Martin Kriegel, M.D., Ph.D.

Yale University, New Haven, CT

2015 New Treatments, Environmental Triggers, Antiphospholipid Syndrome, Microbiome

2015 Controlling Gut Bacteria to Prevent Dangerous Clotting Disorder

The study and what it means to patients

Do certain bacteria that live in the gut trigger the antibodies that can cause blood clots in antiphospholipid syndrome (APS)? Our team will explore this entirely novel theory and if we can control these bacteria with antibiotics or other interventions like diet modifications to protect from APS. 

Summary

Many of the bacteria in our gut evolved with human beings and have coexisted peacefully for generations. These “commensal bacteria” aid in digestion and typically do us no harm. But my team has found that some of the bacteria that evolved with us help sustain the autoantibodies that cause abnormal clotting in APS.

Although factors such as genetics, infections, and underlying lupus are associated with development of APS, most APS develops with no apparent cause. Our goal is to hone in on the specific bacteria that may promote the spontaneous development of APS. We then hope to uncover the mechanism by which these specific bacteria contribute to this disease. This unique approach could lead to new treatment options that target bacteria in the gut rather than treat the abnormal blood clotting. In particular, our research will explore the influence of diets that limit calories and treatment with antibiotics as potential ways to control these bacteria and stop APS from developing.

Scientific Abstract: A Role for Diet-Sensitive Gut Commensals in Antiphospholipid Syndrome

Antiphospholipid syndrome (APS) is a potentially lethal autoimmune clotting disorder that is frequently associated with lupus. The triggers that induce the adaptive immune response against the main autoantigen are unknown. We have evidence in the (NZWxBXSB)F1 hybrid, a spontaneous model for APS, that specific members of the gut microbiota sustain pathogenic autoantibodies and mortality. The phenotype is also reversed by caloric restriction in this model. Since dietary interventions are known to affect the gut microbiota, we hypothesize that caloric restriction prevents APS via suppression of pathobionts or outgrowth of protective symbionts. We will define the microbial community composition of antibiotic-treated as well as calorically restricted mice. Key candidates that emerge from these comparative studies will be cultured and introduced into commensal-ablated animals to demonstrate functionally induction of APS. We plan to dissect also if the pathobionts induce not only autoantibodies but also helper T cell subsets and autoantigen-specific T cell proliferation. These studies will therefore link specific gut commensals to pathogenic adaptive immune responses in APS and uncover entirely novel aspects of this syndrome. We plan to translate our studies to human APS and lupus with the potential to develop new therapeutic avenues aimed at gut commensals.