This grant was awarded to an international team of scientists who will identify and investigate intestinal microbes that trigger human SLE via a leaky gut.
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Martin Kriegel, MD, PhD |
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George Tsokos, MDHarvard School of Medicine |
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Nissan Yissachar, PhD |
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Ilana Brito, PhD |
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Eran Elinav, MD, PhD |
Systemic lupus erythematosus (SLE) is a chronic disease that causes a range of signs and symptoms in the kidneys, skin, brain, and blood. In lupus patients, the immune system targets and attacks a person’s own tissues. The initial triggers of the misdirected immune cell reactions are still largely unknown. Dr. Kriegel’s recent research in mice has shown that certain microbes living in the digestive tract may escape and force the immune system to engage in damaging activity.
Dr. Kriegel and colleagues will use LRA’s Global Team Science Award to identify the intestinal microbes that are leaked into other organs and stimulate the human immune system to destroy the body’s own tissues. The team will employ a comprehensive approach to uncover which microbes that escape the intestines via “leaky gut” trigger inflammation in patients with active lupus. The team will also investigate if and how transferring intestinal microbes suspected to cause or contribute to lupus in humans triggers or worsens lupus in mice.
What this study means for people with lupus
Identification of microbes that cause or worsen lupus in humans could lead to the development of a new set of lupus diagnostic tools and treatments that would target the “unhealthy” gut bacteria.
Systemic Lupus Erythematosus (SLE) is a chronic, debilitating and heterogenous autoimmune disease of an unknown multifactorial pathophysiology. The human microbiota has been recently suggested as an instigator of pathologic immune responses in SLE and its clinical manifestations. In particular, translocation of commensals and associated antigens through an impaired gut barrier may drive non-gut autoimmunity by stimulating lupus-specific innate and adaptive autoimmune responses in genetically susceptible hosts. Similar effects are induced in vitro with human cells and microbiome studies on stool and organ tissues support that such pathobionts contribute to human SLE. However, a systematic search for human translocating pathobionts in lupus has not been done and the mechanisms of pathobiont-driven contributions to SLE remain elusive. We hypothesize that a dysfunctional gut barrier enables microbiota translocation in human SLE, thereby contributing to autoimmunity and organ damage. Combining a multi-omic assessment of the microbiome, 3D gut culture system and gnotobiotic mouse models, will enable us to functionally identify SLE-relevant gut pathobionts that translocate through the intestinal barrier to induce autoimmunity. A combined human cohort, molecular, and animal-modeling approach will uncover new SLE pathobionts as therapeutic targets. To explore this ambitious topic, we will combine a multi-omic microbiome assessment in three human SLE cohorts and mechanistically assess disease-driving commensals in innovative ex vivo and in vivo model systems. First, SLE microbiomes are explored in the stools and blood of our cohorts using the newest metagenomic technologies and complemented with in vitro molecular and immunological assays using human, peripheral immune cells. Next, antibiotic-treated mice will be colonized with SLE patient microbiota and tested for gut barrier breakdown, bacterial translocation, and lupus induction. In addition, a 3D gut culture system is colonized with whole human derived SLE microbiota and selected pathobionts that allows for systematic screening for gut barrier disruption and translocation into lymphoid organs. Lastly, germfree WT and lupus-prone mice colonized with candidate SLE pathobionts are used to demonstrate translocation in vivo and to characterize the autoimmune-promoting capacity. In summary, the proposed study will address critical open questions underlying SLE pathogenesis. It will provide mechanistic insights into the role of the human gut microbiome, and specifically translocated pathobionts, in altering gut barrier function and the pathogenesis and subphenotypes of SLE. Moreover, the anticipated findings may provide new approaches to stratify patients based on translocated pathobionts and their respective markers, and to identify novel modifiable factors that represent new treatment targets for SLE patients in a personalized fashion.