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

• Published in: Cell reports (Cambridge) 2024-11, Vol.43 (11), p.114891, Article 114891
• Main Authors: Alexander, Margaret, Upadhyay, Vaibhav, Rock, Rachel, Ramirez, Lorenzo, Trepka, Kai, Puchalska, Patrycja, Orellana, Diego, Ang, Qi Yan, Whitty, Caroline, Turnbaugh, Jessie A., Tian, Yuan, Dumlao, Darren, Nayak, Renuka, Patterson, Andrew, Newman, John C., Crawford, Peter A., Turnbaugh, Peter J.
• Format: Article
• Language: English
• Subjects: 3-Hydroxybutyric Acid - metabolism; 3-Hydroxybutyric Acid - pharmacology; Animals; autoimmune disease; Autoimmunity; Diet, Ketogenic; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - metabolism; Encephalomyelitis, Autoimmune, Experimental - microbiology; Female; Gastrointestinal Microbiome; gut microbiome; immune activation; ketogenesis; ketogenic diet; lactobacillus; Lactobacillus - metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; multiple sclerosis; neuroinflammation; nutrition; Th17 Cells - immunology; Th17 Cells - metabolism; trytophan metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114891

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. [Display omitted] •Ketogenic diets rescue neuroinflammation in a microbiota-dependent manner•The diet-induced host metabolite β-hydroxybutyrate (βHB) is necessary and sufficient•Transfer of the βHB-associated microbiota protects against neuroinflammation•Gut bacterial indole lactate contributes to these neuroprotective effects Identifying the optimal diet for patients suffering from autoimmune disease remains challenging. Here, Alexander and colleagues dissect the complex host-microbiome interactions, explaining the protective effects of a ketogenic diet for a mouse model of neuroinflammation. They highlight the importance of host β-hydroxybutyrate and bacterial indole lactate, inspiring more precise interventions.