When It Comes to Immunity, You Are What You Eat

In the study, the researchers observed that mice in whom this cascade was interrupted more readily succumbed to a common foodborne pathogen.

The findings, the team said, detail an intricate interplay between gut microbes, food, and immunity. They also underscore the importance of understanding how individual microbial species in the gut could alter specific organ functions and exercise important effects on health.

“The triad of diet-microbes-immune system has attracted considerable attention, with a paucity of detail to demonstrate how these three components work together,” said study senior author Dennis Kasper, the William Ellery Channing Professor of Medicine at Brigham and Women’s Hospital and professor of immunology in the Blavatnik Institute at Harvard Medical School. “We have found one of the clearest demonstrations here of a mechanism underlying how diet and the microbiome build the immune system.”

In the new study, Kasper worked in collaboration with Xinyang Song, a former postdoctoral researcher in the Kasper lab, now a principal investigator at the University of Chinese Academy of Sciences, and colleagues from HMS, Massachusetts General Hospital, Tufts University, and the UMass Chan Medical School.

The team initially noticed that germ-free mice — a common lab model that is not naturally colonized by microorganisms, and thus has no microbiome — were missing a subset of immune cells known as CD4⁺CD8aa⁺ intraepithelial lymphocytes (IELs), which normally reside in a specific part of the small intestine.

Interestingly, mice that were not germ-free but ate a minimal diet composed of just the essential nutrients to keep them alive were also deficient in these cells. However, CD4⁺CD8aa⁺ IELs were present in non-germ-free mice fed a typical rich commercial diet composed of many different nutrients.

Suspicious that an interplay between diet and the microbiome might be responsible for the presence or absence of CD4⁺CD8aa⁺ IELs, the researchers examined which nutrients were lacking from the minimal diet, eventually homing in on various fatty acids. After feeding individual fatty acids to mice on minimal diets with typical microbiomes, they discovered that animals that ate a long-chain fatty acid known as linoleic acid began growing CD4⁺CD8aa⁺ IELs in their small intestines.

Kasper explained that many bacteria that reside in the gut produce an enzyme called linoleic acid isomerase (LAI) that converts linoleic acid into a conjugated form, with some linoleic acid double- and single-chemical bonds rearranged. Further investigation showed that CLA — the conjugated form of linoleic acid — was abnormally low both in mice with a typical microbiome fed a minimal diet or in germ-free mice fed a rich diet, suggesting that bacteria were necessary to convert linoleic acid into CLA.

When the researchers colonized germ-free mice with bacteria that produced LAI and fed them a rich diet, these animals developed CD4⁺CD8aa⁺ IELs in their small intestines. Conversely, when the researchers colonized them with bacteria that had been genetically modified to not produce LAI, they did not develop these immune cells, showing that CLA produced by this bacterial enzyme was essential for these immune cells to grow.

Further investigation revealed a more complete mechanism behind why CLA spurred CD4⁺CD8aa⁺ IEL development: The researchers found that some immune cells in the small intestine produced a protein called hepatocyte nuclear factor 4g (HNF4g) on their surfaces, which serves as a receptor for CLA. When CLA attached to these receptors, the cells produced a different protein called interleukin 18R (IL-18R), which in turn lowered the production of a third protein called ThPOK. The less ThPOK produced, the more CD4⁺CD8aa⁺ IELs developed.

This complex pathway has clear implications for immunity to infection, Kasper said. Indeed, when the researchers tampered with any part of the cascade — for example, preventing production of IL-18R or HNF4g — mice in whom the cascade was turned off didn’t produce CD4⁺CD8aa⁺ IELs and were unable to fight off infection with Salmonella typhimurium, a bacterial species commonly responsible for cases of food poisoning.

“One of the reasons that more examples of the diet-microbes-immune system triad have not yet come to light is that these pathways are so complicated,” Kasper said. “By investigating these intricate pathways, we will have a better understanding of how our microbiomes keep us healthy and how to intervene when they don’t.”

Authorship, funding, disclosures

Co-authors included Haohao Zhang, Yanbo Zhang, Byongsook Goh, Bin Bao, Suelen S. Mello, Ximei Sun, Wen Zheng, Francesca S. Gazzaniga, Meng Wu, Fangfang Qu, Qiangzong Yin, Michael S. Gilmore, and Sungwhan F. Oh.

This work was supported in part by Department of Defense grants W81XWH1910625 and HT9425-23-0226 and Sponsored Research Agreements with Quark Ventures and Evelo Biosciences; National Key R&D Program of China 2022YFA0807300, NSF of China 32270945, and STCSM 22ZR1468700 and 22140902400; China Postdoctoral Science Foundation 2022M723139; NIH R01-AT010268 and Department of Defense W81XWH1910626; and NIH-NICHD T32:5T32HD55148-10 and Quark Ventures A31696 with additional support from the Harvard-wide Program on Antibiotic Resistance (PO1 AI1083214).