Page 6 - Immunology_11_2021
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        Research in mice shows how

        diet alters immune system

        function through a gut microbe

             he cliché “you are what         microbial mediator in the gut, and   converted by a specific enzyme into
             you eat” has been used for      this is a really striking example of   sugar-lipid molecules that also have
        Thundreds of years to illustrate     the diet-microbiota-immunity triad at   branched chains. B. fragilis then
        the link between diet and health.    play,” Kasper said. “What this work   releases branched-chain molecules
        Now, an international team of        really does is provide a step-by-step   that are spotted and picked up by
        researchers has found the molecular   pathway from beginning to end that   a class of immune-signaling cells
        proof of this concept, demonstrating   explains how and why this triad works   known as antigen-presenting cells,
        how diet ultimately affects immunity   and how diet ultimately affects the   which in turn induce NK T cells to
        through the gut microbiome.          immune system.”                     exercise their immunoregulatory
                                                                                 response through upregulating
        The work, conducted in mice, reveals   If confirmed in larger animals and   inflammation-controlling genes and
        that what animals consume initiates   eventually in humans, the findings   immune-regulatory chemicals.
        the release of a metabolic byproduct   can help inform the design of small-
        from a specific gut microbe that,    molecule treatments that enhance    Notably, the experiments
        in turn, modulates the animals’ gut   both intestinal and overall immunity,   demonstrated that it is the
        immunity.                            the researchers said.               branching of the chain structure that
                                                                                 initiates the cascade. Straight-chain
        The findings, published Nov.10 in    “Gut-resident microbes produce      versions of the molecule did not
        Nature, offer a unifying explanation   molecules with enormous structural   yield the same effect. Furthermore,
        for the complex interplay between    diversity. We used microbial and    the team found that B. fragilis
        diet, gut microbiota, and immune     chemical tools to elucidate how these   alters the structure of the sugar-
        function. They are the result of     molecules are synthesized by gut    lipid molecules that it metabolizes
        collaboration among scientists at    bacteria and how they act in the host   and renders them better capable
        Harvard Medical School, Brigham      gut,” said study first author Sungwhan   of binding to receptors on specific
        and Women’s Hospital, Seoul          Oh, a principal investigator at the   immune cells and initiating a
        National University, and Monash      Center for Experimental Therapeutics   signaling cascade that culminates in
        University in Australia.             and Reperfusion Injury at Brigham   downregulating inflammation.
                                             and Women’s Hospital and a former
        The experiments pinpoint a microbial   postdoctoral fellow in the Kasper   The work also showed that each
        molecule, the synthesis and release   lab.”Our findings yield fascinating   of three different branched-chain
        of which are influenced by host diet.   insights about the microbiome,   amino acids consumed by mice
        That molecule, in turn, stimulates the   diet, and immune function and   yielded slightly different structural
        activation and signaling of a subset   provide interesting clues about   changes to the bacterial lipid
        of cells known as natural killer (NK)   how molecules made by our inner   molecules, resulting in different
        T cells, which are involved in immune   neighbors can be used to design   patterns of binding with immune
        regulation and implicated in a range   therapies.”                       cells.
        of inflammatory conditions.
                                             In a series of experiments, the team   Study coinvestigator Seung Bum
        While scientists have surmised for   identified the immune-signaling     Park, professor of chemistry
        a long time that diet plays a role   cascade triggered by the metabolic   at Seoul National University,
        in immune health, the new study      breakdown of dietary amino acids    synthesized, and the Harvard
        elucidates the precise molecular     in the mouse gut. This multistep    team tested, 23 different
        cascade behind this interplay, said   pathway begins with an animal      configurations of the microbe-made
        study senior author Dennis Kasper,   consuming food that contains        immunomodulatory molecule to
        professor of immunology in the       branched-chain amino acids, so      determine how each one interacts
        Blavatnik Institute at Harvard Medical   named for the tree branch-like   with the immune cells that regulate
        School.                              structure of one of their molecular   inflammation.
                                             chains. The branched-chain amino
        “We have shown how diet affects      acids are then taken up by B.                                 7
        the immune system through a          fragilis, a gut-resident microbe, and

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