• Toxin-producing yeast strains in gut fue

    From ScienceDaily@1:317/3 to All on Wed Mar 16 22:30:44 2022
    Toxin-producing yeast strains in gut fuel IBD

    Date:
    March 16, 2022
    Source:
    Weill Cornell Medicine
    Summary:
    Individual Candida albicans yeast strains in the human gut are as
    different from each other as the humans that carry them, and some C.

    albicans strains may damage the gut of patients with inflammatory
    bowel disease (IBD), according to a new study. The findings suggest
    a possible way to tailor treatments to individual patients in
    the future.



    FULL STORY ========================================================================== Individual Candida albicans yeast strains in the human gut are as
    different from each other as the humans that carry them, and some
    C. albicans strains may damage the gut of patients with inflammatory
    bowel disease (IBD), according to a new study from researchers at Weill
    Cornell Medicine. The findings suggest a possible way to tailor treatments
    to individual patients in the future.


    ==========================================================================
    The researchers, who report their findings March 16 in Nature, used an
    array of techniques to study strains, or genetic variants, of Candida
    from the colons of people with or without ulcerative colitis, a chronic, relapsing and remitting inflammatory disorder of the colon and rectum
    and one of the main forms of IBD.

    They found that certain strains, which they call "high-damaging,"
    produce a potent toxin called candidalysin that damages immune cells.

    "Such strains retained their "high-damaging" properties when they were
    removed from the patient's gut and triggered pro-inflammatory immunity
    when colonized in mice, replicating certain disease hallmarks," said
    senior author Dr. Iliyan Iliev, an associate professor of immunology
    in medicine in the Division of Gastroenterology and Hepatology and a
    scientist in the Jill Roberts Institute for Research in Inflammatory
    Bowel Disease at Weill Cornell Medicine.

    IBD affects approximately 3.1 million people in the United States
    and can greatly impair patients' quality of life. Such patients rely
    on a handful of available therapies, but treatments may not always be effective. The new study has suggested one reason steroids, a commonly
    used treatment, may not work; treating mice with the drug to suppress intestinal inflammation failed in the presence of "high-damaging"
    C. albicans strains.

    "Our findings suggest that C. albicans strains do not cause spontaneous intestinal inflammation in a host with intact immunity," Dr. Iliev
    said. "But they do expand in the intestines when inflammation is present
    and can be a factor that influences response to therapy in our models and perhaps in patients." Most studies of the human microbiome in healthy individuals and those with IBD have focused on bacteria and viruses, but
    recent research by Dr. Iliev and others has illuminated the contributions
    of fungi to the effects of microbes on humans and mice. They have found
    that intestinal fungi play an important role in regulating immunity
    at surfaces exposed to the outside, such as the intestines and lungs,
    due to their potent immune-stimulating characteristics.

    While the collective community of fungi in the body, known as
    the mycobiota, has been linked to several diseases, including IBD,
    researchers previously had not understood the mechanisms by which the
    mycobiota contribute to inflammation in the gut.



    ==========================================================================
    In the new study, the investigators initially found that Candida strains,
    while highly diverse in the intestines of both patients with and without colitis, were on average more abundant in the patients with IBD. But
    that did not explain disease outcomes in individual patients. So, the investigators set out to identify the characteristics of these strains
    that cause damage and how they relate to individual patients.

    The researchers observed that in the patients with ulcerative colitis,
    severe disease was associated with the presence of "high-damaging"
    Candida strains, which turned out to have a key factor in common: all
    produce the candidalysin toxin. The scientists showed that the toxin
    damages immune cells called macrophages, prompting a storm of the pro-inflammatory cytokine IL-1b.

    To underscore this strain-specific effect, the researchers grew
    macrophages in the presence of Candida strains and found that the ability
    of the strains to induce IL-1b corresponded closely to the severity of
    colitis in the patients.

    "Our finding shows that a cell-damaging toxin candidalysin released by
    "high damaging" C. albicans strains during the yeast-hyphae morphogenesis triggers pathogenic immunological responses in the gut," said the first
    author Dr. Xin Li, who was a Charles H. Revson Postdoctoral Fellow in
    the Iliev laboratory at the time of the study.

    Experiments in mice delineated that candidalysin-producing "high-damaging" strains induced the expansion of a population of T cells called Th17 cells
    and other immune cells associated with inflammation, such as neutrophils.

    "Neutrophils contribute to tissue damage and their accumulation is
    a hallmark of active IBD," said Dr. Ellen Scherl, the Jill Roberts
    Professor of Inflammatory Bowel Disease at Weill Cornell Medicine and
    a gastroenterologist at NewYork-Presbyterian/Weill Cornell Medical
    Center. "The indication that these processes might in part be driven
    by a fungal toxin released by yeast strains in specific patients could potentially inform personalized treatment approaches." Consistent with
    this finding, blocking IL-1b signaling had a dramatic effect in reducing colitis signs in mice that harbored these highly pro-inflammatory
    strains. The researchers noted that other recent studies have linked IBD
    to IL- 1b in a general way, prompting ongoing investigations of drugs
    targeting related pathways as potential IBD therapies.

    "We do not know whether specific strains are acquired by specific
    patients during the course of disease or whether they have been always
    there and become a problem during episodes of active disease" Dr. Iliev
    said. "Nevertheless, our findings highlight a mechanism by which commensal fungal strains can turn against their host and overdrive inflammation."
    The team is following up with studies of the mechanisms that drive the persistence of candidalysin-producing strains in the inflamed colon of
    specific IBD patients, as well as ways to choose patients for therapy
    targeting the mycobiome.


    ========================================================================== Story Source: Materials provided by Weill_Cornell_Medicine. Note:
    Content may be edited for style and length.


    ========================================================================== Journal Reference:
    1. Xin V. Li, Irina Leonardi, Gregory G. Putzel, Alexa Semon,
    William D.

    Fiers, Takato Kusakabe, Woan-Yu Lin, Iris H. Gao, Itai Doron,
    Alejandra Gutierrez-Guerrero, Meghan B. DeCelie, Guilhermina
    M. Carriche, Marissa Mesko, Chen Yang, Julian R. Naglik, Bernhard
    Hube, Ellen J. Scherl, Iliyan D. Iliev. Immune regulation by
    fungal strain diversity in inflammatory bowel disease. Nature,
    2022; DOI: 10.1038/s41586-022-04502-w ==========================================================================

    Link to news story: https://www.sciencedaily.com/releases/2022/03/220316145804.htm

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