Evaluation of individual FMT as a potential therapeutic to reduce ethanol drinking in mice

Summary
Few safe and effective pharmacotherapies exist for alcohol misuse. Alcohol consumption directly effects the
gut microbiome, altering its diversity and leading to increased bacterial overgrowth. Chronic drinking leads to
microbial dysbiosis, intestinal permeability (“leaky gut”) and changes in immune responses. These microbiome
changes have been associated with other neuropsychiatric symptoms such as anxiety and depression,
frequently associated alcohol misuse symptomology. A growing number of clinical and pre-clinical studies have
provided remarkable promise using fecal microbiota transplant (FMT) as a safe, effective therapy for reducing
ethanol drinking and liver disease. Our own collaborative efforts have recently shown that FMT improved
drinking behavior in humans with cirrhosis, and this was transmissible to germ-free mice through alterations in
the gut immune-inflammatory response. Since fecal transplant of microbiota from patients with AUD can
change the intestinal barrier and affect brain function, we hypothesize that gut microbiota enriched in beneficial
bacteria can reduce ethanol drinking and related anxiety-like behaviors. Dietary fiber may further enhance this
effect by increasing microbial engraftment or length of its effect. This innovative mPI proposal brings together
the specific expertise of human clinical laboratories experienced in using therapeutic FMT and a rodent
behavioral pharmacology laboratory to understand the specific characteristics of gut microbiota needed to
reduce ethanol intake and preference. In Aim 1, we will assess the effects of microbiota transplant into
recipient mice from human donor with varying amounts of Lachnospiraceae and Ruminococcaceae on ethanol
drinking, FMT engraftment and anxiety-like behavior. Four human donor samples will be assessed which differ
in the amount Lachnospiraceae and Ruminococcaceae. In Aim 2, we will evaluate the role of dietary fiber on
microbiome engraftment and its ability to further reduce ethanol drinking in mice. These innovative studies are
an important first step in understanding the mechanisms through which gut microbiota can positively affect the
gut-brain-axis to reduce ethanol drinking and related phenotypes. These studies will establish a pre-clinical
model of therapeutic FMT where we can begin to test the specific mechanisms of these drinking reductions.

Grant Number: 5R21AA031293-02
NIH Institute/Center: NIH
Principal Investigator: Jasmohan Bajaj