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Adaptive downregulated liver Recucalcin enhances tolerance defense to intestinal infection by mediating interorgan immunometabolic communication

ABSTRACT: The gut-liver communication is vital for coordinating a systemic response to intestinal infection, as the liver plays a crucial role in regulating immune tolerance through metabolic reprogramming. However, the mechanisms underlying gut-liver communication during intestinal infection, and the key factors linking these processes, remain poorly investigated. In this study, we identified that Regucalcin expression in the remote liver/fat body (Drosophila analogous) is downregulated in response to intestinal infection. And this adaptive downregulated liver Recucalcin could enhance tolerance defense by limiting intestinal infection-induced lipid wasting. Mechanistically, we uncovered that the loss of Regucalcin facilitated calcium-dependent Dilp6 secretion and suppressed excessive lipid catabolism through the insulin-PI3K-Akt signaling pathway during intestinal infection. Therefore, our work reveals Regucalcin as a novel mediator that orchestrates the cross-talk between the intestine and the liver/fatbody, thereby modulating metabolic tolerance to intestinal infection.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE302415 | GEO | 2026/06/06

REPOSITORIES: GEO

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Project description:Background: Western diet (WD) fed Melanocortin 4 receptor-knockout (MC4R-KO) mice develop a phenotype resembling human metabolic dysfunction-associated steatohepatitis (MASH). Despite its clinical relevance, the role of the gut–liver axis in MASH pathogenesis remains unclear. This study investigated the gut-liver axis through microbiomic and metabolomic analyses of WD-fed MC4R-KO mice, and examined their association with MASH pathology. Methods: We performed an integrated microbiome and metabolome analysis of the liver, small intestinal contents, large intestinal contents, and plasma of wild-type (WT) and MC4R-KO mice fed either a normal diet or WD. Markers of hepatic inflammation, fibrosis, and steatosis measured in this study were used to assess MASH severity and to correlate microbiome and metabolite alterations. Results: WD-fed MC4R-KO mice exhibited significant hepatic steatosis, inflammation, and fibrosis. The abundance of certain microbiota, including Muribaculaceae and Allobaculum, negatively correlated with MASH severity, whereas increased levels of Desulfovibrionaceae and Bacteroides positively correlated with hepatic lipid accumulation, steatosis, and inflammation. Metabolomic profiling revealed increased triglyceride and diglyceride levels in the liver and a concomitant decrease in free fatty acids and monoglycerides in the intestines. Additionally, plasma taurine-conjugated bile acids were elevated in WD-fed MC4R-KO mice, which correlated with the reduced hepatic transport of bile salts from pathway enrichment analysis. These findings highlight substantial alterations in the gut microbiota and lipid and bile acid metabolism, indicating a mechanistic dysregulation of the gut–liver axis that may contribute to MASH progression. Conclusions: The observed gut microbial and metabolic alterations, particularly bile acid and lipid metabolism dysregulation, offer insights into potential therapeutic targets aimed at modulating the gut–liver axis to treat or prevent MASH.

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Adaptive downregulated liver Recucalcin enhances tolerance defense to intestinal infection by mediating interorgan immunometabolic communication

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