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Finding a new home—how good (and bad) bacteria colonize the gut

Three studies have revealed details of what happens when a community of bacteria inhabiting the gut is disrupted and then rebuilt by a change in diet or by adding bacteria from a healthy donor, providing valuable insights that could help with the design of microbe-based therapies for the treatment of gastrointestinal infections and other digestive diseases. The digestive tract provides a home to the gut microbiome (also called gut microbiota), which includes trillions of bacteria that aid digestion and help to prevent disease by acting as a competitive barrier to pathogenic microbes. For example, a healthy microbiome can effectively prevent infections by Clostridium difficile (C. difficile), an opportunistic bacterial species that can thrive in the gut when the microbiome is disrupted, such as after antibiotic-based treatments. C. difficile bacteria produce a toxin that causes inflammation in the intestinal wall, creating an even more welcoming home for themselves but severe diarrhea and pain for their human host. One treatment option in use for this infection is fecal microbiota transplantation (FMT), whereby a sample containing gut bacteria from a healthy donor is introduced to help re-establish a functional microbiome. Although there is accumulating evidence for the effectiveness of this therapy in people with recurrent C. difficile infections, significant roadblocks remain, such as how to predict which bacteria will settle the gut and what factors influence their colonization.

In the first study, researchers sought to develop a method to predict which bacteria will colonize the gut following FMT. To do so, they monitored the microbiomes of 19 people with recurrent C. difficile infections after they underwent FMT from one of four healthy donors. Stool samples were collected from the donors and the C. difficile patients before the procedure and from the patients in follow-up visits afterward to track which types of bacteria from the donors colonized and persisted in the patients’ guts. While previous studies were limited to cataloging gut bacteria at the species level, the researchers developed a more precise method, called “Strain Finder,” to deduce specific strains within the species. Applying Strain Finder to the data garnered from the samples, the researchers found that the degree of colonization was determined by the species of bacteria, along with how much of that species was in the donor’s sample. They also found that only a fraction of bacterial species colonized the gut, and the strains within those species colonized in an all-or-nothing fashion—generally, either all strains from a species colonized the gut, or none did. Based on these results, the researchers were able to create a mathematical formula that they could use to predict which species and strains of bacteria from an FMT donor will successfully colonize a recipient’s gut. To test their formula, the researchers applied it to analyze studies of groups of people who were treated with FMT for C. difficile infections or, in research at an earlier stage of exploration, people who were given FMT to see whether it might affect metabolic syndrome (a condition characterized by a set of risk factors for cardiovascular disease and diabetes). The model’s further evaluation for patients with a condition besides C. difficile infection was particularly important because the C. difficile patients received antibiotics to attempt to treat the infection prior to FMT—potentially affecting colonization of incoming bacteria—while other patients did not. Overall, the results of this study will help to optimize FMT and to develop the composition of specific and effective microbiome-targeted treatments. However, even though these results can be used to predict which bacterial strains will colonize the gut after FMT, they raise the question of why these strains will colonize while others will not.

In the second study, another group of researchers attempted to answer this question by using a mouse model to test whether access to specific nutrients would affect the ability of bacterial strains to settle in the gut. They engineered a strain of gut-friendly Bacteroides bacteria to enable it to metabolize porphyran, a complex carbohydrate found in a species of seaweed. They added porphyran to the diet of the both male and female mice, which harbored either a conventional mouse microbiome or a microbiome from a human fecal sample, to determine whether the porphyran would allow the engineered bacteria to colonize the mice’s guts. The researchers found that not only did the engineered strain readily colonize the mice that were fed porphyran, but it also displaced native Bacteroides strains that were unable to metabolize this nutrient. In fact, the researchers were able to calibrate the number of engineered bacteria that settled in the guts by varying the amount of porphyran in the mice’s diets. These results show that nutrient availability can be an important factor in determining whether a bacterial strain will successfully colonize the gut and that the gut’s environment can potentially be manipulated to favor colonization by a select bacterial strain. This knowledge could help in the design of microbiome-based therapies to enable the introduction of specific desirable bacterial strains into the gut.

The third study examined how changes in diet could bolster the microbiome’s ability to keep C. difficile infections at bay. The researchers focused on microbiota-accessible carbohydrates (MACs)—carbohydrates in fiber from plant-based foods that are resistant to human digestion and therefore available for metabolism by beneficial bacteria in the lower intestine. They had previously shown that a diet low in MACs could stoke inflammation in the gut, so they decided to test whether such a diet could also exacerbate C. difficile infections, presumably by disrupting the microbiome. The researchers infected female and male mice harboring human gut microbiota with C. difficile and fed the mice diets that were either deficient or rich in MACs. While the MAC-deficient mice maintained persistent C. difficile infections, the mice fed the MAC-rich diets were able to clear the infection. These mice also had more diverse communities of bacteria in their microbiomes, but that seemed unrelated to the ability to clear C. difficile infections because mice fed only a specific kind of MAC called inulin also cleared the infections even though inulin did not increase microbiota diversity. Rather, the effects of the MAC-rich diet appeared to be caused by an increase in some products of bacterial metabolism, called short-chain fatty acids, that suppress C. difficile growth. The researchers also found that the amount of C. difficile toxin in the infected mice initially increased under a MAC-rich diet, even as the number of C. difficile bacteria decreased, suggesting that the bacteria respond to a MAC-rich diet by ramping up toxin production in an effort to maintain an inflammatory environment. The overall level of toxin declined after a few days, however, as the C. difficile population decreased. These results point to diet-induced changes in the microbiome as a valuable means of overcoming gastrointestinal infections.

Although it remains to be seen whether the results of these studies in mice can be translated into humans, they offer significant progress in the understanding of the relationships among diet, the intestinal environment, the microbiome, and bacterial infections, including interactions among specific types of bacteria. More importantly, they also provide insight into how future therapies could be designed to treat or prevent disease by shaping the gut microbiome.

References

Smillie CS, Sauk J, Gevers D,…Alm EJ. Strain tracking reveals the determinants of bacterial engraftment in the human gut following fecal microbiota transplantation. Cell Host Microbe. 23: 229-240, doi: 10.1016/j.chom.2018.01.003, 2018.

Shepherd ES, DeLoache WC, Pruss KM, Whitaker WR, Sonnenburg JL. An exclusive metabolic niche enables strain engraftment in the gut microbiota. Nature. 557: 434-438, doi: 10.1038/s41586-018-0092-4, 2018.

Hryckowian AJ, Van Treuren W, Smits SA,...Sonnenburg JL. Microbiota-accessible carbohydrates suppress Clostridium difficile infection in a murine model. Nat Microbiol. 3: 662-669, doi:

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