Functional Dyspepsia is a major functional bowel disorder that affects about 15% to 25% of the U.S. population. The two primary symptoms of Functional Dyspepsia are upper abdominal pain that is exaggerated by ingestion of a meal, and delayed gastric emptying. The etiology of these symptoms is not known, which has hampered efforts to develop effective therapeutic agents. A major obstacle in investigation of the etiologies of these symptoms is the lack of availability of tissues from patients and normal subjects to test novel hypothesis and conduct studies at the cellular, molecular and genetic levels. An animal model that concurrently mimics both the symptoms of Functional Dyspepsia is desperately needed to advance the field. The genes are inherited from two parents. However, the DNA requires epigenetic mechanisms to program the expression of individual genes. This programming is accomplished during the fetal and neonatal stages of developments. The information for epigenetic programming is also inherited from the parents. Its goal is to ensure survival of the fetus and the neonate, and normal functioning of the organs in adulthood. However, if the mother or the neonate is exposed to severe psychological or inflammatory stress, the epigenetic mechanisms adapt to ensure immediate survival of the fetus or the neonate under adverse conditions. However, such reprogramming of the genes persists into adulthood and it may result in complex adult diseases, such as diabetes, hypertension and cancer. This phenomenon is called neonatal or fetal programming. Our hypotheses in this proposal are: 1) Colonic inflammation during the vulnerable neonatal stage of development induces the two cardinal symptoms of Functional Dyspepsia, delayed gastric emptying and visceral hypersensitivity to gastric distension in adulthood. 2) The delay in gastric emptying is due to altered gene expression of key cell signaling proteins of the excitation-contraction coupling in gastric smooth muscle cells. 3) Visceral hypersensitivity is due to increase in the excitability of gastric-specific dorsal root ganglionic neurons. 4) The modulation of HPA-axis and epigenetic regulation of specific genes by neonatal programming mediate these effects. We will test these hypotheses in rats using state-of-the-art cellular, molecular and epigenetic approaches. Our findings are expected to yield novel insights into the cellular mechanisms of a major disorder of the gut and identify potential epigenetic and pharmacologic targets for therapeutic agents.

Public Health Relevance

Functional dyspepsia is a major disorder of the gut. It afflicts about 15% to 25% of the U.S. population. The patients with Functional Dyspepsia display symptoms of abdominal pain and delayed gastric emptying. Currently, there is no effective treatment for this disorder. Our findings will elucidate the mechanisms underlying this disorder and identify targets for the development of effective therapeutic agents.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Clinical, Integrative and Molecular Gastroenterology Study Section (CIMG)
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Hamilton, Frank A
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University of Texas Medical Br Galveston
Internal Medicine/Medicine
Schools of Medicine
United States
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Winston, John H; Aguirre, Jose E; Shi, Xuan-Zheng et al. (2017) Impaired Interoception in a Preclinical Model of Functional Dyspepsia. Dig Dis Sci 62:2327-2337
Li, Qingjie; Winston, John H; Sarna, Sushil K (2016) Noninflammatory upregulation of nerve growth factor underlies gastric hypersensitivity induced by neonatal colon inflammation. Am J Physiol Regul Integr Comp Physiol 310:R235-42
Winston, John H; Sarna, Sushil K (2016) Enhanced sympathetic nerve activity induced by neonatal colon inflammation induces gastric hypersensitivity and anxiety-like behavior in adult rats. Am J Physiol Gastrointest Liver Physiol 311:G32-9
Chen, Jinghong; Winston, John H; Fu, Yu et al. (2015) Genesis of anxiety, depression, and ongoing abdominal discomfort in ulcerative colitis-like colon inflammation. Am J Physiol Regul Integr Comp Physiol 308:R18-27
Sarna, Sushil K; Winston, John H (2015) Symptom Generation by Mucosal Inflammation in Irritable Bowel Syndrome. Gastroenterology 149:287-9
Winston, J H; Li, Q; Sarna, S K (2014) Chronic prenatal stress epigenetically modifies spinal cord BDNF expression to induce sex-specific visceral hypersensitivity in offspring. Neurogastroenterol Motil 26:715-30
Yuan, Su-Bo; Shi, Yuqiang; Chen, Jinghong et al. (2014) Gp120 in the pathogenesis of human immunodeficiency virus-associated pain. Ann Neurol 75:837-50
Winston, John H; Sarna, Sushil K (2013) Developmental origins of functional dyspepsia-like gastric hypersensitivity in rats. Gastroenterology 144:570-579.e3