David Weiss, PhD, Emory Antibiotic Resistance Center, Emory University School of Medicine, Atlanta, Georgia. [e-mail] & Arash Grakoui, PhD, Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia. [e-mail]

• 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
• Journal Title: bioRxiv
• Publisher: NIH | 2023-09-01
• Type of Work: Article | Preprint: Prior to Peer Review
• Publisher DOI: http://doi.org/10.1101/2023.08.30.555630
• Subjects: Biology, Neuroscience
• Keywords: gut-brain axis; microbiome; intestinal permeability; bacterial translocation; vagus nerve; brain

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.