FIG 9.

Multihit model of undernutrition-induced fatty liver and dietary intervention. Chronic exposure to specific, fecal microbes impacts hepatic steatosis and triglyceride accumulation in malnourished mice. Early-life malnutrition triggers an altered liver metabolome characterized by shifts in phenylacetate (phenylacetic acid [PA]), vitamin A (retinoids [A, a]), long-chain fatty acid, and glycerophospholipid metabolism. These changes are accompanied by striking alterations in gut microbiota community and function. Notably, enriched metabolism of phenylacetic acid, a bacterial product of AAAM metabolism, corresponds with increased relative frequency of AAAM predicted microbiome pathways in MBG mice, while altered glycerophospholipid metabolism correlates with both microbiome functional profiles and hepatic steatosis. Adult-onset malnutrition elicits metabolomic shifts largely uncoupled from hepatic steatosis (not shown), highlighting the importance of an early-life development period in liver function. In contrast, sustained dietary intervention largely mitigates microbial and host metabolic shifts during malnutrition, reducing hepatic steatosis and improving growth. Collectively, these findings demonstrate a putative role for commensal gut microbes in NAFLD and highlight putative host/microbial targets to reduce fatty liver burden in undernourished communities. This figure was created using Biorender.