Studies in mice by researchers at the University of Utah have shown how specialized immune cells can protect against obesity and associated metabolic syndrome by controlling communities of intestinal bacteria that either promote or reduce fat absorption. The studies, reported in Science, found that immune-compromised mice with a lack of IgA production in the gut had reduced numbers of Clostridia bacteria in their microbiomes. Even when a fed a healthy diet these animals eventually became obese, but if their microbiomes were supplemented with Clostridia they remained slim. The researchers suggest that the findings could lead to the development of new therapeutic approaches to obesity that have advantages over microbiome-restoring fecal transplant or probiotic-based strategies.
“Now that we’ve found the minimal bacteria responsible for this slimming effect, we have the potential to really understand what the organisms are doing and whether they have therapeutic value,” suggested June Round, PhD, an associate professor of pathology at the University of Utah Health, who is co-senior author of the researchers published paper, which is titled, “T cell-mediated regulation of the microbiota protects against obesity.” Charisse Petersen, PhD, who led the research, commented, “These bacteria have evolved to live with us and benefit us. We have a lot to learn from them.”
More than 1.9 billion people around the world are now obese and at risk of developing metabolic disorders such as type 2 diabetes, cardiovascular or liver disease, the authors noted. Multiple studies have focused on the role of the immune system in metabolic disease, and in particular on inflammatory responses in obesity.
The microbiome is believed to act as a key regulator of metabolism, and may be altered in obese people, the authors continued. The immune system, and IgA antibodies, in particular, are thought to play a role in controlling the mix of bacteria in the microbiome. “We and others have recently shown that gut immune responses are critical in regulating the composition of the microbiota … Defective immune control of the microbiota may contribute to metabolic disease.” Interestingly, human studies suggest that obese individuals have lower mucosal immunoglobulin A (IgA) levels, suggesting that they can’t mount an effective immune response. Suboptimal immune responses are also associated with MetS [metabolic syndrome] and obesity. However, the authors wrote, “the mechanisms by which defective immune reactions influence metabolic disease remain unclear.”
The researchers’ latest studies focused on a strain of genetically engineered immune-compromised mice (T-Myd88-/- animals) that exhibit defective T follicular helper (TFH cell) development and IgA production in the gut. This lack of gut IgA production means the animals can’t effectively control gut microbiome composition. The team discovered that these T-Myd88-/- mice inevitably became obese as they got older, even when fed a normal “chow” diet, and they developed many of the obesity-related metabolic diseases that are found in obese humans.
Further studies in T-Myd88-/- and normal animals showed that the T-Myd88-/- animals’ gut microbiomes had reduced numbers and diversity of multiple types of Clostridia bacteria, and increased numbers of a bacterium called Desulfovibrio. This organism has previously been linked with inflammatory bowel disease and type 2 diabetes and obesity, the authors pointed out. The experiments indicated that the Desulfovibrio species flourished in the immune-compromised animals, at the expense of the Clostridia species. When they supplemented the T-Myd88-/- animals with Clostridia bacteria the animals showed much less weight gain. “Thus, the loss of Clostridia is causally associated with obesity and MetS in T-Myd88-/- animals mice,” the authors wrote.
The team found that in the T-Myd88-/- animals defective IgA targeting of the microbiome meant the populations of Clostridia and Desulfovibrio bacteria weren’t maintained at the same levels as in wild type animals. “Thus, reductions in Clostridia and their functional contributions may arise from a combination of inappropriate targeting by IgA and the expansion of Desulfovibrio,” they wrote. “Appropriate TFH cell function is required to regulate the microbiota to prevent obesity.”
Liver RNA sequencing (RNA-seq) and gene set enrichment analysis (GSEA) data showed that lipid metabolism pathways were disrupted in the T-Myd88-/- animals, even when they were fed a normal chow diet. Genes including CD36, which are required for lipid absorption, were upregulated in the T-Myd88-/- animal livers, but could be downregulated by treating the mice with antibiotics or giving the animals supplements of Clostridia bacteria, “suggesting that Clostridia function to reduce lipid uptake,” the investigators stated. “CD36 is a critical regulator of lipid absorption within the intestine, and its deficiency results in resistance to the development of obesity and MetS upon HFD feeding,” they further pointed out.
Interestingly, when mice that were bred with no natural microbiome (germ-free mice) were colonized with Clostridia they developed far less body fat than control animals, or those that were colonized with just Desulfovibrio. “The addition of Desulfovibrio to germ-free mice colonized with the Clostridia consortia alone led to an increase in body fat percentage,” they noted. Thus, gut bacteria can differentially regulate lipid metabolism. Products secreted by Desulfovibrio up-regulate CD36 expression, whereas products produced by Clostridia can down-regulate CD36 expression. Therefore, the loss of organisms that function to temper CD36 expression may lead to the inappropriate absorption of lipids, which can accumulate over time, leading to obesity and MetS.”
Having found Clostridia produce molecules that prevent the gut from absorbing fat, the next step will be to try and isolate these molecules and characterize how they work, and to determine whether they could lead to the development of treatments for obesity, type 2 diabetes, and other related metabolic disorders. “We’ve stumbled onto a relatively unexplored aspect of type 2 diabetes and obesity,” Round said. “This work will open new investigations on how the immune response regulates the microbiome and metabolic disease.”