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

The results, published in the journal gut microbes, This may shed light on how ovarian production of female sex hormones declines after menopause, when women are at increased risk for metabolic diseases such as obesity and type 2 diabetes.

“Overall, the results show that removal of the ovaries and female hormones increased the permeability and inflammation of the gut and metabolic organs, and that a high-fat diet exacerbated these conditions,” Kelly S. Swanson said. said Kraft Heinz is a professor of nutritional sciences and human nutrition at the University of Illinois at Urbana-Champaign and is the corresponding author of this paper. “The findings suggest that the gut microbiome responds to changes in female hormones and exacerbates metabolic dysfunction.”

“This is the first time it has been shown that the microbiome’s response to loss of ovarian hormone production can exacerbate metabolic dysfunction,” said first author Tzu-Wen L. Cross, professor of nutrition science and director of the Gnotobiotic Animal Facility. The director said. at Purdue University. Cross was a doctoral student at the U. of I. when she began the research.

“The gut microbiome is sensitive to sex hormone changes and may further influence the risk of disease development.”

Early microbiome research, which began around 2005, looked at how the microbiome contributed to the development of obesity, but most of those studies focused on men, Cross said.

“The metabolic dysfunction that results from loss of ovarian function in menopausal women — and how much the gut microbiome contributes to it — has not been studied. The etiology is clearly very complex, but they are linked to the gut microbiome. Related factors are certainly components that we hypothesize play a role,” he said.

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

In the second phase of the study, ovarian samples were obtained from mice with or without ovariectomy and implanted into sterile mice to measure weight gain and metabolic and inflammatory activity in the intestine, liver, and adipose tissue. The effects can be studied.

“Mice that were recipients of the gut microbiome of ovariectomized mice gained more weight and increased fat mass, and their livers overexpressed genes associated with inflammation, obesity, type 2 diabetes, fatty liver disease and atherosclerosis. was the control group,” Swanson said.

In evaluating the magnitude of fatty tissue and triglyceride concentrations in the liver, the scientists found that triglyceride levels were significantly higher and fatty deposits in the liver and intestine were significantly higher in mice fed the high-fat diet than in all other treatment groups. There were more. , according to the study.

Those who were on a high-fat diet and without ovaries had significantly larger fat cells, associated with cell death and infiltration of macrophages – a type of white blood cell that destroys dead cells and destroy microorganisms and secrete pro-inflammatory proteins. Along with elevated expression of genes associated with inflammation and macrophage markers, these mice had lower expression of genes associated with glucose and lipid metabolism.

In ovariectomized donor mice fed a low-fat diet, the scientists found increased levels of beta-glucuronidase, an enzyme produced by the colon and some intestinal bacteria that breaks down steroidal metabolites. Cycles like estrogen and various toxins, including carcinogens. .

The scientists also examined the expression of genes coding for tight junction proteins, which affect the permeability of cell membranes. They found that mice without ovaries and fed a high-fat diet had lower levels of these proteins in their livers and colons, suggesting that their intestinal barriers were more permeable, either because of their diet. Or compromised by the absence of female hormones.

In the livers of recipient mice that received transplants from donors without ovaries, the scientists found elevated levels of expression of the gene for organase-1, which plays an important role in eliminating nitrogenous waste. According to studies, high levels of this protein have been linked to heart problems such as high blood pressure and atherosclerosis.

This paper was co-authored by Eric R. Nelson, Professor of Molecular and Integrative Physiology. Animal Science Professor Brett R. Lowman; and Matthew A. Wallig, professor emeritus of pathobiology, all at the UI.

Additional co-authors were Audra P. Bhatt, professor in the Division of Gastroenterology and Hepatology; and Matthew R. Redenbaugh, professor of biochemistry and biophysics, both at the University of North Carolina at Chapel Hill.

Co-authors also included Bacteriology Professor Federico E. Rei and Senior Scientist Eugenio I. Vivas, both at the University of Wisconsin-Madison; and John S. Suchodolski, associate director of research and chair of microbiome sciences in veterinary medicine and biomedical sciences at Texas A&M University.

Additional co-authors were Abigail MR Simpson, then a research assistant at Purdue University, and Chung Yin Lin, then a graduate student, and Natasha M. Houtman, then an undergraduate student, both at the U.

This research was supported by the National Institutes of Health and the National Heart, Lung, and Blood Institute.