Gut Instinct: How the Gut Microbiome Influences the Body

Aside from the expected effects the gut microbiome has on metabolism, researchers are finding more and more consequences from the ecosystem inside every GI tract. From hypertension to depression, the gut microbiome influences the entire human body.

Rather than some disorganized mass of bacteria, the microbiota residing in the human gut can be conceptualized as an essential organ integrated into the body and interacting indispensably with the body’s other organs. The study of this internal ecosystem is a relatively new field, but the findings are having wide-ranging consequences for our understanding of many of the body’s functions.

Advances in gene sequencing and other genomic techniques have enabled researchers to unlock the effects of specific bacterial genera and species — a daunting task considering that there are hundreds of species in the average gastrointestinal system. Discoveries that the microbiome is a major player in important endocrine conditions, such as obesity and diabetes, should come as no surprise when you consider that humans and their microbes evolved together, according to Lee Kaplan, MD, PhD, director of the Obesity, Metabolism, and Nutrition Institute at Massachusetts General Hospital in Boston. Humans commonly eat food—even a mother’s milk—that they could not digest without the help of bacteria.

“The microbiota is not a foreign body, it is part of the human body,” Kaplan says. “You have to be adapted to live in the gut, and that adaptation process has occurred over millions of years. You can think of the microbiota as an organ, and one of its functions appears to be to help regulate metabolic functions in the other organs.”

Why Gastric Bypass Works

One of the first places where this interplay became apparent was in the unexpected aftereffects of Roux-en-Y gastric bypass (RYGB) surgery, such as resolving diabetes long before weight loss occurs, effects on the secretion of gut hormones, and alterations in energy balance.

Researchers discovered several years ago that gastric bypass changes the microbiota, and mice have proven to be a good model for investigating the significance of the changes:

A fecal transplant from an obese human can lead to obesity in a mouse, and the bacterial changes that result from RYGB in mice are similar to those seen in humans. In order to see whether the microbiota itself conveys any of the effects of the surgery, Kaplan’s team transplanted gut microbes from mice that had undergone gastric bypass to normal-weight mice. After the transplants, the mice lost about 5% of their body weight and had less body fat, without any alteration in their food intake. Published in 2013 in Science Translational Medicine, the report says: “These findings provide the first empirical support for the claim that changes in the gut microbiota contribute to reduced host weight and adiposity after RYGB surgery.”

“The bottom line is that if you transfer the microbiota from animals that had surgery, it transfers some of the weight loss effects and improvement in metabolic function. It tells us that the microbiota is mediating some of the therapeutic physiological benefits of surgery,” Kaplan says. “RYGB surgery does not work by limiting how much food you can eat, and it doesn’t work by causing malabsorption. Th ose are the most common misconceptions. It works by changing physiology, and it changes physiology in hundreds of different ways. One of those ways is through the microbiota.”

This weight-changing power of the microbiome could cut both ways: A recent case in Open Forum Infectious Diseases described a woman treated with a fecal transplant for C. difficile who became obese. This patient gained 34 pounds over 16 months despite following a medically supervised liquid protein diet and exercise program. The transplant came from her healthy but overweight daughter, who was on her way to becoming obese.

More Calories from the Same Food

Obese people have diff erent microbiota than normal-weight people, and one hypothesis is that the effi ciency of their microbiota contributes to weight gain, according to Rosa Krajmalnik-Brown, PhD, an associate professor of environmental engineering at the Swette Center for Environmental Biotechnology at Arizona State University, who was a featured speaker at a recent obesity management workshop co-sponsored by the Endocrine Society and the Obesity Society. “You might have some really efficient microbes that might help you get a lot more energy out of your food, and you can have less efficient microbes that don’t allow you to get so much energy out of your food,” she says.

Krajmalnik-Brown’s team was the first to describe the changes after gastric bypass. In a 2009 study in the Proceedings of the National Academy of Sciences, they compared the microbiota of morbidly obese, normal weight, and gastric bypass patients. The obese subjects had a higher abundance of bacteria that produce hydrogen and of bacteria that take up that hydrogen to produce methane. The researchers proposed that the high hydrogen uptake by these methanogenic bacteria accelerates the fermentation of plant polysaccharides and allows the absorption of otherwise indigestible material.

“The microbiota is not a foreign body, it is part of the human body. You have to be adapted to live in the gut, and that adaptation process has occurred over millions of years. You can think of the microbiota as an organ, and one of its functions appears to be to help regulate metabolic functions in the other organs.” — Lee Kaplan, MD, PhD, director of the Obesity, Metabolism, and Nutrition Institute, Massachusetts General Hospital, Boston

A 2013 study in the Journal of Clinical Endocrinology & Metabolism reported similar findings: People whose breath has high concentrations of hydrogen and methane gases are more likely to have a higher body mass index and percentage of body fat. These researchers also suggested that the breath gases indicated higher amounts of a microorganism that scavenges hydrogen from other bacteria, which helps the host extract nutrients more efficiently.

But improving digestion of some foods is just one way bacteria can affect metabolism. “They make all kinds of enzymes. They regulate … carbohydrate metabolism, which is what underlies diabetes,” Kaplan says.

“They break down foods … into short-chain fatty acids that can interact with hormones, like appetite hormones. So they could send signals to the brain of satiety or nonsatiety,” KrajmalnikBrown says. They also affect bile acid metabolism, which can affect satiety feelings as well as fat production and storage.

Effects Well Beyond Metabolism

Effects on metabolism are the most studied so far, but the known associations of the microbiota continue to grow and include such diverse conditions as colon cancer, hypertension, depression, asthma, irritable bowel syndrome, inflammatory bowel disease, C. difficile, fatty liver disease, depression, and brain function. “Microbiota has really only been studied in detail for a decade, so it probably does many more things than we know about,” Kaplan says.

For example, Krajmalnik-Brown’s group published a study in PLOS One in 2013 comparing the gut microbiomes of neurotypical and autistic children. They found that autism is closely associated with a distinct gut microflora characterized by reduced diversity

That reduced diversity seems to be a hallmark of many conditions, and one effect of gastric bypass is to increase diversity. In experiments like Kaplan’s transplants, researchers transfer a whole pool of bacteria without regard to particular species, but researchers are moving toward finding associations of specific effects with specific genera and species. A 2013 study in the American Journal of Clinical Nutrition found that bacteria in the genus Lactobaccillus had a positive correlation with decreases in BMI and leptin.

A 2010 study in Diabetes found that Faecalibacterium prausnitzii, a dominant species in healthy individuals, is less abundant in patients with diabetes. The researchers reported an inverse relationship between F. prausnitzii and the low-grade inflammation state characteristic of obesity and diabetes

Krajmalnik-Brown says that such findings could one day lead to the development of targeted probiotics derived from humans that could replace the current ones, which are all cow-derived. For the present, clinicians might advise their patients to cultivate a better inner garden by eating more fiber, including more fruit and vegetables. Not new advice, but perhaps one more argument to convince patients that they are what they eat.

“You might have some really efficient microbes that might help you get a lot more energy out of your food, and you can have less efficient microbes that don’t allow you to get so much energy out of your food.” — Rosa Krajmalnik-Brown, PhD, associate professor of environmental engineering, Swette Center for Environmental Biotechnology, Arizona State University, Tempe

“The microbiota has a large role to play not just in disease, but in the normal conditions of healthy people. The microbiota is keeping you healthy, and so an altered microbiota could fail to keep you healthy, and potentially cause disease,” Kaplan concludes.

— Seaborg is a freelance writer based in Charlottesville, Va. He wrote about
inherited endocrine disorders in the February issue