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December 22, 2016

The Microbiome and Risk for Obesity and Diabetes

Author Affiliations
  • 1Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
JAMA. Published online December 22, 2016. doi:10.1001/jama.2016.20099

Obesity and type 2 diabetes mellitus are influenced both by genes and lifestyle. That is not news. However, the genes in the human microbiome also may play an important role, and that is news.

It has been known for decades that gut bacteria synthesize essential vitamins and amino acids and help degrade toxins. During the past decade, it has become clear that the influence of the microbiome on health may be even more profound.

Beginning at the moment of birth, each human increasingly coexists with microbes. By the time individuals reach adulthood, they are colonized by many more microbial cells than the roughly 13 trillion human cells. More important still, these microbial cells (the microbiota), collectively, have exponentially more genes (the microbiome) than do human cells, around 250 to 800 times more.

Moreover, many genes in the human microbiome generate proteins, including hormones, neurotransmitters, and molecules of inflammation, that can enter the circulation and affect health. In light of this, it is reasonable to question whether the genes of the microbiome might play a greater role in health than do human genes. Recent evidence suggests that the microbiome may affect the probability of many major diseases, including obesity and diabetes.

Obesity

How could microbiota in the gut affect obesity? First, microbiota could influence the calories the body absorbs. Body weight is not affected by the calories that are ingested, but rather by the calories that are absorbed. Simple sugars in the diet are easily absorbed, and human enzymes convert starches into simple sugars, but human enzymes fail to digest many dietary polysaccharides. Microbial enzymes can turn those polysaccharides into digestible sources of energy, particularly monosaccharides and short-chain fatty acids.

About 90% of gut bacteria are in 1 of 2 phyla: Bacteroidetes and Firmicutes. Firmicutes generate more harvestable energy than Bacteroidetes. Obese humans have relatively more Firmicutes, as do rodents placed on a high-fat diet.1

Various experiments suggest that microbiota may powerfully affect obesity in mammals. For example:

  • Gut microbiota from obese mice and from lean mice were transplanted into germ-free, lean mice, all of whom had the same daily caloric intake. Over the next 2 weeks, the mice receiving microbiota from obese mice became obese, whereas those receiving microbiota from lean mice remained lean.1

  • Gut microbiota from conventionally raised farm animals were placed in the guts of lean germ-free mice. Without any increase in daily caloric intake, the body fat content of the animals increased by 60% within 14 days, and they developed insulin resistance.2

  • Obese mice underwent Roux-en-Y gastric bypass (RYGB) surgery or sham surgery. Mice that underwent RYGB surgery had the expected weight loss and a characteristic change in the gut microbiome, whereas mice that underwent the sham surgery did not. Transfer of bacteria from mice that underwent RYGB surgery to mice that underwent the sham surgery resulted in weight loss, although not as great as seen following RYGB surgery.3

  • Investigators studied human twin pairs (mostly monozygotic) in which 1 person was obese. Feces from the fat twins and feces from the lean twins were fed to the germ-free mice, which were of normal weight. The mice fed feces from the fat twins became fat; those fed feces from the lean twins remained lean. The fat and lean mice were then housed together. Mice eat each other’s feces. Gradually, the obese mice became lean, and their gut flora came to resemble the flora of the lean mice. This finding suggests that the flora of lean mice may be able to dominate the flora of obese mice.4

These experiments suggest that the composition of gut microbiota can influence obesity. However, other experiments suggest that obesity can influence the composition of gut microbiota. For example, when obese people diet and lose weight, the proportion of Bacteroidetes increases relative to Firmicutes.4 Conversely, when obese people resume their previous diets and gain weight, the proportion of Firmicutes increases.4 These experiments suggest that the microbiome may be a reflection of obesity (or leanness), as well as a cause of it. In addition, low-grade gut inflammation caused by gut microbiota may increase the risk of obesity along with the risk of type 2 diabetes.

