at Investigating Beta-Diversity in Medically Relevant 16S Amplicon Sequencing Data

“…The abundance of this genus relative to the geometric mean of each sample suggests that high abundance will push samples to be less lesion-like. This is an encouraging result since work has shown that an elevated abundance of Anaerotruncus , a butyrate producer, may exert a protective effect by inhibiting glucose transport and glycolysis (65,66). Additional support for our method comes from the results of the Crohn’s disease dataset.…”

Decision Tree Ensembles Utilizing Multivariate Splits Are Effective at Investigating Beta Diversity in Medically Relevant 16S Amplicon Sequencing Data

“…The abundance of this genus relative to the geometric mean of each sample suggests that high abundance will push samples to be less lesion-like. This is an encouraging result, since work has shown that an elevated abundance of Anaerotruncus , a butyrate producer, may exert a protective effect by inhibiting glucose transport and glycolysis ( 50 , 51 ). Additional support for our method comes from the results of the Crohn’s disease data set.…”

The causality between gut microbiota and ankylosing spondylitis: Insights from a bidirectional two‐sample Mendelian randomization analysis

“…Although no research has been conducted on the effects of Anaerotruncus on inflammation in osteoarticular disease, Paola Bianchimano et al. discovered that increasing Anaerotruncus in patients with multiple sclerosis (MS) improved the disease, which may be related to the inflammatory suppressive effect of RORγt+ regulatory T cells in mesenteric lymph nodes 34 . The above two intestinal microorganisms' protective effect may be related to their production of short‐chain fatty acids (SCFA) 33,35 …”

“…discovered that increasing Anaerotruncus in patients with multiple sclerosis (MS) improved the disease, which may be related to the inflammatory suppressive effect of RORγt+ regulatory T cells in mesenteric lymph nodes. 34 The above two intestinal microorganisms' protective effect may be related to their production of short-chain fatty acids (SCFA). 33,35 SCFA has an important regulatory effect on the human body's energy homeostasis and immune cells' function.…”