Reducing gut microbiome-driven adipose tissue inflammation alleviates metabolic syndrome

Authors: NEWMAN, NOLAN - Oregon State University; ZHANG, YANG - Oregon State University; PADIADPU, JYOTI - Oregon State University; MIRANDA, CRISTOBAL - Oregon State University; MAGANA, ARMANDO - Oregon State University; WONG, CARMEN - Oregon State University; Gurung, Manoj; GOMBART, ADRIAN - Oregon State University; MORGUN, AAUDREY - Oregon State University; SHULZHENKO, NATALIA - Oregon State University

Submitted to: Microbiome
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/1/2023
Publication Date: 9/21/2023
Citation: Newman, N.K., Zhang, Y., Padiadpu, J., Miranda, C.L., Magana, A.A., Wong, C.P., Gurung, M., Gombart, A.F., Morgun, A.F., Shulzhenko, N. 2023. Reducing gut microbiome-driven adipose tissue inflammation alleviates metabolic syndrome. Microbiome. 11:208. https://doi.org/10.1186/s40168-023-01637-4.
DOI: https://doi.org/10.1186/s40168-023-01637-4

Interpretive Summary: Metabolic syndrome, which is a early stage to type 2 diabetes and related liver diseases, is now a global epidemic. This condition is caused by sedentary lifestyle and consumption of unhealthy diets like diets rich in fats and sugar. White fat or adipose tissue inflammation is one of the features of metabolic disease. Polyphenol-rich plants have been shown to provide health benefits. One such plant is Hops ((Humulus lupulus L), which contains a type of polyphenol called xanthohumol (XN). Xanthohumol and its semi-synthetic derivative, tetrahydroxanthohumol (TXN) have been found to improve the symptoms and lower markers of metabolic diseases. TXN was also found to change the composition of microbes in the gut, suggesting that TXN improves metabolic health by changing gut microbes. However, the exact mechanism of the TXN's role was not known. Using a mouse model of metabolic disease, this study found that TXN can reduce a gut microbe, Oscillibacter, associated with obesity. This microbe is increased when mice are fed a diet that causes obesity and induces metabolic syndrome. Supplementation of mice diet with TXN reduced the number of this microbe. A decrease in the number of Oscillibacter consequently improved the inflammation of white fat. Hence, this study shows the mechanism by which Hops plant-associated product, TXN, improves metabolic syndrome in obese mice.

Technical 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.