Microbiota-derived bile acid ameliorates lung inflammation through metabolic rewiring of alveolar macrophages
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE307734 | GEO | 2025/11/13
REPOSITORIES: GEO
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Project description:Rationale: Physical exercise is essential for skeletal integrity and bone health. The gut microbiome, as a pivotal modulator of overall physiologic states, is closely associated with skeletal homeostasis and bone metabolism. However, the potential role of intestinal microbiota in the exercise-mediated bone gain remains unclear. Methods: We conducted microbiota depletion and fecal microbiota transplantation (FMT) in ovariectomy (OVX) mice and aged mice to investigate whether the transfer of gut ecological traits could confer the exercise-induced bone protective effects. The study analyzed the gut microbiota and metabolic profiles via 16S rRNA gene sequencing and LC-MS untargeted metabolomics to identify key microbial communities and metabolites responsible for bone protection. Transcriptome sequencing and RNA interference were employed to explore the molecular mechanisms. Results: We found that gut microbiota depletion hindered the osteogenic benefits of exercise, and FMT from exercised osteoporotic mice effectively mitigated osteopenia. Comprehensive profiling of the microbiome and metabolome revealed that the exercise-matched FMT reshaped intestinal microecology and metabolic landscape. Notably, alterations in bile acid metabolism, specifically the enrichment of taurine and ursodeoxycholic acid, mediated the protective effects on bone mass. Mechanistically, FMT from exercised mice activated the apelin signaling pathway and restored the bone-fat balance in recipient MSCs. Conclusion: Our study underscored the important role of the microbiota-metabolic axis in the exercise-mediated bone gain, heralding a potential breakthrough in the treatment of osteoporosis.
2024-12-24 | GSE283332 | GEO
Project description:Bile acids are multifunctional signaling molecules that play significant roles in maintaining microbial homeostasis. N6-methyladenine (m6A), the most abundant epitranscriptomic modification, mediates various biological processes by modulating RNA metabolism. However, the precise regulatory mechanisms of m6A methylation in bile acid metabolism, and its downstream effects on microbiota remain unclear. In this study, liver-specific Mettl14 knockout (Mettl14-LKO) reshaped bile acid profile and expression levels of protein related to bile acid metabolism, namely CYP7A1, FXR, and BSEP. M6A-seq data revealed m6A methylated peaks on CYP7A1. Mettl14-LKO significantly elevated expression of m6A “reader” IGF2BP3. Knockdown of IGF2BP3 inhibited CYP7A1 expression by decreasing mRNA stability. Mechanistically, Mettl14-LKO promoted bile acid synthesis by upregulating CYP7A1 expression in an m6A-IGF2BP3-dependent manner. Interestingly, Mettl14-LKO reduced bile acid content in ileum due to decreased BSEP level in liver. Noteworthy, we discovered for the first time that Mettl14 knockout in the liver altered fecal microbiota composition. Specifically, it changed the abundance of Cyanobacteria and Patescibacteria at phylum level, and Lachnochostridium, Candidatus-Saccharimonas, and Roseburia at genera level. Remarkably, Roseburia was negatively correlated with the bile acid levels and CYP7A1 expression. Our findings provide new insights into the role of METTL14 in regulating bile acid homeostasis and its impact on fecal microbiota. Roseburia emerges as a potential target for addressing metabolic diseases linked to disrupted METTL14 signaling.
2025-04-09 | GSE293836 | GEO
Project description:The microbiota generates structurally diverse small molecules that can regulate host physiology and disease. Of these microbiota metabolites, bile acids have emerged as important modulators of host immunity and microbial pathogenesis. While the modes of action for different bile acids on host pathways are becoming more apparent, the mechanisms by which these prominent microbiota metabolites suppress microbial virulence pathways are less clear. To identify the direct protein targets of bile acids in Salmonella, we have generated three photoaffinity bile acid reporters (alk-X-CDCA, alk-X-UDCA, alk-X-LCA) and performed chemical proteomics. Using a combination of photocrosslinking with bile acid chemical reporters and label-free proteomics, we performed a quantitative analysis of bile acid interacting proteins in Salmonella with or without UV-mediated photocrosslinking. These studies revealed bile acid can interact with many Salmonella proteins, such as extracellular or secreted proteins, T3SS components and motility-related proteins, as predicted by Gene Ontology analysis. In addition, cytoplasmic and membrane proteins including metabolic enzymes are also identified. Notably, HilD, an important transcriptional regulator of S. Typhimurium virulence was also identified by the alk-X-CDCA reporter. This study highlights the utility of chemical proteomics to identify the direct protein targets and mechanisms of action for microbiota metabolites in bacterial pathogens.
