Guardian, Intermediary, or Perpetrator? New Insights Into Environmental Exposure, the Gut Microbiome, and Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) affects more than 25% of the population, and is now the leading cause of liver-related morbidity and mortality worldwide. Its evolution represents the net sum of interactions between genetic and environmental factors. Two ubiquitous exposures that confer added risk for NAFLD progression include cigarette smoke and ethanol exposure. What has remained enigmatic, however, is the degree, directionality, and mechanisms by which gut microbial interactions can modify NAFLD pathophysiology. Two recent studies bring new and intriguing light to this issue. Chen B, Sun L, Zeng G, et al. Gut bacteria alleviate smoking-related NASH by degrading gut nicotine. Nature 2022;610(7932):562–568. Chen et al show that nicotine accumulates in the terminal ileum of smokers vs nonsmokers, and in mice exposed to cigarette smoke or nicotine. They found that nicotine accumulation promotes ileal ceramide formation by activating AMPKα-dependent stabilization of the ceramide biosynthetic enzyme, sphingomyelin phosphodiesterase 3. Next, they identified a nicotine-metabolizing bacterial species, Bacteroides xylanisolvens, which expresses a nicotine oxidoreductase homolog, nicX. Colonizing mice with B xylanisolvens reduced intestinal nicotine, intestinal ceramide content, and nicotine-exacerbated hepatosteatosis. Finally, B xylanisolvens correlated inversely with nicotine, intestinal ceramides, and advanced liver disease in patients with NAFLD. Although the human microbiota is diverse, and the full spectrum of implicated species and nicotine-modulatory pathways are unlikely to be represented here, this work mechanistically links NAFLD pathophysiology with gut nicotine catabolism and identifies a potential therapeutic target for smokers with NAFLD through manipulation of nicotine-degrading microbes. Meijnikman AS, Davids M, Herrema H, et al. Microbiome-derived ethanol in nonalcoholic fatty liver disease. Nat Med 2022;28:2100–2106. Conversely, new data from Meijnikman et al highlight an exacerbating role for host-microbial interactions in NAFLD progression. NAFLD, by definition, precludes “significant” exogenous ethanol exposure. The gut microbiome produces endogenous ethanol, but first-pass hepatic ethanol clearance has been a barrier to quantify the extent to which microbially derived ethanol exposure contributes to NAFLD pathogenesis. Meijnikman et al address this by quantifying fasting portal blood ethanol in patients with NAFL or nonalcoholic steatohepatitis (NASH) obtained at the time of bariatric surgery. Patients with NAFL had elevated portal venous ethanol compared with subjects without steatosis in the primary cohort, and patients with NASH had elevated portal venous ethanol compared with individuals without steatosis in the external validation cohort. Mixed-meal testing (MMT) in a subsequent prospective cohort then demonstrated higher fasting and post-prandial peripheral ethanol levels in 146 body mass index–matched patients with NAFL or NASH vs healthy control subjects, and these differences were abrogated in a subset of patients treated with broad-spectrum antibiotics before MMT. In this prospective cohort, Lactobacillaceae correlated with post-prandial ethanol levels. Although the generalizability of this study is limited by its predominantly female enrollment, it nonetheless shows that hepatic first-pass metabolism previously obscured the extent of hepatic exposure to microbially derived ethanol, and that microbially derived ethanol exposure could drive advanced NAFLD, independently from exogenous exposure. To be human is to comprise at least as many bacterial as somatic cells. To our benefit or detriment, metabolic processes between the kingdoms are intertwined. Together, these studies now highlight ethanol production and nicotine catabolism as novel examples of this paradigm. Modulating these bacterial processes, or the involved species themselves, thus represents a new target to attenuate NAFLD progression. The number and nature and the interactions between our kingdoms continues to expand, and it is likely that further connections will be declared over time. Nonetheless, what should no longer surprise us is that our microbial residents not only modify our response to environmental exposures, but also might even create the exposure itself, and thus provide an opportunity for therapeutic intervention.