Metabolic Diseases May Be Driven by Gut Microbiome, Loss of Ovarian Hormones

The gut microbiome interacts with the loss of female sex hormones to exacerbate metabolic disease, including weight gain, fat in the liver and the expression of genes linked with inflammation, researchers found in a new rodent study.

The findings, published in the journal Gut Microbes, may shed light on why women are at significantly greater risk of metabolic diseases such as obesity and Type 2 diabetes after menopause, when ovarian production of female sex hormones diminishes.

The scientists created diet-induced obesity in female mice and simulated the loss of female sex hormones by removing the ovaries in half of the population to examine any metabolic and inflammatory changes, including those to enzymes in the gut. The diets for both groups of mice were identical except for the proportion of fat, which constituted 60% or 10% of calories for those in the high-fat and low-fat groups, respectively.

In the second leg of the study, fecal samples were harvested from mice with or without ovaries and implanted in germ-free mice to study the impact on weight gain and metabolic and inflammatory activity in the gut, liver and fat tissue.

In assessing the severity of fatty tissue and triglyceride concentrations in the liver, the scientists found that the triglyceride levels were significantly higher and fatty deposits in the liver and groin were greater in the mice that consumed the high-fat diet compared with all other treatment groups, according to the study.

Those on the high-fat diet and those without ovaries had significantly larger fat cells, which are associated with cell death and the infiltration of macrophages — a type of white blood cell that destroys dead cells and microorganisms and secretes pro-inflammatory proteins. Along with elevated expression of the genes associated with inflammation and macrophage markers, these mice had lower expression of genes that are involved with glucose and lipid metabolism.

In the donor mice without ovaries that consumed the low-fat diet, the scientists found increased levels of beta-glucuronidase, an enzyme produced by the colon and some intestinal bacteria that breaks down and recycles steroidal metabolites such as estrogen and various toxins, including carcinogens.

The scientists also examined the expression of genes coding for tight-junction proteins, which affect cell membranes’ permeability. They found that the mice without ovaries and those fed the high-fat diet had lower levels of these proteins in the liver and colon, which suggested their gut barriers were more permeable, compromised by either their diet or the absence of female hormones.

In the livers of the recipient mice that received transplants from donors without ovaries, the scientists found elevated expression levels of the gene for arginase-1, which plays a critical role in the elimination of nitrogenous waste. High levels of this protein have been associated with cardiovascular problems such as hypertension and atherosclerosis, according to the study.

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Sources:

Tzu-Wen L. Cross, Abigayle M. R. Simpson, Ching-Yen Lin, Natasha M. Hottmann, Aadra P. Bhatt, Samuel J. Pellock, Erik R. Nelson, Brett R. Loman, Matthew A. Wallig, Eugenio I. Vivas, Jan Suchodolski, Matthew R. Redinbo, Federico E. Rey, Kelly S. Swanson. Gut microbiome responds to alteration in female sex hormone status and exacerbates metabolic dysfunction. Gut Microbes, 2023; 16 (1) DOI: 10.1080/19490976.2023.2295429

University of Illinois at Urbana-Champaign, News Bureau. (2024, February 22). Metabolic diseases may be driven by gut microbiome, loss of ovarian hormones. ScienceDaily. Retrieved February 23, 2024 from www.sciencedaily.com/releases/2024/02/240222132204.htm

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