The gut microbiome interacts with the loss of female sex hormones to exacerbate metabolic diseases, including weight gain, liver fat, and the expression of genes related to 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 increased risk of metabolic diseases such as obesity and type 2 diabetes after menopause, when ovarian production of female sex hormones declines.
“Taken together, the findings demonstrate that the removal of ovaries and female hormones led to increased permeability and inflammation of the intestine and metabolic organs, and the high-fat diet exacerbated these conditions,” said Kelly S. Swanson, director of Division of Nutritional Sciences and the Kraft Heinz Professor of Human Nutrition at the University of Illinois Urbana-Champaign, corresponding author of the article. “The results indicated that the gut microbiome responds to changes in female hormones and worsens metabolic dysfunction.”
“This is the first time it has been shown that the microbiome response to loss of ovarian hormone production can increase metabolic dysfunction,” said first author Tzu-Wen L. Cross, professor of nutritional sciences and director of the Gnotobiotic Animal Facility. at Purdue University. Cross was a doctoral student at the U. of I. when he began the research.
“The gut microbiome is sensitive to changes in sex hormones and may further affect the risk of disease development.”
Cross said early research on the microbiome, which began around 2005, looked at how the microbiome contributes to the development of obesity, but most of those studies focused on men.
“Metabolic dysfunction driven by loss of ovarian function in menopausal women, and to what extent the gut microbiome contributes to it, has not been studied. The etiology is clearly very complex, but those factors related to the gut microbiome are certainly components that we speculate play a role,” he said.
The scientists created 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 those to enzymes in the gut. The diets for both groups of mice were identical except for the proportion of fat, which made up 60% or 10% of calories for the high-fat and low-fat groups, respectively.
In the second stage of the study, fecal samples were collected from mice with or without ovaries and implanted into germ-free mice to study the impact on weight gain and metabolic and inflammatory activity in the intestine, liver, and adipose tissue. .
“Mice that received the gut microbiome from ovariectomized mice gained more weight and fat mass, and had higher expression of genes in the liver associated with inflammation, obesity, type 2 diabetes, fatty liver disease, and atherosclerosis in compared to those in the control group,” Swanson said.
When assessing the severity of fatty tissue and triglyceride concentrations in the liver, the scientists found that triglyceride levels were significantly higher and fat deposits in the liver and groin were greater in mice that consumed the high-fat diet. fats compared to all other treatment groups. , according to the study.
Those on a 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 genes associated with inflammation and macrophage markers, these mice had lower expression of genes related to glucose and lipid metabolism.
In donor mice without ovaries that ate the low-fat diet, the scientists found elevated levels of beta-glucuronidase, an enzyme produced by the colon and some intestinal bacteria that breaks down and recycles steroid metabolites such as estrogen and various toxins, including carcinogens. .
The scientists also examined the expression of genes that encode tight junction proteins, which affect the permeability of cell membranes. They found that mice without ovaries and those fed a high-fat diet had lower levels of these proteins in the liver and colon, suggesting that their intestinal barriers were more permeable, compromised either by their diet or 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 arginase-1 gene, which plays a critical role in removing nitrogenous waste. High levels of this protein have been associated with cardiovascular problems such as hypertension and atherosclerosis, according to the study.
The article was co-written by Erik R. Nelson, professor of molecular and integrative physiology; animal sciences professor Brett R. Loman; and Matthew A. Wallig, professor emeritus of pathobiology, all at the U. of I.
Other co-authors were Aadra P. Bhatt, professor in the Division of Gastroenterology and Hepatology; and Matthew R. Redinbo, professor of biochemistry and biophysics, both at the University of North Carolina at Chapel Hill.
Co-authors also included bacteriology professor Federico E. Rey and senior scientist Eugenio I. Vivas, both of the University of Wisconsin-Madison; and Jan S. Suchodolski, associate director of research and chief of microbiome sciences in veterinary medicine and biomedical sciences at Texas A&M University.
Other co-authors were then-research assistant Abigayle M.R. Simpson at Purdue University, and then-graduate student Ching-Yen Lin and then-undergraduate student Natasha M. Hottmann, both at the U. of I.
The research was supported by the National Institutes of Health and the National Heart, Lung, and Blood Institute.