Reducing gut microbiome-driven adipose tissue inflammation alleviates metabolic syndrome

Abstract

Background The gut microbiota contributes to macrophage-mediated inflammation in adipose tissue with consumption of an obesogenic diet, thus driving the development of metabolic syndrome. There is a need to identify and develop interventions that abrogate this condition. The hops-derived prenylated flavonoid xanthohumol (XN) and its semi-synthetic derivative tetrahydroxanthohumol (TXN) attenuate high-fat diet-induced obesity, hepatosteatosis, and metabolic syndrome in C57Bl/6J mice. This coincides with a decrease in pro-inflammatory gene expression in the gut and adipose tissue, together with alterations in the gut microbiota and bile acid composition. Results In this study, we integrated and interrogated multi-omics data from different organs with fecal 16S rRNA sequences and systemic metabolic phenotypic data using a Transkingdom Network Analysis. By incorporating cell type information from single-cell RNA-seq data, we discovered TXN attenuates macrophage inflammatory processes in adipose tissue. TXN treatment also reduced levels of inflammation-inducing microbes, such as Oscillibacter valericigenes, that lead to adverse metabolic phenotypes. Furthermore, in vitro validation in macrophage cell lines and in vivo mouse supplementation showed addition of O. valericigenes supernatant induced the expression of metabolic macrophage signature genes that are downregulated by TXN in vivo. Conclusions Our findings establish an important mechanism by which TXN mitigates adverse phenotypic outcomes of diet-induced obesity and metabolic syndrome. TXN primarily reduces the abundance of pro-inflammatory gut microbes that can otherwise promote macrophage-associated inflammation in white adipose tissue.

Reduced functional fungal communities in two species of sloths (Bradypus variegatusandCholoepus hoffmanni) suggest a link to slow digestion

“…However, these were in very low abundance or absent from metagenomic or metatranscriptomic reads, aligning with findings from Dill-McFarland et al 13 Several abundant bacterial taxa identified, such as Clostridium, Corynebacterium, Oscillibacter, Pseudoflavonifractor, and Ruminococcus, are well-known residents of herbivore guts. These bacteria play crucial roles in fermenting and breaking down plant polysaccharides and detoxifying plant alkaloids and other secondary metabolites 17,42,50,[52][53][54][55] . For instance, Lachnospiraceae (Eubacteriales), one of the most abundant families found in the present study, is a group of obligately anaerobic bacteria that are among the most abundant taxa in the rumen 50 and in wild sloths 13 .…”

The Hepatic Antisteatosis Effect of Xanthohumol in High-Fat Diet-Fed Rats Entails Activation of AMPK as a Possible Protective Mechanism

“…Interestingly XH is also able to attenuate lipogenesis in cultured hepatocytes and protect against NAFLD in mice and rats by suppressing the hepatic SREBP1 and diacylglycerol acyltransferase (DAG), activation of farnesoid X receptor (FXR), antagonizing PPARγ, and stimulating the Nrf2/RAGE/NF-κB axis [48][49][50][51]. This data indicates that XH may act by various mechanisms under a common umbrella.…”

Microbiome Dynamics: A Paradigm Shift in Combatting Infectious Diseases

“…The microbiome also exerts influence over host metabolic inflammation, particularly in conditions such as obesity and metabolic syndrome [150,151]. Dysbiosis observed in these conditions can lead to changes in the production of inflammatory mediators and adipokines, ultimately contributing to a pro-inflammatory state.…”