Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models
Egle Cekanaviciute, Bryan B Yoo, Tessel F Runia, Justine W Debelius, Sneha Singh, Charlotte A Nelson, Rachel Kanner, Yadira Bencosme, Yun Kyung Lee, Stephen L Hauser, Elizabeth Crabtree-Hartman, Ilana Katz Sand, Mar Gacias, Yunjiao Zhu, Patrizia Casaccia, Bruce A C Cree, Rob Knight, Sarkis K Mazmanian, Sergio E Baranzini, Egle Cekanaviciute, Bryan B Yoo, Tessel F Runia, Justine W Debelius, Sneha Singh, Charlotte A Nelson, Rachel Kanner, Yadira Bencosme, Yun Kyung Lee, Stephen L Hauser, Elizabeth Crabtree-Hartman, Ilana Katz Sand, Mar Gacias, Yunjiao Zhu, Patrizia Casaccia, Bruce A C Cree, Rob Knight, Sarkis K Mazmanian, Sergio E Baranzini
Abstract
The gut microbiota regulates T cell functions throughout the body. We hypothesized that intestinal bacteria impact the pathogenesis of multiple sclerosis (MS), an autoimmune disorder of the CNS and thus analyzed the microbiomes of 71 MS patients not undergoing treatment and 71 healthy controls. Although no major shifts in microbial community structure were found, we identified specific bacterial taxa that were significantly associated with MS. Akkermansia muciniphila and Acinetobacter calcoaceticus, both increased in MS patients, induced proinflammatory responses in human peripheral blood mononuclear cells and in monocolonized mice. In contrast, Parabacteroides distasonis, which was reduced in MS patients, stimulated antiinflammatory IL-10-expressing human CD4+CD25+ T cells and IL-10+FoxP3+ Tregs in mice. Finally, microbiota transplants from MS patients into germ-free mice resulted in more severe symptoms of experimental autoimmune encephalomyelitis and reduced proportions of IL-10+ Tregs compared with mice "humanized" with microbiota from healthy controls. This study identifies specific human gut bacteria that regulate adaptive autoimmune responses, suggesting therapeutic targeting of the microbiota as a treatment for MS.
Keywords: autoimmunity; microbiome; multiple sclerosis.
Conflict of interest statement
The authors declare no conflict of interest.
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References
- Lee YK, Mazmanian SK. Has the microbiota played a critical role in the evolution of the adaptive immune system? Science. 2010;330:1768–1773.
- Faith JJ, Ahern PP, Ridaura VK, Cheng J, Gordon JI. Identifying gut microbe-host phenotype relationships using combinatorial communities in gnotobiotic mice. Sci Transl Med. 2014;6:220ra11.
- Round JL, Mazmanian SK. Inducible Foxp3+ regulatory T-cell development by a commensal bacterium of the intestinal microbiota. Proc Natl Acad Sci USA. 2010;107:12204–12209.
- Lozupone CA, et al. Alterations in the gut microbiota associated with HIV-1 infection. Cell Host Microbe. 2013;14:329–339.
- Chu H, et al. Gene-microbiota interactions contribute to the pathogenesis of inflammatory bowel disease. Science. 2016;352:1116–1120.
- Varrin-Doyer M, et al. Aquaporin 4-specific T cells in neuromyelitis optica exhibit a Th17 bias and recognize Clostridium ABC transporter. Ann Neurol. 2012;72:53–64.
- Scher JU, et al. Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. Elife. 2013;2:e01202.
- Gevers D, et al. The treatment-naive microbiome in new-onset Crohn’s disease. Cell Host Microbe. 2014;15:382–392.
- Cantarel BL, et al. Gut microbiota in multiple sclerosis: Possible influence of immunomodulators. J Investig Med. 2015;63:729–734.
- Miyake S, et al. Dysbiosis in the gut microbiota of patients with multiple sclerosis, with a striking depletion of species belonging to Clostridia XIVa and IV clusters. PLoS One. 2015;10:e0137429.
- Tremlett H, et al. US Network of Pediatric MS Centers Gut microbiota composition and relapse risk in pediatric MS: A pilot study. J Neurol Sci. 2016;363:153–157.
- Jangi S, et al. Alterations of the human gut microbiome in multiple sclerosis. Nat Commun. 2016;7:12015.
