Male mice are three times more likely to survive an E. coli infection than females

Male mice are three times more likely to survive an E. coli infection than females

Scientists at UC San Francisco (UCSF) have developed a new perspective on gender-specific diseases that is rooted in evolutionary biology.

They theorize that men and women took opposite paths in a trade-off between immunity and metabolism that occurs in the liver. This helped males fight bacterial infections through wounds sustained during dominance fights, while helping females store subcutaneous fat to survive when food is scarce.

Using mice, the scientists describe the activity of a signaling pathway that regulates lipids, stores fat in the liver in men and releases it into the bloodstream in women. This signaling pathway also responds to growth hormones.

This phenomenon may have shaped male biology in ways that pose risks in today's high-calorie environment. The findings have particular relevance to fatty liver disease, which affects a quarter of the U.S. population. It is predominantly seen in men until women reach menopause.

“Scientists have only recently begun to understand that there are these profound differences between men and women,” said Holly Ingraham, PhD, Herzstein Professor of Molecular Physiology at UCSF and co-author of the study, which appears October 21, 2022 in Science. "Understanding these differences will be key to unlocking therapeutics for gender-specific diseases. Fatty liver disease is one example."

The experiments showed that male mice were three times more likely to survive an infection with the E. coli bacterium than female mice. The females developed hyperlipidemia, a condition that also occurs in humans with severe sepsis. Lowering their lipid levels helped them survive.

The researchers then examined how males and females respond to the current environmental challenge of overeating by feeding the mice high-fat food. Men developed fatty liver disease and glucose intolerance, which can lead to type 2 diabetes, but women did not. This was true even when males and females gained a similar amount of weight.

The team searched the literature for something that might explain this and identified a transcription factor called BCL6, which prevents fat breakdown in the liver and is much more common in male mice.

Deleting the gene for this protein eliminated liver fat in the males and thus their ability to survive the infection.

“The host defense programs in the liver are the predisposing factors that drive fatty liver disease in men,” said Joni Nikkanen, PhD, a postdoctoral fellow in the Department of Cellular Molecular Pharmacology who began the work with co-senior author Ajay Chawla, PhD, formerly of UCSF and now at Merck Research Labs.

"We have an evolutionary perspective as to why such programs have evolved - because they protect men from bacterial infections," he said. “But in a different context, the same programs are no longer good for you, and you will develop more severe fatty liver disease.”

The team also examined how the presence of BCL6 affected gene expression in the liver. This process begins at puberty, when men produce more testosterone and their pituitary gland begins secreting growth hormone in sharp peaks and valleys.

These intermittent bursts, likely regulated by testosterone, are important. When researchers continuously injected male mice with growth hormone like that secreted by females, BCL6 disappeared from their livers and they lost the ability to fight E. coli infections.

The results point to growth hormone as a potential therapy for adults with fatty liver disease, an idea that is currently being tested. Its effect is already well established in children whose pituitary glands do not produce enough growth hormone. Male children in particular are prone to developing fatty liver disease, but this disappears when they are given growth hormones to treat their short stature.

The work also expands the scientific view of how the body fights infections to include organs such as the liver.

The battle is still between the infection and the immune system. But the liver rules the battlefield.”

Omer Gokcumen, PhD, evolutionary anthropologist, University at Buffalo and co-author of the study

Source:

University of California – San Francisco

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