Nfil3 integrates circadian rhythm and microbial metabolite signaling to maintain gut–liver immune–metabolic homeostasis under high-fat diet stress

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BACKGROUND: Disruption of circadian regulation and gut microbial homeostasis is a hallmark of metabolic dysfunction associated with steatotic liver disease (MASLD). Nuclear factor interleukin 3 (Nfil3) integrates circadian and immune signaling; however, how Nfil3 interfaces with microbiota-associated metabolic cues in MASLD remains incompletely understood. We investigated the role of Nfil3 in linking microbial functional states to hepatic metabolic and immune responses under high-fat diet (HFD) stress and assessed the modulatory impact of probiotic VSL#3 intervention. METHODS: We integrated exploratory human peripheral blood mononuclear cell (PBMC) transcriptomic profiling with genetic Nfil3 deletion and probiotic VSL#3 supplementation in HFD-fed mice. Experimental assessments included liver histopathology, metabolic phenotyping, immune flow cytometry, gut epithelial barrier analysis, 16S rRNA microbiome profiling with predictive functional inference, and RT-PCR. RESULTS: Exploratory PBMC transcriptomic analysis of obese individuals suggested that NFIL3 may function as a candidate transcriptional node associated with circadian-related genes and short-chain fatty acid (SCFA) sensing receptors in inflammatory signaling pathways. In mice, HFD feeding was associated with increased Nfil3 expression, hepatic steatosis, metabolic dysfunction, immune cell expansion, and impaired intestinal epithelial barrier integrity. Probiotic VSL#3 supplementation mitigated several HFD-associated phenotypes, including weight gain, glucose intolerance, dyslipidemia, transaminase elevation, hepatic lipid accumulation, and gut epithelial permeability, while partially normalizing intrahepatic immune cell composition. Nfil3-deficient mice displayed attenuated responses to several HFD-induced metabolic and inflammatory alterations, with partial phenotypic overlap with probiotic-treated wild-type (WT) mice. Microbiome analyses showed that VSL#3 enriched SCFA- and mucin-associated taxa while suppressing endotoxin-associated bacteria (Desulfovibrionaceae, Romboutsia). Predictive functional profiling suggested restoration of microbial pathways related to amino acid, redox, and energy metabolism, alongside reduced representation of lipopolysaccharide and toxin biosynthesis pathways. CONCLUSIONS: These findings support a role for Nfil3 as a regulatory node linking microbial functional potential with immune and metabolic responses in MASLD. Although preclinical in nature, this work provides a mechanistic framework that may inform future translational investigations into how microbiota-associated metabolic reprogramming influences host immune-metabolic homeostasis. Further circadian-resolved and metabolite-level studies, together with human interventional validation, will be required to determine the clinical relevance of the microbiota-Nfil3 axis.

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