2022-09-29 | PXD034373 | Pride
Project description:Specific bile acids are potent signaling molecules that modulate metabolic pathways affecting lipid, glucose and bile acid homeostasis, and the microbiota. Bile acids are synthesized from cholesterol in the liver, and the key enzymes involved in bile acid synthesis (Cyp7a1, Cyp8b1) are regulated transcriptionally by the nuclear receptor FXR. We have identified an FXR-regulated pathway upstream of a transcriptional repressor that controls multiple bile acid metabolism genes. We identify MafG as an FXR target gene and show that hepatic MAFG overexpression represses genes of the bile acid synthetic pathway and modifies the biliary bile acid composition. In contrast, loss-of-function studies using MafG(+/-) mice causes de-repression of the same genes with concordant changes in biliary bile acid levels. Finally, we identify functional MafG response elements in bile acid metabolism genes using ChIP-seq analysis. Our studies identify a molecular mechanism for the complex feedback regulation of bile acid synthesis controlled by FXR.
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Project description:the commensal gut microbiota modulates multiple sclerosis with unknown mechanisms. Commensal bacteria producing bile acid-deconjugating enzymes are fundamental to generate secondary bile acid metabolites (BAM) with immunoregulatory function. We show that immune regulatory BAM prevent autoimmunity in the central nervous system by inducing immune tolerance at the intestinal level and peripherally limiting effector function and aggressiveness of myelin-reactive T cells. We validated the key role of microbiota-induced BAM in humans by showing that relapsing-remitting multiple sclerosis patients have significantly reduced level of an important immune regulatory BAM (deoxycholic acid) and lower abundance of BAM-producing bacteria that correlate with increased percentages of peripheral effector Th17 cells. Our data indicate that the immune regulatory biliary network is crucial for the prevention of central nervous system autoimmunity.
2025-03-17 | GSE233771 | GEO
Project description:Gut microbiota contributes to the regulation of host immune response and homeostasis. Bile acid (BA) derivatives from gut microbiota can affect the differentiation and function of the immune cells. However, it is incompletely clear for the regulation of BA metabolites in the macrophages. We here find that BA metabolites can regulate sensitivity of macrophages to LPS and or Gram-negative bacteria. BA derivatives could induce lncRNA57RIK expression through sphingosine-1-phosphate receptor 2 (S1PR2) in the macrophages of mice and humans, which play a critical role in Gram-negative bacteria mediated IL-1β maturation and pyroptosis of macrophages. This lncRNA57RIK could bind intracellular proteases caspase-4/11 with guanylate-binding protein 1 (GBP1) in the human and mice together to cause LPS mediated activation of caspase-4/11. Murine or human lncRNA57RIK knockout (KO) macrophages did not produce response(s) to LPS or gram negative bacteria. LncRNA57RIK KO mice had also reduced inflammatory responses to LPS or Salmonella typhimurium (S.T) infection. Taken together, gut microbiota derived BA metabolites mediated lncRNA57RIK is necessary for LPS induced caspase-4/11 activation.
