Evaluating the effect of zonulin-mediated intestinal trafficking on gastrointestinal macrophages and their function on gastric motility

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Project Summary/ Abstract Gastric dysmotility affects 40-80% of critically ill children and is associated with significant morbidity and mor- tality. There are knowledge gaps regarding the mechanisms for gastric dysmotility in critically ill children, which limit the therapeutic options for this cohort. Gastrointestinal (GI) macrophages regulate gastric motility and have been shown to have microbiome-dependent changes on their function. Microbiome-dependent changes on macrophage activation are mediated by trans-epithelial intestinal trafficking of microbial products. Zonulin is a protein that increases trans-epithelial trafficking of microbial products. Models of zonulin expression, includ- ing a Zonulin transgenic mouse (Ztm), have dysbiosis and activation of pro-inflammatory macrophages. In criti- cally ill children who express zonulin and in Ztm mice we have identified gastric dysmotility. Our central hy- pothesis is that zonulin upregulation under conditions of inflammation, increases trans-epithelial trafficking of microbial products from an altered microbiome which activate macrophages associated with gastric dysmotility. In Aim 1 we evaluate whether zonulin-mediated increases in trans-epithelial intestinal trafficking due to system- ic inflammation result in dysbiosis and activation of macrophages associated with gastric dysmotility. We will complete Aim 1 with Ztm mice and the use of a zonulin inhibitor. In Aim 2a, we will identify differences in mi- crobiome composition and markers of trans-epithelial intestinal trafficking in relation to gastric motility in pa- tients with and without the zonulin-producing allele. Direct examination of GI macrophage differences in pa- tients is not feasible. Therefore, in Aim 2b, we employ a translational mouse model of fecal material transplant from patients in Aim 2a to examine whether differences in microbiota from patients with and without the zonu- lin-producing allele and gastric dysmotility result in macrophage activation and gastric dysmotility in the mice. This proposal fills a knowledge gap in our understanding of mechanisms for gastric dysmotility in critical illness. Our long-term goal is to identify novel diagnostic markers and therapeutic targets for gastric dysmotility in criti- cal illness, which can impact clinical outcomes for this cohort. This proposal details a four-year project in which Dr. Martinez will gain experience in clinical-translational research and expertise in GI physiology, mucosal im- munology, host-microbiome interactions and the neuro-enteric system. These educational opportunities, the surrounding ideal research environment and established mentoring team that is working with Dr. Martinez will prepare her to apply for a NIH R01 grant and promote her advancement towards an independent academic career.