The Fundamental Link Between Body Weight and The Immune System

    Abdulaziz Sobh

    It's simple: eat less.

    Sometimes combined with the directive movement more, this mantra has a clear point. If you can't lose weight, it's stupid or lazy, or probably both. See also: Calories inside, calories outside.

    But if things were that simple, diets would work. Middle-aged people would not suddenly start to gain weight despite eating and moving similarly year after year. No one would have to endure the presence of that friend with "fast metabolism" who can eat whatever he wants. And who, even though he knows you're on a diet, says through his full mouth, "I couldn't even gain weight if I tried."

    Instead, it is increasingly clear that the bowels of some people are simply more efficient than others to extract calories from food. When two people eat the same 3,000-calorie pizza, for example, their bodies absorb different amounts of energy. And those calorie conversion skills can change during the life of a person with age and other variables.

    The question is why? And is it possible to make changes, if a person wanted to?

    If so, the solution will involve the billions of microbes in our intestines and how they work in concert with another variable that has just begun to attract attention. The immune system determines the levels of inflammation in the intestine that are constantly shaping the way we digest food: how many calories are absorbed and how many nutrients simply pass.

    The relationship between microbes and weight gain has been overlooked in humans, but people have known about similar effects on animals for decades. After World War II, antibiotics became affordable and abundant for the first time. Farmers began giving drugs to their cattle, for example, to treat the infected udder of a dairy cow, and noted that animals that received antibiotics became larger and faster.

    This led to an avalanche of patent applications for food loaded with antibiotics for all types of livestock. In 1950, the pharmaceutical company Merck filed a patent for "a method to accelerate the growth of animals" with "a new growth-promoting factor" that was simply penicillin. Eli Lilly patented three new antibiotics to mix in the feeding of sheep, goats, and cattle because the agents that kill the microbes "increased food efficiency." In the following decades, it became a standard practice to give cattle copious doses of antibiotics to grow faster and bigger, even though no one knew why this happened, or what other effects the practice could have.

    Researchers have recently shown that these antibiotics eliminate some of the microbes that normally occur in the intestine and help livestock and people digest food. By breaking down nutrients and helping them cross the walls of the intestine, these microbes serve as a kind of guardian between what is eaten and what actually enters the body.

    Killing them is not without consequences. Just as antibiotics are associated with faster growth in cattle, a decrease in diversity in the human microbiome is associated with obesity. As the use of animal antibiotics exploded in the twentieth century, so did the use in humans. The increase coincides with the obesity epidemic. This could be a spurious correlation, of course, many things have been on the rise since the 1950s. But discarding it altogether would require ignoring growing evidence that our metabolic health is inseparable from the health of our intestinal microbes.

    In 2006, Jeffrey Gordon, a biologist at the University of Washington in St. Louis, reported that the microbiomes of obese mice had something in common: compared to their thin counterparts, the heavier mice had fewer Bacteroides and more Firmicutes species in your intestines, In addition, biochemical analyzes showed that this proportion improved microbes in the "energy harvest", essentially by extracting calories from food and passing them to the body. That is, even when the mice ate the same amount and type of food, bacterial populations meant that some developed metabolic problems, while others did not. Since then similar bacterial patterns have been confirmed in obese humans.

    In addition, Gordon discovered that the microbiome associated with obesity is transferable. In 2013, his laboratory took intestinal bacteria from pairs of human twins in which only one twin was obese, then fed the samples to mice. Mice that received bacteria from obese humans quickly

    Intestinal bacteria are also transferred between humans, in the form of fecal transplants, as an experimental treatment for serious infections such as Clostridium difficile. In one study, obese patients who received transplants from thin donors then had healthier responses to insulin.

    In the absence of this type of complete microbiome restoration, preliminary research has shown that adding even a single bacterial species to a person's intestine can alter their metabolism. In a clinical trial published last month in the journal Nature Medicine, people who took a probiotic containing Akkermansia muciniphila, which is usually found in large quantities in non-obese people, saw subtle metabolic improvements, including weight loss.

    The study authors do not suggest that someone go out to buy this bacteria. But they call it a "proof of concept" because of the idea that it is possible to change a person's microbiome so that it has metabolic benefits.

    Because thinness and obesity seem to be transmissible through the microbiome, "metabolic disease turns out to be, in some way, an infectious disease," says Lora Hooper, president of the immunology department at the University of Southwestern Medical Center Texas. Hooper did his postdoctoral research at Gordon's lab in St. Louis. While other researchers focused on the intestinal microbiome itself, she became interested in the immune system. Specifically, I wanted to know how an inflammatory response could influence these microscopic populations and, therefore, be related to weight gain.

