This application is to support my career development at Columbia University under the sponsorship of Michael D. Gershon (enteric neurophysiology/development), Charalabos Pothoulakis (intestinal inflammation) and Lloyd Mayer (immunology). The training plan includes courses, mentored research, and protected research time. My investigation is designed to analyze putative contributions of the enteric nervous system (ENS) to the pathophysiology of intestinal inflammation and neuroimmune interactions in the bowel wall. Increased numbers of enteric neurons have been reported in inflamed regions of the gut in patients with inflammatory bowel disease (IBD) or intestinal neurogangliomatosis. It is impossible to determine in humans whether neuronal hyperplasia predates intestinal inflammation, results from it, or contributes to its severity. We have used, as genetic models, mice in which the ENS is hyperplastic (NSE-noggin mice) or hypoplastic (Hand2+/- mice) to test the hypothesis that ENS hyperplasia is proinflammatory. Preliminary data show that measures of severity (survival, clinical and histological scores, intestinal expression of genes encoding proinflammatory molecules, levels of neutrophil elastase and p50 NF?B) of TNBS- and DSS-induced colitis are higher in NSE- noggin and lower in Hand2+/- mice than in their wild-type (WT) littermates. In neither mouse, however, are differences from WT found in measures of the severity (edema, T cell and neutrophil infiltration, and expression of IL1 , IFN?, and TNF?) of delayed type hypersensitivity evoked in the ears with dinitrofluorobenzene. Transgene effects on inflammation are thus limited to the bowel. These observations are consistent with the hypotheses that ENS hyperplasia contributes to the severity of intestinal inflammation and, potentially also therefore, to the pathogenesis of IBD. I now propose to investigate mechanisms by which the ENS affects intestinal inflammation. I will determine whether the proinflammatory effects of ENS hyperplasia are due to altered (i) intestinal barrier function, (ii) innate immunity, and (iii) immunoregulation. The ability of enterc neurons to affect TLR4 and TLR5 signaling at baseline and during inflammation will be examined. I will determine the effect of the ENS on the integrity of epithelial tight junctions and basal laminae as well as bidirectional translocation of macromolecules across the intestinal epithelium. Analyses of numbers, location, and proportions of regulatory T cell (Treg) subsets (from lamina propria and spleen) as well as their ability to inhibit lymphocyte proliferation will e employed to test hypotheses that ENS hyperplasia decreases Treg number and/or function. Intestinal inflammation occurs in intestinal disorders besides IBD, including necrotizing enterocolitis, infectious diarrhea, and irritable bowel syndrome; the ENS may contribute to any or all of them. Knowledge of interactions between the ENS and inflammatory effectors, therefore, has the potential to transform understanding and, ultimately, treatment of many intestinal disorders.

Public Health Relevance

Increased numbers of nerve cells (hyperplasia) have been reported to be present in inflamed regions of the bowel in patients with Inflammatory bowel disease (IBD), a human intestinal inflammatory disorder that affects ~one million Americans and causes a significant decrease in the quality of life. There is no way in humans with IBD to determine whether this hyperplasia was present before their bowel became inflamed or whether it contributed to the inflammation; therefore, we studied genetically engineered mice in which the numbers of intestinal nerve cells was greater or less than normal and found that hyperplasia of the nervous system of the gut increases the severity of intestinal inflammation and thus may contribute to IBD. Because IBD may be caused in part by abnormalities in the immune system or the intestinal barrier, the current proposal is designed to determine whether hyperplasia of the intestinal nervous system promotes inflammation because it compromises the intestinal barrier, enhances innate immunity, or reduces the number or activity of cells that regulate immunity.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Clinical Investigator Award (CIA) (K08)
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Kidney, Urologic and Hematologic Diseases D Subcommittee (DDK)
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Saslowsky, David E
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Columbia University (N.Y.)
Schools of Medicine
New York
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Robson, Matthew J; Quinlan, Meagan A; Margolis, Kara Gross et al. (2018) p38? MAPK signaling drives pharmacologically reversible brain and gastrointestinal phenotypes in the SERT Ala56 mouse. Proc Natl Acad Sci U S A 115:E10245-E10254
Margolis, Kara G; Buie, Timothy M; Turner, J Blake et al. (2018) Development of a Brief Parent-Report Screen for Common Gastrointestinal Disorders in Autism Spectrum Disorder. J Autism Dev Disord :
Khlevner, Julie; Park, Yeji; Margolis, Kara Gross (2018) Brain-Gut Axis: Clinical Implications. Gastroenterol Clin North Am 47:727-739
Israelyan, Narek; Margolis, Kara Gross (2018) Serotonin as a link between the gut-brain-microbiome axis in autism spectrum disorders. Pharmacol Res 132:1-6
Terry, Natalie; Margolis, Kara Gross (2017) Serotonergic Mechanisms Regulating the GI Tract: Experimental Evidence and Therapeutic Relevance. Handb Exp Pharmacol 239:319-342
Marler, Sarah; Ferguson, Bradley J; Lee, Evon Batey et al. (2017) Association of Rigid-Compulsive Behavior with Functional Constipation in Autism Spectrum Disorder. J Autism Dev Disord 47:1673-1681
Margolis, Kara Gross (2017) A role for the serotonin reuptake transporter in the brain and intestinal features of autism spectrum disorders and developmental antidepressant exposure. J Chem Neuroanat 83-84:36-40
Israelyan, Narek; Margolis, Kara Gross (2017) KLF-5 extends its fingers to desmosomes: the next frontier for enteric epithelial research? Am J Physiol Gastrointest Liver Physiol 313:G476-G477
Gross Margolis, Kara; Vittorio, Jennifer; Talavera, Maria et al. (2017) Enteric serotonin and oxytocin: endogenous regulation of severity in a murine model of necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol 313:G386-G398
Ferguson, Bradley J; Marler, Sarah; Altstein, Lily L et al. (2017) Psychophysiological Associations with Gastrointestinal Symptomatology in Autism Spectrum Disorder. Autism Res 10:276-288

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