Immune system defects seem to contribute to obesity in mice

Similar changes that alter the microbiome and change fat uptake may be at work in people too

mice

WEIGHING IN  In one study of mice, how some immune cells function influenced weight gain. Gut microbes appear to have a say, too.  

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Subtle defects in the immune system may lead to obesity and type 2 diabetes, a study of mice suggests.

Mice gained weight and developed health problems when they carried a genetic defect that dampens some immune functions, researchers report in the July 26 Science. The immune problems were linked to shifts in the gut microbiome — the collection of friendly bacteria and other microbes living in the intestines. Altering the gut microbe mix, particularly in the small intestine, may lead to increased absorption of fat from the diet, the researchers found.

These findings, if they hold up in human studies, could lead to strategies for boosting immune system function in order to help prevent obesity and associated health problems.

People with obesity and those with type 2 diabetes also have gut microbe compositions  and subtle immune system deficiencies similar to those seen in the mice, says June Round, a microbiome researcher at the University of Utah School of Medicine in Salt Lake City. “It’s possible that things that are happening in our mice are also happening in individual [humans],” she says.

Round and colleagues noticed that mice with a defect in the Myd88 gene started gaining weight at about 5 months old. By about a year old, those mice, which lack Myd88 protein in immune cells called T cells, weighed up to 60 grams — about twice as much as a normal mouse. The mutant mice also had developed metabolic problems associated with obesity, such as insulin resistance, a hallmark of type 2 diabetes in people.

Those mice lacking Myd88 had reduced activity of a subset of specialized T cells called T follicular helper cells. These helper cells tell other immune cells called B cells to make antibodies against certain microbes. The mice also made fewer IgA antibodies aimed at controlling certain microbes.

Obese mice had fewer types and lower numbers of Clostridia bacteria and more Desulfovibrio bacteria in their intestines, particularly the small intestine, the researchers found. That pattern also has been seen in obese people and people with type 2 diabetes. Some Clostridia species in the Myd88 mutant mice were coated with more IgA antibodies, suggesting those bacteria were inappropriately targeted for destruction. But other Clostridia species had fewer IgA antibodies clinging to them, perhaps hampering their ability to effectively colonize the intestine. Desulfovibrio also was more heavily antibody-coated than usual, but the researchers aren’t sure if or how that aids its growth. 

Giving fat mice more Clostridia led to weight loss. But the researchers couldn’t make normal mice fat just by giving them Desulfovibrio, probably because the immune system in normal mice can keep the bacteria in check, Round says.

Altered microbiomes may affect how much fat is absorbed in the small intestine. Giving Myd88 mutant mice extra Clostridia reduced the production of a protein involved in fat absorption. But giving the mice Desulfovibrio had the opposite effect, increasing the protein’s production. Those results suggest that Clostridia protect against obesity, while Desulfovibrio promotes it.

Previous research has indicated that both gut microbes and diet are involved in determining body weight. But the new study “shows that the immune system is really important in how that plays out,” says Lora Hooper, a microbiologist and immunologist at the University of Texas Southwestern Medical Center in Dallas. She was not involved in the study, but coauthored a commentary that appears in the same issue of Science.

The work raises many questions, Hooper says. “Why is our microbiome in charge of how much lipid (fat) we take up?” She doubts that Clostridia evolved to protect against obesity, a relatively modern problem. Instead, she speculates, ramped up fat absorption may have evolved to meet the body’s increased energy needs when dealing with pathogens or overgrowth of Desulfovibrio and other gut bacteria.

Tina Hesman Saey is the senior staff writer and reports on molecular biology. She has a Ph.D. in molecular genetics from Washington University in St. Louis and a master’s degree in science journalism from Boston University.