A microbial metabolite reduces alcohol-induced inflammation via dual modulation of NF-κB and Interferon pathway.

Background and aims: Alcohol-associated hepatitis (AH) is characterized by excessive inflammation and blunted antiviral interferon (IFN) responses. We hypothesized that specific gut microbiome-derived metabolites could selectively enhance interferon signaling while limiting NF-κB mediated inflammation, thereby restoring immune balance in AH. Our goal is to identify microbiome-derived metabolites that differentially regulate the NF-κB and IFN signaling pathways. Methods and results: We used human monocytic THP1-Dual cells, which secrete reporters for NF-κB and IFN signaling, to model innate immune responses and screened a library of 152 gut microbiome-derived metabolites. From the metabolite screen, 4-hydroxyphenylacetic acid (4-HPAA) emerged as a unique immunomodulator: in LPS-challenged cells, 4-HPAA selectively increased IFN signaling with minimal NF-κB activation. 4-HPAA was evaluated Conclusions: 4-HPAA enhances interferon signaling and antiviral gene induction while dampening NF-κB-driven inflammation in the presence of LPS, both