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Gut Microbiome Drives Metabolic Diseases in Post-Menopausal Mice

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Post-menopausal women face an increased susceptibility to metabolic diseases, including obesity and type-2 diabetes. Now a new study, published in Gut Microbes, sheds light on the factors that potentially drive this risk and how the gut microbiome could play a role.

A loss of female sex hormones

Menopause is characterized by an age-related loss of the female sex hormones estrogen and progesterone. Along with several cardiometabolic and physiological changes, post-menopausal women also observe an increased risk of metabolic conditions – until now the driver of this metabolic dysfunction has not been studied.

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The gut microbiome has been associated with metabolic diseases, such as obesity, in previous studies of mice. Although this strong link is already established, how the microbiome responds to a change in sex hormones post-menopause is yet to be investigated.

“Metabolic dysfunction that is driven by the loss of ovarian-function in menopausal women – and how much the gut microbiome contributes to that – has not been studied. The etiology is clearly very complex, but those gut-microbiome related factors are certainly components that we speculated play a role,” said first author Dr. Tzu-Wen L. Cross, professor of nutrition science and the director of the Gnotobiotic Animal Facility at Purdue University.

The gut microbiome responds to changes in female sex hormone status

Cross and the team first characterized inflammatory and metabolic phenotypes associated with obesity and the loss of female sex hormones in mice. They performed an ovariectomy to simulate menopause in half of the specimens and fed them an identical diet that differed in the proportion of fat: 60% of total calories for the high-fat group and 10% of total calories for the low-fat group.

They also performed fecal microbiota transplantations (FMT) in germ-free mice, using samples harvested from mice with or without ovaries, to investigate the effect of an ovariectomy-associated gut microbiome on weight gain and metabolic and inflammatory activity.

What are fecal microbiota transplantations?

Fecal microbiota transplant (FMT) involves transferring fecal matter obtained from a donor to a recipient’s intestinal tract to affect the recipient’s gut microbiota. In some cases, the procedure can restore the balance of bacteria in the recipient's gut, treating conditions like recurrent Clostridioides difficile infection. By introducing healthy bacteria, FMT can help rebuild a diverse and functional microbiome, potentially alleviating symptoms and promoting gastrointestinal health.

The researchers found that mice subjected to a high-fat diet and those undergoing ovariectomy exhibited enlarged fat cells, which is associated with both cell death and the infiltration of macrophages that secrete pro-inflammatory proteins. Additionally, these mice showed heightened expression of inflammation-related genes and a reduced expression of genes involved in glucose and lipid metabolism.


The mice that received FMT from the ovariectomized mice gained more weight and increased levels of fat compared to those in the control group. The researchers also observed an increase in the expression of genes associated with inflammation, obesity, Type 2 diabetes, fatty liver disease and atherosclerosis.

Cross and colleagues also investigated cell membrane permeability by looking at the expression of genes coding for tight-junction proteins. The mice who underwent ovariectomies and those fed a high-fat diet exhibited lower levels of these proteins in the liver and colon, suggesting their gut barriers were more permeable compared to the other groups. They also observed high levels of arginase-1, which plays a critical role in eliminating nitrogenous waste. This protein has been linked to cardiovascular problems such as hypertension and atherosclerosis.

Treating menopause-related diseases

Cross and team demonstrated that the loss of female sex hormones simulated via an ovariectomy led to greater gastrointestinal permeability and inflammation of the gut and metabolic organs, and that a high-fat diet exacerbated these phenotypes.

“This is the first time it has been shown that the response of microbiome to the loss of ovarian hormone production can increase metabolic dysfunction,” said Cross.

The researchers hope their study will pave the way to further understanding how menopause can increase the risk of metabolic diseases and may lead to future therapeutics.


“Identifying and developing gut microbiome-targeted modulators to regulate sex hormones may be useful therapeutically in remediating menopause-related diseases,” the authors wrote.

Reference: Cross TWL, Simpson AMR, Lin CY, et al. Gut microbiome responds to alteration in female sex hormone status and exacerbates metabolic dysfunction. Gut Microbes. 2024;16(1):2295429. doi: 10.1080/19490976.2023.2295429

This article is a rework of a press release issued by the University of Illinois Urbana-Champaign. Material has been edited for length and content.