Translocation of gut commensal bacteria to the brain

• Type of Material: Article
• Authors: Manoj Thapa, Emory University; Anuradha Kumari, Emory University; Chui-Yoke Chin, Emory University; Jake Choby, Emory University; Fengzhi Jin, Emory University; Bikash Bogati, Emory University; Daniel M. Chopyk, Emory University; Nitya Koduri, Emory University; Andrew Pahnke, Emory Unviersity; Elizabeth J. Elrod, Emory University; Eileen Burd, Emory University; David S Weiss, Emory University; Arash Grakoui, Emory University
• Language: English
• Date: 2023-09-01
• Publisher: NIH
• Publication Version: Preprint (Prior to Peer Review)
• Copyright Statement: The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): https://doi.org/10.1101%2F2023.08.30.555630
• Title of Journal or Parent Work: bioRxiv
• Grant/Funding Information: This project was supported by NIH grants R01AI124680, R01AI126890, R01AI136533, U19AI159819 to A.G., ORIP/OD P51OD011132 (formerly NCRR P51RR000165) to the Emory National Primate Research Center (A.G.), and a Burroughs Wellcome Fund Investigator in the Pathogenesis of Infectious Disease award (D.S.W.). M.T. was supported by National Institute of Diabetes, and Digestive and Kidney Diseases (NIDDK) Mentored Career Development Award (K01DK109025). A.K. is supported by Alzheimer’s Association Fellowship (AARFD-23-1145367). This work was facilitated by the Immunology and Flow Cytometry Core of the Center for AIDS Research at Emory University (P30AI050409). J.E.C. was supported by T32DK108735 from NIDDK and the Cystic Fibrosis Foundation (CHOBY19F0).
• Keywords: intestinal permeability; microbiome; brain; gut-brain axis; bacterial translocation; vagus nerve

Abstract

The gut-brain axis, a bidirectional signaling network between the intestine and the central nervous system, is crucial to the regulation of host physiology and inflammation. Recent advances suggest a strong correlation between gut dysbiosis and neurological diseases, however, relatively little is known about how gut bacteria impact the brain. Here, we reveal that gut commensal bacteria can translocate directly to the brain when mice are fed an altered diet that causes dysbiosis and intestinal permeability, and that this also occurs without diet alteration in distinct murine models of neurological disease. The bacteria were not found in other systemic sites or the blood, but were detected in the vagus nerve. Unilateral cervical vagotomy significantly reduced the number of bacteria in the brain, implicating the vagus nerve as a conduit for translocation. The presence of bacteria in the brain correlated with microglial activation, a marker of neuroinflammation, and with neural protein aggregation, a hallmark of several neurodegenerative diseases. In at least one model, the presence of bacteria in the brain was reversible as a switch from high-fat to standard diet resulted in amelioration of intestinal permeability, led to a gradual loss of detectable bacteria in the brain, and reduced the number of neural protein aggregates. Further, in murine models of Alzheimer’s disease, Parkinson’s disease, and autism spectrum disorder, we observed gut dysbiosis, gut leakiness, bacterial translocation to the brain, and microglial activation. These data reveal a commensal bacterial translocation axis to the brain in models of diverse neurological diseases.