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Elucidating Complex Interactions Between Human Gut Microbes, Diet, and Response

Research is illuminating the multiple levels of complex interactions that contribute to how human gut microbes affect health: at the level of communities of people with different diets, within an individual’s gut microbial community, and among metabolites produced by these gut microbes.

One research group explored the larger social context of how a community of people and their dietary habits can affect an individual’s gut microbial community and response to changes in diet. They used genetic sequencing of bacterial DNA in fecal samples from adult Americans—either from those following a typical American diet or a diet restricted in calories but with sufficient nutrients—to identify unique gut microbial communities associated with these diets. Gut microbial diversity, which is a marker of digestive health, was enriched in the individuals who consumed the calorie-restricted diet. To model how microbial exchange among a close community of individuals affects response to diet, the scientists collected fecal microbes from people in the two diet groups and transplanted these into male mice that had been raised in a sterile environment to be “germ-free.” The mice colonized with microbes from the people consuming a typical American diet were then housed with mice that harbored microbes from people on a calorie-restricted diet, and all the mice were given a calorie-restricted diet. The researchers found that the mice originally colonized with the American-diet microbes developed a more diverse gut microbial community, resembling that of their cage-mates. These animals also showed metabolic changes in their use of dietary components such as glucose. Because mice share gut microbes more easily than humans, further human studies are needed. However, these findings show the potentially profound effects of the gut microbes present in people who come into contact with one another and how this exchange may enhance response to dietary interventions.

Another group of researchers, many of whom also worked on the previous study, focused on interactions within the gut microbial community in the context of malnutrition, a leading cause of childhood mortality worldwide. Fecal samples had been collected for an earlier study from two, 2-year-old children living in low-income households in Dhaka, Bangladesh. One child was stunted in growth, underweight, and harbored a pathogenic strain of the microbial species Bacteroides fragilis that causes diarrhea, while the other child showed normal growth and had harmless strains of B. fragilis bacteria. The researchers transplanted the children’s fecal microbes into adult, male, germ-free mice whose food was similar to the children’s diets. Mice transplanted with the underweight child’s microbes suffered significant weight loss within a few weeks while those transplanted with the healthy child’s microbes maintained their weight. The scientists then isolated the microbial strains present in the children’s fecal samples and created custom microbial communities for transplantation that contained the pathogenic strain of B. fragilis, the harmless strain, or a mixture of the two—along with other microbes from each fecal sample. They found that the pathogenic B. fragilis from the stunted donor caused weight loss in mice when in the context of its original microbial community, but not when transplanted with the healthy donor’s microbial community containing harmless B. fragilis strains, in addition to other microbes. The weight loss associated with the growth-stunted donor’s microbial community was passed down between generations, from pregnant mice harboring the microbes to their offspring. The scientists also showed how nutrient metabolism and immune function in the host mice were adversely affected by the presence of microbes from the stunted donor. These studies reveal the importance of microbial community context in influencing how the total burden of microbes harbored by young children can affect metabolism and growth, immune function, and disease.

A third study, from a separate research group mining data from the NIH Human Microbiome Project, focused on the biologically active small molecules produced by resident gut microbes and how they might affect health or disease in their human hosts. Using computational analysis, they searched the genomes of human gut microbes to identify bacterial gene clusters that are present in samples from a majority of people and are unique to their intestinal niche, but were of unknown function at the time. They put these gene clusters into two common types of gut bacteria, turned on the genes, and then purified and analyzed the molecules that were produced as a consequence. They found that the active component produced by the gene clusters was a group of molecules called peptide aldehydes, which can affect human host cells by inhibiting enzymes that play important roles in antimicrobial defense. The findings suggest that the peptide aldehydes produced by gut microbes may help human hosts to tolerate “friendly” bacterial species.

This trio of studies provides a snapshot of the vibrant research efforts on the gut microbial community that are taking place at many levels simultaneously—from the social to the microbial to the molecular. Studies such as these are helping to improve understanding of the complex mechanisms by which gut microbes affect human health. This work can serve as a basis for developing future dietary and other interventions that are more effective by virtue of being tailored to individuals and their microbes, specifically by considering the impacts of diet, social interactions, and the totality of the gut microbial community and its metabolic output.