2024-09-21 | GSE277195 | GEO
Project description:Background & Aims: Wilson disease (WD) is an autosomal recessive disorder that results in excessive hepatic copper causing hepatic steatosis, inflammation, fibrosis, cirrhosis, and liver failure. Previous studies have revealed dysregulation of many FXR metabolic target genes in animal models of WD, including Bsep, the major determinant of bile flow. Approach & Results: We tested the hypothesis that the FXR-cistrome is decreased in Atp7b-/- mice in accord with dysregulated bile acid homeostasis. RNA-Seq and ChIP-Seq analyses of Atp7b-/- and wild-type (WT) mouse livers confirmed that significantly altered transcripts and FXR-binding events overlapped. Decreased FXR occupancy in Atp7b-/- versus WT mice was observed genes of metabolic pathways and bile acid homeostasis, while enrichment of FXR binding was observed pathways associated with cellular damage, such as the focal adhesion pathway. Consistent with decreased FXR function, serum and liver bile acid concentrations were higher in Atp7b-/- mice than in WT mice. Comparison of bile acid profiles in the serum of WD patients with “liver,” “neurological,” or “mixed” disease vs. healthy controls also revealed increases in specific bile acids in WD-liver vs. healthy controls. Conclusions: Atp7b-/- mice and WD patients exhibited changes in serum bile acid speciation, likely due to FXR dysfunction. These findings provide new insights into possible aberrant bile acid homeostasis in patients with WD.
2025-06-04 | GSE287020 | GEO
Project description:Lactobacillus salivarius is a member of the indigenous microbiota of the human gastrointestinal tract (GIT). Tolerance to bile stress is crucial for intestinal lactobacilli to survive in the GIT and to exert their beneficial actions. In this work, the Next-Generation Sequencing platform Illumina HiSeq 2000 was used to investigate the global response to bile in L. salivarius Ren, a potential probiotic strain isolated from a healthy centenarian. In the presence of 0.75 g liter-1 oxgall, the transcription of nearly 200 genes was detected to be associated with bile stress, including genes involved in carbohydrate and amino acid metabolism, cell envelope and fatty acid biogenesis, transcription and translation. This study improves our understanding on bile stress response in L. salivarius Ren.
2019-12-18 | GSE68033 | GEO
Project description:Background & Aims: Wilson disease (WD) is an autosomal recessive disorder that results in excessive hepatic copper causing hepatic steatosis, inflammation, fibrosis, cirrhosis, and liver failure. Previous studies have revealed dysregulation of many FXR metabolic target genes in animal models of WD, including Bsep, the major determinant of bile flow. Approach & Results: We tested the hypothesis that the FXR-cistrome is decreased in Atp7b-/- mice in accord with dysregulated bile acid homeostasis. RNA-Seq and ChIP-Seq analyses of Atp7b-/- and wild-type (WT) mouse livers confirmed that significantly altered transcripts and FXR-binding events overlapped. Decreased FXR occupancy in Atp7b-/- versus WT mice was observed genes of metabolic pathways and bile acid homeostasis, while enrichment of FXR binding was observed pathways associated with cellular damage, such as the focal adhesion pathway. Consistent with decreased FXR function, serum and liver bile acid concentrations were higher in Atp7b-/- mice than in WT mice. Comparison of bile acid profiles in the serum of WD patients with “liver,” “neurological,” or “mixed” disease vs. healthy controls also revealed increases in specific bile acids in WD-liver vs. healthy controls. Conclusions: Atp7b-/- mice and WD patients exhibited changes in serum bile acid speciation, likely due to FXR dysfunction. These findings provide new insights into possible aberrant bile acid homeostasis in patients with WD.
2025-06-04 | GSE286956 | GEO
Project description:Innate lymphoid cells (ILCs) can promote host defense, chronic inflammation or tissue protection and are regulated by cytokines and neuropeptides. However, their regulation by diet and microbiota-derived signals remains unclear. We show that an inulin fiber diet promotes Tph1-expressing inflammatory ILC2s (ILC2INFLAM) in the colon which produce IL-5 but not tissue-protective amphiregulin (AREG), resulting in accumulation of eosinophils. This exacerbates inflammation in a murine model of intestinal damage and inflammation in an ILC2- and eosinophil-dependent manner. Mechanistically, inulin fiber diet elevated microbiota-derived bile acids, including cholic acid (CA) that induced expression of ILC2-activating IL-33. In IBD patients, bile acids, their receptor farnesoid X receptor (FXR), IL-33, and eosinophils were all upregulated compared to controls, suggesting relevance of this diet-ILC2 axis in human IBD pathogenesis. Together, these data reveal that dietary fiber-induced changes in microbial metabolites operate as a rheostat that governs protective versus pathologic ILC2 responses with relevance to precision nutrition for inflammatory diseases.
2024-02-12 | GSE255243 | GEO