Human microbiome-derived peptide affects the development of experimental autoimmune encephalomyelitis via molecular mimicry

Abstract

BackgroundGut commensal microbiota has been identified as a potential environmental risk factor for multiple sclerosis (MS), and numerous studies have linked the commensal microorganism with the onset of MS. However, little is known about the mechanisms underlying the gut microbiome and host-immune system interaction. MethodsWe employed bioinformatics methodologies to identify human microbial-derived peptides by analyzing their similarity to the MHC II-TCR binding patterns of self-antigens. Subsequently, we conducted a range of in vitro and in vivo assays to assess the encephalitogenic potential of these microbial-derived peptides. FindingsWe analyzed 304,246 human microbiome genomes and 103 metagenomes collected from the MS cohort and identified 731 nonredundant analogs of myelin oligodendrocyte glycoprotein peptide 35-55 (MOG35-55). Of note, half of these analogs could bind to MHC II and interact with TCR through structural modeling of the interaction using fine-tuned AlphaFold. Among the 8 selected peptides, the peptide (P3) shows the ability to activate MOG35-55-specific CD4+ T cells in vitro. Furthermore, P3 shows encephalitogenic capacity and has the potential to induce EAE in some animals. Notably, mice immunized with a combination of P3 and MOG35-55 develop severe EAE. Additionally, dendritic cells could process and present P3 to MOG-specific CD4+ T cells and activate these cells. InterpretationOur data suggests the potential involvement of a MOG35-55-mimic peptide derived from the gut microbiota as a molecular trigger of EAE pathogenesis. Our findings offer direct evidence of how microbes can initiate the development of EAE, suggesting a potential microbiome-based therapeutic target for inhibiting the progression of MS. FundingNational Natural Science Foundation of China (82371350 to GY) Research in contextO_ST_ABSEvidence before this studyC_ST_ABSOn July 31, 2024, we conducted a search on PubMed for articles containing the phrases "gut microbiome and multiple sclerosis" and "gut microbiome and experimental autoimmune encephalomyelitis." This search yielded a total of 630 and 151 articles, respectively, indicating that the relationship between gut microbiota and the development of MS and EAE is well established. In contrast, our search for "gut microbiome and molecular mimicry and experimental autoimmune encephalomyelitis" revealed only two review papers, highlighting a significant gap in the literature regarding the role of molecular mimicry in connecting gut microbiome dynamics to the development of EAE. Added value of this studyIn this study, we employed bioinformatics tools to screen for microbial-derived peptides in the gut that potentially cross-react with autoantigen-specific TCR. Our key findings include: 1) Identification of MOG35-55 mimics within the human gut microbiome by employing a combination of TCR-binding footprint screening and prediction model of peptide-MHC II-TCR complexes; 2) Microbial-derived MOG35-55 mimics can cross-react with MOG35-55-specific CD4+ T cells; 3) Among them, peptide 3 predicted from Akkermansia muciniphila can induce moderate EAE in mice; 4) Dendritic cells could process and present peptide 3 to MOG-specific CD4+ T cells and activate these cells. Implications of all the available evidenceThis study suggests the potential involvement of a MOG35-55-mimic peptide derived from the gut microbiota as a molecular trigger of EAE pathogenesis. These data may provide a potential microbiome-based therapeutic target for inhibiting the progression of MS.