{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T14:49:10Z","timestamp":1782398950376,"version":"3.54.5"},"posted":{"date-parts":[[2026,6,23]]},"group-title":"Immunology","reference-count":71,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T00:00:00Z","timestamp":1782172800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000027","name":"National Institute on Alcohol Abuse and Alcoholism","doi-asserted-by":"crossref","award":["K99\/R00AA028048"],"award-info":[{"award-number":["K99\/R00AA028048"]}],"id":[{"id":"10.13039\/100000027","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background and aims<\/jats:title>\n                  <jats:p>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-\u03baB mediated inflammation, thereby restoring immune balance in AH. Our goal is to identify microbiome-derived metabolites that differentially regulate the NF-\u03baB and IFN signaling pathways.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>\n                    We used human monocytic THP1-Dual cells, which secrete reporters for NF-\u03baB 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-\u03baB activation. 4-HPAA was evaluated\n                    <jats:italic>in vivo<\/jats:italic>\n                    using a NIAAA-model, with 4-HPAA supplementation (0.4mg\/ml) added to the diet. In the NIAAA-model, dietary 4-HPAA did not induce liver injury and was associated with enhanced interferon-stimulated gene expression. Simultaneously, 4-HPAA reduced pro-inflammatory markers such as\n                    <jats:italic>Il1\u03b2<\/jats:italic>\n                    ,\n                    <jats:italic>Ly6g<\/jats:italic>\n                    and\n                    <jats:italic>F4\/80<\/jats:italic>\n                    compared to the group exposed to ethanol alone. Metabolomic profiling of mouse cecal contents revealed 4-HPAA supplementation counteracted ethanol\u2019s metabolic effects, selectively reducing triglyceride-associated lipids that had accumulated with ethanol feeding.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>\n                    4-HPAA enhances interferon signaling and antiviral gene induction while dampening NF-\u03baB-driven inflammation in the presence of LPS, both\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    . In an acute-on-chronic alcohol injury model, 4-HPAA attenuated hepatic inflammation, reduced immune cell recruitment, and activated antioxidant defenses, reflecting a shift toward a more hepatoprotective effect. 4-HPAA treatment was associated with reduced pro-inflammatory markers and modest attenuation of ethanol-induced liver injury. Additionally, 4-HPAA reversed ethanol-induced lipid-dysregulation, particularly triglyceride accumulation, highlighting its metabolic benefit in alcohol-fed mice. In conclusion, 4-HPAA rebalances immune and metabolic pathways by enhancing IFN signaling, suppressing NF-\u03baB inflammation, and reversing alcohol-induced hepatic injury and lipid accumulation.\n                  <\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.06.18.733199","type":"posted-content","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T22:30:23Z","timestamp":1782253823000},"source":"Crossref","is-referenced-by-count":0,"title":["A microbial metabolite reduces alcohol-induced inflammation via dual modulation of NF-\u03baB and Interferon pathway"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6718-0278","authenticated-orcid":false,"given":"Yurui","family":"Zheng","sequence":"first","affiliation":[{"name":"Department of Medicine, UConn Health, Farmington, CT 06030"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Handali","sequence":"additional","affiliation":[{"name":"Department of Medicine, UConn Health, Farmington, CT 06030"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dana","family":"Moradi","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Connecticut, Storrs, CT 06269"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin","family":"Varnet","sequence":"additional","affiliation":[{"name":"Department of Medicine, UConn Health, Farmington, CT 06030"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farhin","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Medicine, UConn Health, Farmington, CT 06030"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Aksenov","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Connecticut, Storrs, CT 06269"},{"name":"Arome Science, Farmington, CT 06032"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3186-3912","authenticated-orcid":false,"given":"Adam","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Medicine, UConn Health, Farmington, CT 06030"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026062507050559000_2026.06.18.733199v1.1","doi-asserted-by":"publisher","DOI":"10.4254\/wjh.v4.i3.81"},{"issue":"7","key":"2026062507050559000_2026.06.18.733199v1.2","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.3390\/antiox11071258","article-title":"Ethanol Metabolism in the Liver, the Induction of Oxidant Stress, and the Antioxidant Defense System","volume":"11","year":"2022","journal-title":"Antioxidants"},{"key":"2026062507050559000_2026.06.18.733199v1.3","doi-asserted-by":"crossref","unstructured":"Luzio, N.R.D. and T.E. 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