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Gut microbe helps program immune cells via dietary metabolites

Scientists have identified an important role for a gut bacterial species and its metabolites in the maturation of a key immune cell. Many cells of the immune system rely on the presence of specific gut bacteria to be programmed into mature, functioning immune cells. In fact, these immune programming processes are absent in animals lacking gut bacteria, such as mice raised in germ-free conditions. Researchers endeavored to find the gut bacteria responsible for promoting maturation of a recently discovered gut immune cell called the double-positive intraepithelial lymphocyte (DP IEL). DP IELs are formed in the intestine from another immune cell type—the CD4+ T cell—upon activation of a specific molecular program known to be influenced by the presence of gut microbes. The DP IEL performs a wide range of important functions, including ensuring the immune system’s tolerance of substances in the gastrointestinal (GI) tract, such as food components and microbes, that might otherwise provoke a negative reaction and inflammation. Their first clue to identifying the gut microbe(s) important for DP IEL formation came from the observation of a wide variation in levels of these immune cells between mice of the same genetic strain obtained from two different companies. When the mice from different sources were co-housed, those animals initially lacking the immune cells went on to develop them, indicating that some transmissible factor—such as a microbe—was at work. The researchers were able to identify the gut bacteria present in the mice by sequencing genetic material from the animals’ intestines. Honing in on a bacterial species called Lactobacillus reuteri (L. reuteri) present in the mice with high DP IELs, the scientists tested two L. reuteri strains and found they were able to induce DP IEL formation when given to mice lacking these immune cells. Next, scientists wanted to uncover the mechanism by which L. reuteri bacteria accomplish this feat. Some bacteria exert powerful effects on human cells through metabolism of dietary components to create bioactive metabolites, such as short-chain fatty acids. Likewise, L. reuteri bacteria grown in culture in the presence of tryptophan—an amino acid present in high-protein foods—were found to produce a class of metabolites called indole derivatives. When added to CD4+ T cells in culture, these metabolites set off a cascade of molecular signals to transform the cells into the DP IEL cell type. Additionally, mice harboring L. reuteri and other bacteria in their guts had elevated DP IELs when given a high-tryptophan diet compared to animals eating a standard chow or low-tryptophan diet. Yet, L. reuteri bacteria do not appear to act alone—female germ-free mice colonized solely with one L. reuteri bacterial strain and given a high-tryptophan diet did not form DP IELs at all. Additionally, as observed in one of the earlier experiments, germ-free mice colonized only with the other L. reuteri bacterial strain and fed a regular diet experienced only a slight increase in DP IELs. In other words, the larger microbial context also plays a role in this immune cell programming process. Future studies will be needed to explore potential applications for these findings that L. reuteri prompts formation of this key intestinal immune cell, and whether this is also the case in humans. One possible use for the bacteria could be as a probiotic, along with tryptophan-rich foods, for digestive diseases in which the immune system is overly active, such as inflammatory bowel disease.

References

Cervantes-Barragan L, Chai JN, Tianero MD,…Colonna M.  Lactobacillus reuteri induces gut intraepithelial CD4+CD8αα+ T cells. Science 357(6353): 806-810, doi: 10.1126/science.aah5825, 2017.
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