FRONT PAGES: Diet, Gut Microbes, And Immunity

dWeb.News Article from Daniel Webster dWeb.News

Newswise — For hundreds of years, the cliche “you’re what you eat” has been used to demonstrate the connection between diet and health. A team of international researchers have now found molecular evidence that diet can affect immunity via the gut microbiome. The work was done in mice and revealed that animals consume a metabolic byproduct of a particular gut microbe, which in turn modulates their gut immunity.

The findings, published Nov.10 in Nature, offer a unifying explanation for the complex interplay between diet, gut microbiota, and immune function. These findings are the result collaboration between scientists from Harvard Medical School, Brigham and Women’s Hospital and Seoul National University.

The experiments revealed a microbial compound whose synthesis and release are affected by the host’s diet. This molecule stimulates the activation of natural killer (NKT) T cells which are involved with immune regulation and implicated for a variety of inflammatory conditions.

Scientists have known for some time that diet has a significant impact on immune health. However, this new study provides a detailed molecular explanation.

“We have shown how diet affects the immune system through a microbial mediator in the gut, and this is a really striking example of the diet-microbiota-immunity triad at play,” Kasper said. The researchers stated that the work provides a step-by–step guideline from beginning to finish that explains how the triad works, and how it ultimately affects the immune systems If confirmed in larger animals, and eventually in humans the findings could help in the development of small-molecule treatments that improve intestinal and overall immunity.

“Gut-resident microbes produce molecules with enormous structural diversity. We used microbial and chemical tools to elucidate how these molecules are synthesized by gut bacteria and how they act in the host gut,” said study first author Sungwhan Oh, a principal investigator at the Center for Experimental Therapeutics and Reperfusion Injury at Brigham and Women’s Hospital and a former postdoctoral fellow in the Kasper lab.”Our findings yield fascinating insights about the microbiome, diet, and immune function and provide interesting clues about how molecules made by our inner neighbors can be used to design therapies.”

In a series of experiments, the team identified the immune-signaling cascade triggered by the metabolic breakdown of dietary amino acids in the mouse gut. The multi-step process begins when an animal consumes branched-chain amino acids. This is named after the tree-like structure of one their molecular chains. The branched chain amino acids are then taken by B. fragileis, a gut-resident microbe. They are then converted by an enzyme into sugar-lipid compounds that also have branched links. B. fragilis then releases branched-chain molecules that are spotted and picked up by a class of immune-signaling cells known as antigen-presenting cells, which in turn induce NK T cells to exercise their immunoregulatory response through upregulating inflammation-controlling genes and immune-regulatory chemicals.

The cascade is initiated by the branching in the chain structure, as demonstrated by experiments. The same effect was not seen in straight-chain versions. The team also discovered that B. fragileis alters sugar-lipid molecules it metabolizes, making them more capable of binding to specific immune cells. This triggers a signaling cascade which ultimately leads to downregulating inflammation. It was also shown that the three different branched chain amino acids used by mice produced slightly different structural modifications to the bacterial cholesterol molecules. This resulted in different patterns for binding to immune cells.

Study coinvestigator Seung Bum Park, professor of chemistry at Seoul National University, synthesized, and the Harvard team tested, 23 different configurations of the microbe-made immunomodulatory molecule to determine how each one interacts with the immune cells that regulate inflammation. The Harvard team discovered that synthetically-made branched chain lipid molecules inducing NK T cells release the immuno-signaling chemical IL-2. This was different from the laboratory-made straight-chained versions. The NK T cells were activated and induced gene expression that regulates immunity, but not those that drive inflammation.

Using a structural biology approach Jamie Rossjohn ,, professor of biochemistry at Monash Biomedicine Discovery Institute, Australia, explained how the lipid structure interacts with and binds antigen-presenting cells, which are immune cells that allow NK T cells to produce anti-inflammatory drugs. The researchers then treated ulcerative colitis in mice using the branched chain sugar-lipid molecule. The branched-chain molecule was more effective than the untreated animals. Researchers found that the mice gained weight and had no signs of colon inflammation when they examined their gut cells under a microscope.

These experiments offer a structural and molecular explanation for previously observed anti-inflammatory effects from this class of sugar-lipids made by the gut microbe B. fragilis.

” This work is a great example transdisciplinary discovery-based science that aims to answer a major question of biomedical sciences, namely how the immune system can modulate by the interplay between diet, microbiota.” Rossjohn stated.

In 2014, Kasper and colleagues published a study showing that a sugar-lipid molecule released by B. fragilis had anti-inflammatory effects on the gut and protected mice from colitis, but the scientists did not know how these molecules were made by the microbe, nor the specific structural features of the sugar-lipids that conferred the anti-inflammatory effect. This question is answered by the current study. It shows that sugar-lipid molecules produced by this organism are branched chain and that it is precisely this branched-chain structure which allows them to bind with immune cells in a manner that reduces proinflammatory signaling.

” Our new research shows that branching in lipid structures induces a different response. The branching causes an anti-inflammatory, rather than proinflammatory response.

The findings offer hope that inflammatory diseases mediated by these NK T cells could one day be treated with inflammation-dampening microbial molecules made in the lab, the researchers said.

The exact function of the NK T cells, which are immune cells activated by microbe-made molecules to control colonic inflammation and mice’s colon, is not known. These cells are found in the liver, spleen and human gastrointestinal tract, and also in the liver. This suggests that they play an important role in immune regulation. Previous research points to these cells’ likely involvement in a range of inflammatory conditions, including ulcerative colitis, and to a possible role in airway inflammatory conditions such as asthma. Although we cannot isolate enough immune-modulatory molecules in bacteria to make therapeutic use of them, the beauty of this technology is that they can be synthesized in the laboratory. “The idea would be that we’d have a drug that can modulate inflammation in the colon and beyond.”

Co-authors included T. Praveena, Heebum Song, Ji-Sun Yoo, Da-Jung Jung, Deniz Erturk-Hasdemir, Yoon Soo Hwang, ChangWon Lee, Jerome Le Nours, Hyunsoo Kim, Jesang Lee, and Richard Blumberg.The work was supported by National Institutes of Health grants K01-DK102771, R01-AT010268, and R01-DK044319; by Department of Defense grant W81XWH-19-1-0625; by Brigham and Women’s Hospital Department of Anesthesiology, Perioperative and Pain Medicine Basic Science Grant; by the National Research Foundation of Korea grants 2014R1A3A2030423 and 2012M3A9C404878; and by the Australian Research Council grant CE140100011 and Australian Research Council Laureate Fellowship and Future Fellowships.

Relevant disclosures:
Oh, Blumberg, and Kasper have filed a patent for Bacteroides fragilis a-galactosylceramides (BfaGCs) and related structures. Oh, Park and Kasper filed a patent for the functions of BfaGCs, and related structures.

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