Printed Poster | Session 1

023 – Fecal Transplantation from Alcoholic Hepatitis Patients Drives Systemic and Brain Inflammation

Ben Charpentier (1) – John Greenwell (2) – Paula Chilton (2) – Richa Signal (2) – Manicka Vadhanam (2) – Smita Ghare (2) – Scott Myers (3) – Swati Joshi-Barve (2) – Craig McClain (2, 4) – Leila Gobejishvili (2) – Scott Whittemore (1, 3) – Shirish Barve (1,2)
Departments of Anatomical Sciences and Neurobiology (1) – Departments of Medicine (2) – Departments of Neurological Surgery; University of Louisville (3) – VA Medical Center, Louisville, KY 40202 (4)

Negative effects of alcohol consumption on the nervous system include neuroinflammation that may contribute to cognitive decline and neurodegeneration. Perturbations in the gut microbiome play a role in Alzheimer’s and Parkinson’s diseases, but the role of the microbiome in ethanol-induced neuroinflammation is yet to be elucidated. In this study, we assessed the direct role of alcohol-induced gut microbial dysbiosis in the development of neuroinflammation. Fecal samples from patients with AH were well characterized by metagenomics analysis which revealed severe reduction of diversity and loss of beneficial bacteria. Development of neuroinflammation with and without chronic ethanol feeding in response to AH fecal matter transplantion (AH- FMT) was examined using conventional mice. Systemic inflammation and increased neutrophils in the circulation, liver and brain were induced by AH fecal transplantation. Particularly, immune cells isolated from the brains of AH-transplanted mice that were fed ethanol showed a decrease in the critical anti-inflammatory cytokine IL-10. Moreover, AH microbiome alone led to an increase in CD4:CD8 T-cell ratio in the brain parenchyma that was predominated by the CD4 T-cell expansion. In contrast, in AH-FMT mice fed ethanol, the ratio increased due to CD8 T cell depletion. Furthermore, immunohistochemical analysis showed that AH microbiome by itself induced neuroinflammation, as documented by an increase in reactive astrocytes and morphological changes in microglia as well as an up regulation of the inflammatory marker COX-2. These neuro inflammatory changes were further enhanced by ethanol feeding, demonstrating a more severe phenotype. Significantly, all the pathological changes induced by the AH fecal transplant were absent in animals receiving fecal transplantation from control non-alcoholic individuals. These data strongly indicate that the alcohol-induced changes in the gut microbiome play a causal role in the pathological changes in the gut-liver-brain axis and development of neuro-inflammation. Importantly, these data also indicate that the gut may be a potential therapeutic target in the treatment of alcohol-induced neuro-inflammation.
Supported by NIH/NIAAA U01 AA022618 (SB), Commonwealth of Kentucky Challenge for Excellence, Norton Healthcare (SRW)