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Butyrate limits inflammatory macrophage niche in NASH [ChIP-seq]

ABSTRACT: Lipid accumulation associated with immune cell infiltration leading to hepatocellular ballooning and lobular inflammation are the cardinal features of NASH. With onset and development of multi-omics approaches in the last decade, we have been able to comprehend the existence and functionality of gut microbial ecology. Apart from the compositional variation (dysbiosis), functional alteration of the microbial population i.e., the impact of the crosstalk between gut microbiota-derived metabolites with host cells also remains elusive in terms of regulation of immunometabolic homeostasis and overall human health and disease. Sodium butyrate (NaBu), a short chain fatty acid derived metabolite is known to modulate the inflammatory status of NASH pathogenesis; however, its mechanism of action is not clearly deciphered. To unveil the immunomodulatory activity of NaBu, we found robust anti-inflammatory effect of NaBu in diet induced NASH model with reduced macrophage infiltration. Mechanistically, independent of p65 nuclear translocation, by maintaining the enhanced acetylation status of p65 along with differential p65 recruitment to the proinflammatory gene promoter, NaBu suppressed the inflammatory milieu and resulted in better prognosis. Along with transcriptional rewiring, NaBu also altered the metabolic status, modified the functional outcome and exhibited differential secretome which ultimately resulted skewing of macrophages towards a prohealing phenotype and induced autocrine as well as paracrine death of proinflammatory macrophages to abrogate inflammation in both isolated LMs and in vivo model.

ORGANISM(S): Mus musculus

PROVIDER: GSE219093 | GEO | 2023/01/15

REPOSITORIES: GEO

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Project description:Objective: Nonalcoholic fatty liver disease (NAFLD) is linked to obesity and diabetes, suggesting an important role of adipose tissue in the pathogenesis of NAFLD. Here we aim to investigate the interaction between adipose tissue and liver in NAFLD, and identify potential early plasma markers that predict NASH. Research Design and Methods: C57Bl/6 mice were chronically fed a high fat diet to induce NAFLD and compared with mice fed low fat diet. Extensive histological and phenotypical analyses coupled with a time-course study of plasma proteins using multiplex assay was performed. Results: Mice exhibited pronounced heterogeneity in liver histological scoring, leading to classification into 4 subgroups: LF-low (LFL) responders displaying normal liver morphology, LF-high (LFH) responders showing benign hepatic steatosis, HF-low (HFL) responders displaying pre-NASH with macrovesicular lipid droplets, and HF-high (HFH) responders exhibiting overt NASH characterized by ballooning of hepatocytes, presence of Mallory bodies, and activated inflammatory cells. Compared to HFL responders, HFH mice gained weight more rapidly and exhibited adipose tissue dysfunction characterized by decreased final fat mass, enhanced macrophage infiltration and inflammation, and adipose tissue remodelling. Plasma haptoglobin, IL-1β, TIMP-1, adiponectin and leptin were significantly changed in HFH mice. Multivariate analysis indicated that in addition to leptin, plasma CRP, haptoglobin, eotaxin and MIP-1α early in the intervention were positively associated with liver triglycerides. Intermediate prognostic markers of liver triglycerides included IL-18, IL-1β, MIP-1γ and MIP-2, whereas insulin, TIMP-1, GCP-2 and MPO emerged as late markers. Conclusions: Our data support the existence of a tight relationship between adipose tissue dysfunction and NASH pathogenesis and point to several novel potential predictive biomarkers for NASH. Keywords: Expression profiling by array Male wildtype C57Bl/6 mice were fed LFD or HFD for 21 weeks. Mice were divided into 4 groups based on liver histology.

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Butyrate limits inflammatory macrophage niche in NASH [ChIP-seq]

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