- Berer K, et al. Commensal microbiota and myelin autoantigen cooperate to trigger autoimmune demyelination. Nature. 2011;479:538–541.
- Lee YK, Menezes JS, Umesaki Y, Mazmanian SK. Proinflammatory T-cell responses to gut microbiota promote experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA. 2011;108:4615–4622.
- Simmons SB, Pierson ER, Lee SY, Goverman JM. Modeling the heterogeneity of multiple sclerosis in animals. Trends Immunol. 2013;34:410–422.
- Carbajal KS, et al. Th cell diversity in experimental autoimmune encephalomyelitis and multiple sclerosis. J Immunol. 2015;195:2552–2559.
- Kverka M, et al. Oral administration of Parabacteroides distasonis antigens attenuates experimental murine colitis through modulation of immunity and microbiota composition. Clin Exp Immunol. 2011;163:250–259.
- Geuking MB, et al. Intestinal bacterial colonization induces mutualistic regulatory T cell responses. Immunity. 2011;34:794–806.
- Peleg AY, Seifert H, Paterson DL. Acinetobacter baumannii: Emergence of a successful pathogen. Clin Microbiol Rev. 2008;21:538–582.
- Almeida LA, Araujo R. Highlights on molecular identification of closely related species. Infect Genet Evol. 2013;13:67–75.
- Hughes LE, et al. Cross-reactivity between related sequences found in Acinetobacter sp., Pseudomonas aeruginosa, myelin basic protein and myelin oligodendrocyte glycoprotein in multiple sclerosis. J Neuroimmunol. 2003;144:105–115.
- Everard A, et al. Microbiome of prebiotic-treated mice reveals novel targets involved in host response during obesity. ISME J. 2014;8:2116–2130.
- Ganesh BP, Klopfleisch R, Loh G, Blaut M. Commensal Akkermansia muciniphila exacerbates gut inflammation in Salmonella Typhimurium-infected gnotobiotic mice. PLoS One. 2013;8:e74963.
- Hua J, Davis SP, Hill JA, Yamagata T. Diverse gene expression in human regulatory T cell subsets uncovers connection between regulatory T cell genes and suppressive function. J Immunol. 2015;195:3642–3653.
- Berer K, et al. (2017) Gut microbiota from multiple sclerosis patients enables spontaneous autoimmune encephalomyelitis in mice. Proc Nat Acad Sci USA 10.1073/pnas1711233114.
- Wang Y, et al. A commensal bacterial product elicits and modulates migratory capacity of CD39(+) CD4 T regulatory subsets in the suppression of neuroinflammation. Gut Microbes. 2014;5:552–561.
- Arpaia N, et al. Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature. 2013;504:451–455.
- Rothhammer V, et al. Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat Med. 2016;22:586–597.
- Erny D, et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat Neurosci. 2015;18:965–977.
- Sampson TR, et al. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell. 2016;167:1469–1480.e1412.
- Derrien M, Belzer C, de Vos WM. Akkermansia muciniphila and its role in regulating host functions. Microb Pathog. 2016;106:171–181.
- Miller PG, Bonn MB, Franklin CL, Ericsson AC, McKarns SC. TNFR2 deficiency acts in concert with gut microbiota to precipitate spontaneous sex-biased central nervous system demyelinating autoimmune disease. J Immunol. 2015;195:4668–4684.
- Hughes LE, et al. Antibody responses to Acinetobacter spp. and Pseudomonas aeruginosa in multiple sclerosis: Prospects for diagnosis using the myelin-acinetobacter-neurofilament antibody index. Clin Diagn Lab Immunol. 2001;8:1181–1188.
- Derfuss T, Meinl E. Identifying autoantigens in demyelinating diseases: Valuable clues to diagnosis and treatment? Curr Opin Neurol. 2012;25:231–238.
- Cree BA, Spencer CM, Varrin-Doyer M, Baranzini SE, Zamvil SS. Gut microbiome analysis in neuromyelitis optica reveals overabundance of Clostridium perfringens. Ann Neurol. 2016;80:443–447.
- Ridaura VK, et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science. 2013;341:1241214.
- Sokol H, et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci USA. 2008;105:16731–16736.
Source: PubMed