Type 2 Diabetes Mellitus

Given the increased risk of developing type 2 diabetes in obesity, it is not surprising that the microbiome might also influence type 2 diabetes. However, more than enhanced absorption of carbohydrates may be involved.

Relatively high ratios of Firmicutes to Bacteroidetes not only influence carbohydrate metabolism, but also alter the production of short-chain fatty acids. In particular, acetate production is increased and butyrate production decreased. A recent study5 found that increased blood levels of acetate cause insulin resistance and increase production of ghrelin (the appetite-stimulating hormone) in the stomach. Lower butyrate levels in the gut encourage low-level inflammation, which evokes insulin resistance.6

Gut inflammation has another effect. In rodent studies, inflammation weakens epithelial tight junctions in the gut mucosa, facilitating the entry of bacterial endotoxins into the blood. This “metabolic endotoxemia” leads to increased activity of the innate immune system, which leads to insulin resistance and weight gain.7

Studies in humans also suggest a role for the gut microbiota in type 2 diabetes. Most studies have found that individuals with type 2 diabetes have a reduced abundance of butyrate-producing species, leading to low-grade inflammation in the gut. This has been found in people of different races and ethnicities and after controlling for the effect of medications (particularly metformin) on the gut microbiome.8 A prospective study of more than 7000 children has linked the use of probiotics during the first month of life to a lower risk of islet autoantibodies, suggesting that the gut microbiome may also play a role in type 1 diabetes mellitus.9

It is unlikely that a single species of gut bacteria plays a dominant role in altering the risk of type 2 diabetes, although several studies have found that increased numbers of Akkermansia muciniphila reduce inflammation in adipose tissue and improve insulin signaling.

Even though many studies have reported associations between the microbiome and type 2 diabetes in humans, only experimental evidence can suggest a causal connection. At least 1 study does. Treatment-naive men with the metabolic syndrome had their gut flora eliminated by polyethylene glycol lavage. Then they were randomized to receive small intestinal infusions (through a gastroduodenal tube) either from lean male donors or from their own feces. In men who received infusions from lean individuals, insulin sensitivity increased. This effect declined over time, and there was considerable individual variability. Recipients of feces from lean donors had a higher abundance of butyrate-producing bacteria.10

Conclusions

It is plausible that the human microbiome may affect the risk of obesity and type 2 diabetes and other diseases such as atherosclerosis, and that manipulations of the microbiome might reduce that risk. However, biomedical science is a long way from proving either proposition. Dissecting the possible role of the microbiome in these and other diseases will be a great challenge, because (1) human genes influence the composition of the gut microbiota, (2) microbial genes influence the expression of human genes, (3) the metabolism of some gut microbes influences the metabolism of other gut microbes, and (4) diet influences both the microbiota and (possibly) the expression of human genes. In short, human genes, microbial genes, and diet share a complicated set of interdependencies.

It might seem unlikely, at first, that the microbiome could affect the risk of major metabolic diseases. During the past decade, research has revealed that it is not unlikely at all. In the end, disease is the result of disordered biochemistry. Genes drive biochemistry, the human microbiome contains exponentially more genes than there are human genes, and those microbial genes produce molecules that affect human physiology.

New technologies (particularly rapid, inexpensive nucleic acid sequencing) have provided the tools to understand how the microbiota might affect health. Scientists have learned a great deal during the past 50 years about modifiable risk factors for obesity and type 2 diabetes. During the past decade, scientists have discovered that perhaps the microbiota are the most important modifiable risk factor of all.

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Article Information

Corresponding Author: Anthony L. Komaroff, MD, Brigham and Women’s Hospital, Harvard Medical School, 10 Shattuck St, Boston, MA 02115 (anthony_komaroff@hms.harvard.edu).

Published Online: December 22, 2016. doi:10.1001/jama.2016.20099

Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Additional Contributions: I thank George Weinstock for providing valuable comments.

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