Profiling Microbial Metabolites To Elucidate The Relationship Between SCFAs, Intestinal Permeability, and Alcohol

The community of bacteria populating the gut, the gut microbiota, recently emerged as a major modulator of neuropsychiatric phenotypes. The gut microbiota are implicated in several substance use disorders including alcohol use disorder. Alcohol consumption alters the gut microbiota, the population of bacteria that colonize the gastrointestinal tract. One study found that altered gut microbiota in abstinent individuals with alcohol use disorder predicted worse withdrawal symptoms and likelihood of relapse. The same individuals showed greater intestinal permeability, a phenotype that is also modulated by the gut microbiota and can lead to systemic inflammation. This finding suggests that intestinal permeability may also play a role in behavioral aspects of alcohol consumption, consistent with the neuroinflammatory effects of alcohol. Evidence in rodents suggests that differences in the types of bacteria populating the gut can predict alcohol consumption and related gene expression in the brain. Dietary changes, fecal microbial transplantation, or antibiotic administration have been reported to modulate alcohol consumption or withdrawal symptoms in rodents. Prebiotics are a type of fiber that “feeds” beneficial bacteria in the gastrointestinal tract, promoting healthy microbiota. Incorporation of prebiotics into the diet protects against alcohol-induced changes in the microbiota and leakage of bacteria from the gastrointestinal tract that leads to systemic inflammation. Recent work found that prebiotics reduced signs of withdrawal from chronic alcohol consumption in rats, suggesting that prebiotics could influence behavioral consequences of chronic alcohol consumption. Indeed, prebiotics ameliorate stress-induced anxiety- and depression-like behavior and gene expression in the brain of rodents. However, there are multiple candidate mechanisms for a role of prebiotics in alcohol use behaviors. One possibility is that prebiotic-induced fortification of the intestinal lining reduces downstream neuroimmune effects, which are heavily implicated in alcohol use behaviors. Another possibility is that prebiotics facilitate production of short-chain fatty acids (SCFAs) that enter circulation and affect central signaling directly. SCFAs are metabolites produced by the beneficial bacteria that increase in growth by fermenting prebiotics. SCFAs play a causal role in maintaining the lining of the gastrointestinal tract and protecting it from alcohol-induced injury. Furthermore, SCFA levels in the gut are reduced in chronic alcohol users and are restored by fecal transplant associated with decreased alcohol craving, but SCFA levels in the brain following alcohol intake have not been documented. Numerous studies have documented behavioral effects of SCFAs, which are known to cross the blood-brain barrier and be psychoactive, but the exact mechanisms of these effects remain incompletely understood. In addition, measuring SCFA levels can be challenging; SCFA levels are sparse in the brain, whereas fecal samples are highly complex in combination with the low molecular mass of SCFAs, together requiring innovative approaches for accurate measurement. These findings highlight the need for a better understanding of the role of SCFAs in alcohol use. Here, we seek to determine how prebiotics alter SCFA levels in the gut and brain in mice that chronically self-administered alcohol.