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.