Do you know someone who seems to “eat like a bird,” yet struggles with obesity? Or someone who “eats like a horse,” but remains thin as a rail? If so, you’re probably suspicious that there’s more to how much one weighs than just nurture (eating too much of the wrong kinds of food) or nature (genes). This week, a study published in the journal Science provided insight into a mechanism that may help explain these observations. In their article T Cell-Mediated Regulation of the Microbiota Protects Against Obesity (Science 365:340, 2019), Charisse Petersen and her colleagues reported that not only microbes but also cells of the immune system within the gut are involved in controlling weight. They confirmed that the composition of the gut microbiota is important in this regard: in a model using germ-free mice, Clostridia protected against obesity, whereas Desulfovibrio inhibited leanness. But what was really interesting, when they dug further they found that cells of the immune system, called T cells, that reside within the gut regulate which bacteria are allowed to stay put while weeding out those that are unwanted. To understand the importance of their study it needs to be put into a broader context.
There’s been a revolution going on in the field of microbiology that started towards the end of the last century. In the case of human biology evidence has accumulated over the past decade that the make-up of the microbes (aka the microbiota) in your gut plays a key role in the metabolism of nutrients.
Because of a breakthrough technology, called metagenomics, that originated in the 1970s in the laboratory of Carl Woese and his colleagues at the University of Illinois Urbana, it became possible to identify microbes in all kinds of ecosystems using probes for genetic material (DNA and RNA). Thus, it was no longer necessary to grow (or culture) them in the laboratory. Subsequently, a vast number and species of bacteria, archaea, fungi, viruses, and parasites have been discovered—over 99% of which we didn’t even know existed!
Investigation of human ecosystems began in earnest in 2008 when a large study supported by the National Institutes of Health called the Human Microbiome Project (HMP) was launched. (The term microbiome is used to describe the microbes that share our body surfaces.) Of the five ecosystems studied: the gastrointestinal tract or gut, skin, oral cavity, lungs, and vagina, the gut has been most intensively investigated. Of the five different kinds of germs, bacteria have received the most attention. Amazingly, we now know that the human gut harbors more bacterial cells (about 39 trillion of them) than cells in the entire body (around 37.2 trillion). And the 2-8 million genes of the more than 2,000 species of bacteria in the gut outnumber the 20,000 genes in the human genome by more than 100-fold.
So far, the findings of the HMP have been nothing short of astounding. Correlations of the gut microbiome with health as well as with a large number of ailments have been established. Along with other disorders associated with the so-called metabolic syndrome, such as type 2 diabetes, obesity has received a great deal of attention. (This isn’t surprising given that an estimated 30% of the world’s population is overweight or obese. Many, if not most, of these people have tried unsuccessfully to control their weight by various diets and exercise).
The first reports of a correlation between the microbiome and obesity came from observational studies of infants who received antibiotics early in life. Antibiotics are well known to alter the gut microbiome. And, infants who received multiple courses of antibiotics were significantly more likely to be overweight as youngsters than were control groups of infants.
Studies from Washington University’s Center for Genome Sciences provided evidence that genetic factors may also be involved. Researchers, led by Jeffrey Gordon, transplanted bacteria from obese or lean identical twins into germ-free mice. They found that the mice that received microbes from obese twins gained significantly more weight, even though they didn’t eat any more than the mice that were given bacteria from lean twins.
In a study from China published in Nature in 2017, the bacterium Bacteroides thetaiotaomicron was found depleted in stool samples from obese subjects. And when this bacterium was given to mice it prevented diet-induce obesity. Also, restoration of an abundance of B. thetaiotamicron was seen in obese patients after bariatric surgery to treat their obesity.
But, the reason that the recent study of Petersen and colleagues is so fascinating is that it helps answer the question of what controls the composition of the gut microbiota? Pointing to a role of the immune system, they found that mice with T cells that lacked Myd88, a receptor involved in production of IgA antibodies, experienced noticeable weight gain, accompanied by fatty liver disease, inflammatory adipose tissue, and insulin resistance reminiscent of obese people. The key feature of the microbiota of these mice was a reduction in colonization of the gut by Clostridia bacteria. And colonization of germ-free mice with protective Clostridia resulted in leanness that was opposed by Desolfovibrio bacteria.
Like most research so far examining the relationship between the gut microbiome and obesity, the study of Petersen, et al, relied on mouse models to tease out the roles of microbes and the intestinal immune system. Of course, the key question now is will such studies lead to new therapies of obesity in humans? A preliminary answer may come from randomized clinical trials that are underway of fecal microbiota transplantation for obesity. Who knows what the future will bring us?
