by Sébastien Matamoros
It is comforting to think that we will always be able to rely on our beloved ones for help and support. And no one is closer to us than our own gut bacteria: they protect us from infections, digest food for us, help strengthen the walls of our intestines, and keep us company during our whole life. Bless them. However during the past few years, it has become more and more obvious that some microbes benefit us more than others. There appears to be a very close connection between the identity of one’s gut microbiota (a term used to describe a collection of microbe species) and the development of obesity. If you give the microbes from a thin human twin and his obese (but genetically identical) brother to each of two genetically identical mice and then feed the mice identically (same kind of food, same amount of food, same time of day), the mouse who received microbes from the obese twin becomes obese, but not the mouse that received microbes from the thin twin. To put this even more plainly, you and someone with exactly the same genes as you could eat the same diet and depending on just which microbes you had, you might gain much more (or less) weight.
One of the characteristic features of the composition of microbes in obese people and mice (or, one presumes, squirrels, badgers, wart hogs and every other mammal) associated with obesity is that they tend to be composed of fewer kinds of microbes. Obese microbiota are low in biodiversity. Your gut microbiota may become low in biodiversity because of the use of antibiotics or because of chance events. But the most predictable determinant of whether or not you have a microbiota low in diversity (and hence a predisposition to obesity-inducing microbes) is diet. A diet rich in fat and sugar, and poor in vegetables seems to reduce the number of kinds of microbes present in the gut, favoring those best able to get lots of calories from simple-to-digest foods.
Once it was well established that microbes associated with obesity tend to be less diverse, the lab of which I am a part started to investigate the mystery of which specific microbes were affected: who was missing from obese guts?
The genus Bifidobacterium is a well-known probiotic; you can buy yogurt teaming with it. It is also one of the kinds of bacteria that appears to decrease in commonness in the guts of mice (and maybe people) suffering from obesity. Conversely, artificially increasing the number of Bifidobacterium in the gut appears to help reduce obesity. These facts strongly point toward the direction of Bifidobacterium as an important agent of the healthy gut microbiota, and thus as a marker of healthy gut barrier. But how or why?
One benefit Bifidobacterium or other species may offer (in terms of preventing diabetes or obesity) is through their effects on inflammation (hear me out here, there are a few steps in this process). It has long been known that in obese individuals the immune system seems to constantly suffer from low-level inflammation, the body is irritated through and through. Our work suggests that this inflammation (which is bad and will tend to make obesity worse and precipitate the onset of diabetes) might be due to compounds produced by specific microbes in the gut. These compounds are called lipoplysacccharide molecules or LPS for short. These molecules are recognized by the immune system as “danger” signals, tuning it up and prepping it for a fight. Now here is the last step, most of the time the beneficial microbes lining the gut prevent these LPS molecules from actually reaching the gut. Our team, led by my fearless and friendly boss, Dr. Patrice D. Cani at the Université Catholique de Louvain (Belgium), demonstrated that when the integrity of the intestinal barrier is damaged as it is in obesity, when Bifidobacterium and other key bacteria are missing or rare, these molecules pass through the gut and stimulate inflammation, which in turn contributes to metabolic disorders. But there appears to also be more at play.
Bifidobacterium may help as a physical barrier to LPS molecules, but in and among the mess of microbes in which it lives, there is a bacterium that does even more: Akkermansia muciniphila. A. muciniphila was originally isolated by the team of Professor W. de Vos from the Wageningen University (Netherlands). In the complex ecosystem of our gut, this bacterium is generally located closer to our intestinal cell wall than nearly any other bacteria, even closer than Bifidobacterium. It has the unique capacity to feed on mucin, a mucus-forming protein produced by our intestinal cells (imagine the mucus as the “grease” covering the intestinal walls, keeping the machinery working smoothly and maintaining bacteria at a safe distance from the intestinal cells). While eating the mucin, A. muciniphila also releases signaling molecules that stimulate and reinforce the intestinal cell wall. It is in the best interest of the bacterium to keep the intestinal barrier as sound as possible, for it is its major source of nutrients. By reinforcing the gut wall, this species not only blocks LPS itself, with its own small body, but it also makes our bodies better able to do so as well.
So what happens when A. muciniphila species becomes rare? In humans, similar to the case for Bifidobacterium, this bacterium is more abundant in subjects with low body weight and fat mass and less abundant in pre-diabetic and type 2 diabetic subjects. Similarly in studies with mice, Akkermansia becomes much more rare in mice fed a Western-type diet than those fed healthier diets. But the most exciting result comes from a new study by our team. When A. muciniphila was given as an oral supplement to obese mice, it reduced the symptoms of obesity, suggesting that, someday individual microbe species, such as A. muciniphila, might be given, perhaps even in pills, to help restore the missing biodiversity of our bowels in the way scientists re-introduce rare species to wilderness areas, to help these ecosystems function optimally.
The relationship between obesity and the intestinal microbiota is still very far from being fully explained. I have told you about just two of hundreds of kinds of microbes out of thousands of potentially important species. Although some bacteria may improve gut functions by their presence alone (e.g., Bifidobacterium spp., Akkermansia muciniphila), preservation of the microbiota’s diversity in the first place through a balanced diet and the careful use (rather than misuse) of antibiotics seems to be the easiest way to conserve the biodiversity upon which your health, well-being and weight depend.
Ley, R.E., et al., Obesity alters gut microbial ecology. Proc Natl Acad Sci U S A, 2005. 102(31): p. 11070-5.
Turnbaugh, P.J., et al., An obesity-associated gut microbiome with increased capacity for energy harvest. Nature, 2006. 444(7122): p. 1027-31.
Turnbaugh, P.J., et al., A core gut microbiome in obese and lean twins. Nature, 2009. 457(7228): p. 480-4.
Cani, P.D., et al., Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes, 2007. 56(7): p. 1761-72.
Cani, P.D., et al., Selective increases of bifidobacteria in gut microflora improve high-fat-diet-induced diabetes in mice through a mechanism associated with endotoxaemia. Diabetologia, 2007. 50(11): p. 2374-83.
Everard, A., et al., Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci U S A, 2013. 110(22): p. 9066-71.
About the Author
Sébastien Matamoros is a microbiologist and molecular biologist. Originally trained as a food scientist, he’s very interested in the relationship between people, our food and the microbes associated with both. Sébastien is currently a post-doctoral researcher in Brussels (Belgium), working with Professor Patrice D. Cani, and studying the influence of diet on the intestinal microbiota, particularly the importance of this interaction in the development of obesity.