    Over the past decade or so, multiple studies have shown that obese adults mount less effective immune responses to vaccines and that both overweight and low-weight people have high rates of infection. But these were supposed to be effects of obesity, not causes.

    "When I started my laboratory, not much was known about how the immune system perceives intestinal microbes," says Hooper. "Many people thought that the intestinal immune system could be somewhat blind to them." For her, it was obvious that this could not be the case. The human intestine harbors around 100 billion bacteria. They fulfill vital metabolic functions, but can quickly kill a person if they enter the bloodstream. "So clearly the immune system has to be involved in its maintenance," she says. It made sense to her that even subtle changes in the functioning of the immune system could influence microbial populations and, therefore, weight gain and metabolism.

    This theory was confirmed at the end of last month in an article in Science. Zac Stephens, a microbial ecologist at the University of Utah, and his colleagues had been working with mice with altered immune T cells. They realized that over time, these mice "swelled," as Stephens puts it. One of his colleagues began calling them "pancakes."

    To discover how such an immune change could cause obesity, they tested the biomes of the mice with and without the immune alteration. They discovered that healthy mice have many bacteria of a genus called Clostridia, but few of Desulfovibrio, and that their intestines let most of the fat pass. Those with an altered immune system had less Clostridia and more Desulfovibrio, and this microbial balance helped the intestine absorb more fats from food. These mice gained more weight and exhibited signs of type 2 diabetes.

    "If this applies to humans, we don't know," says Hooper, "but this is a tempting clue."

    Mice are not human, but their microbiomes are almost as complex as ours. Clostridia reduction and increased Desulfovibrio are seen in people with obesity and type 2 diabetes. Bacteria can reasonably be expected to function similarly in the guts of different species. But even if they don't, this experiment is a demonstration of principles: the immune system helps control the composition of the intestinal microbiome.

    It does this by regularly assembling low-level immune responses to keep bacteria populations under control. "The intestine is under a constant state of inflammation, so to speak: constant immune stimulation of all microbes," says Stephens, rejecting the common misconception that inflammation is always bad. The role of the immune system in the intestine is to maintain balance. Changes in the body's defenses, which can occur as a result of age or disease, can cause certain species to flourish at the expense of others.

    This is the interesting part for Steven Lindemann, a Purdue University researcher who was not involved in the Utah study. Study the effects of food on the intestinal microbiome. "Although we know that, in general, the diet is the one that most contributes to the composition of the intestinal microbiome," he said, this study suggests that when immune control of the colon breaks down, growth can become uncontrolled and cause problems with regulation. metabolic

    Lindemann says that the fact that the immune system regulates the inhabitants of the small intestine is well established. Compare the bowel wall with a customs control point: the goal is to eliminate bad actors and illegal cargo, but allow legitimate trade to progress as quickly as possible. In the case of immuno-altered mice, he says, "we have a border patrol that apparently goes out for lunch, allowing the bad actor Desulfovibrio to flourish."

    If similar microbial changes have comparable effects on humans, it could have far-reaching implications for our diets. The very ideas of "nutritional value" and "caloric content" of food seem to vary according to the microbial population of the person who consumes it and, potentially, their immune status. A person's own microbes and those contained in any given food would have to be considered as another component of the already weak equation of incoming and outgoing calories. This would also aggravate the challenges that nutritional labels already face.

    People trying to control their weight could conclude that the solution is to play with their own microbiomes. This may feed the already dubious and barely regulated industry of "probiotic" supplements, which are expected to grow to $ 7 billion by 2025. But the answer will probably not be so simple.

    "Many of the recent research on probiotics suggests that it is really not easy to maintain and maintain new communities," says Stephens. The immune system could explain that. "It may well be that your immune response is" stuck "at an early age depending on what you have exposed it to. Probiotics may not be enough to change a person's microbiome, because their immune system determined from the beginning that certain microbes are appropriate or inappropriate in your gut. "

    Stephens says that the relationship between weight and the immune system is likely to become more complicated before it is simplified. That makes it difficult to give concrete advice. "Maintaining various intestinal microbes with various dietary sources is probably the safest advice for now," he says. "That will stimulate a healthy and strong immune system that can learn and regulate and do everything it does, in a way we barely begin to understand."

    If all this uncertainty makes nutritional patterns and nutrition even more inscrutable, you can also do something good by undermining moralistic and simplistic judgments often associated with body weight. Seeing obesity as a manifestation of the interaction between many systems (genetic, microbial, environmental) invites us to understand that human physiology has changed along with our relationship with the species that surround us. As these new scientific models develop, they challenge the idea of ​​weight as a defect of an individual nature, revealing it by the self-destructive myth that it has always been.


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