A diet-dependent host metabolite shapes the gut microbiota to protect from autoimmunity

Margaret Alexander; Vaibhav Upadhyay; Rachel Rock; Lorenzo Ramirez; Kai Trepka; Patrycja Puchalska; Diego Orellana; Qi Yan Ang; Caroline Whitty; Jessie A Turnbaugh; Yuan Tian; Darren Dumlao; Renuka Nayak; Andrew Patterson; John C Newman; Peter A Crawford; Peter J Turnbaugh

doi:10.1016/j.celrep.2024.114891

A diet-dependent host metabolite shapes the gut microbiota to protect from autoimmunity

Cell Rep. 2024 Nov 26;43(11):114891. doi: 10.1016/j.celrep.2024.114891. Epub 2024 Nov 4.

Authors

Margaret Alexander¹, Vaibhav Upadhyay², Rachel Rock³, Lorenzo Ramirez³, Kai Trepka³, Patrycja Puchalska⁴, Diego Orellana⁵, Qi Yan Ang³, Caroline Whitty³, Jessie A Turnbaugh³, Yuan Tian⁶, Darren Dumlao⁵, Renuka Nayak⁷, Andrew Patterson⁶, John C Newman⁸, Peter A Crawford⁹, Peter J Turnbaugh¹⁰

Affiliations

¹ Department of Microbiology & Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Medical Microbiology and Immunology, University of Wisconsin - Madison, Madison, WI 53706, USA.
² Department of Microbiology & Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA.
³ Department of Microbiology & Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.
⁴ Division of Molecular Medicine, University of Minnesota, Minneapolis, MN 55455, USA.
⁵ Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA.
⁶ Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802, USA.
⁷ Department of Medicine, University of California, San Francisco, San Francisco, CA 94158, USA; San Francisco VA Medical Center, San Francisco, CA 94121, USA.
⁸ Buck Institute for Research on Aging, Novato, CA 94945, USA; Division of Geriatrics, University of California, San Francisco, San Francisco, CA 94158, USA.
⁹ Division of Molecular Medicine, University of Minnesota, Minneapolis, MN 55455, USA; Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, MN 55455, USA.
¹⁰ Department of Microbiology & Immunology, University of California, San Francisco, San Francisco, CA 94143, USA; Chan Zuckerberg Biohub - San Francisco, San Francisco, CA 94158, USA. Electronic address: peter.turnbaugh@ucsf.edu.

Abstract

Diet can protect from autoimmune disease; however, whether diet acts via the host and/or microbiome remains unclear. Here, we use a ketogenic diet (KD) as a model to dissect these complex interactions. A KD rescued the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis in a microbiota-dependent fashion. Dietary supplementation with a single KD-dependent host metabolite (β-hydroxybutyrate [βHB]) rescued EAE, whereas transgenic mice unable to produce βHB in the intestine developed more severe disease. Transplantation of the βHB-shaped gut microbiota was protective. Lactobacillus sequence variants were associated with decreased T helper 17 cell activation in vitro. Finally, we isolated an L. murinus strain that protected from EAE, which was phenocopied by a Lactobacillus metabolite enriched by βHB supplementation, indole lactate. Thus, diet alters the immunomodulatory potential of the gut microbiota by shifting host metabolism, emphasizing the utility of taking a more integrative approach to study diet-host-microbiome interactions.

Keywords: CP: Immunology; CP: Microbiology; autoimmune disease; gut microbiome; immune activation; ketogenesis; ketogenic diet; lactobacillus; multiple sclerosis; neuroinflammation; nutrition; trytophan metabolism.

MeSH terms

3-Hydroxybutyric Acid / metabolism
3-Hydroxybutyric Acid / pharmacology
Animals
Autoimmunity*
Diet, Ketogenic*
Encephalomyelitis, Autoimmune, Experimental* / immunology
Encephalomyelitis, Autoimmune, Experimental* / metabolism
Encephalomyelitis, Autoimmune, Experimental* / microbiology
Female
Gastrointestinal Microbiome*
Lactobacillus / metabolism
Mice
Mice, Inbred C57BL
Mice, Transgenic
Th17 Cells / immunology
Th17 Cells / metabolism

Substances

3-Hydroxybutyric Acid