Grant

Entero-endocrinology including the effects of bariatric surgery

Funder: Medical Research Council

Dimensions: grant.8469512

Investigators

Affiliations

Organisations

  1. (1) University of Cambridge, grid.5335.0

Research Organisations

Countries

United Kingdom

Continents

Europe

Abstract

The gut releases signals that coordinate how it handles food, how nutrients are distributed in the body and how much food is consumed. Modifying these signals presents an opportunity to treat obesity and high blood sugar and it is thought that changes in these signals are important in the positive effects of bariatric surgery. We use mice that have been genetically altered to either label the cells that produce these signals or the cells that receive the signals, enabling us to identify and characterise changes when these mice undergo bariatric surgery. We hope that understanding these changes will, in the long term, enable us to modify gut-derived signals to treat metabolic diseases in humans without the need of surgical intervention. Technical Summary The enteroendocrine system is a key player in the control of postprandial nutrient homeostasis, modulating the transit and digestion of nutrients within the intestine, the disposal of nutrients in peripheral organs and affecting future feeding behaviour/appetite. Some peptide hormones, notably glucagon-like peptide-1, are already exploited to treat diabetes and obesity, whilst changes in enteroendcrine responses are thought to contribute to the beneficial metabolic outcomes of bariatric surgery. This programme uses genetically modified mouse models to address the mechanisms underlying enteroendocrine changes in response to bariatric surgery with the aim to modulate the enteroendocrine system for the treatment of metabolic disease. We compare in vivo results in mice after vertical sleeve gastrectomy with observations in human volunteers, which have undergone gastrectomy with Roux-en-Y type reconstruction of the upper small intestine and in vitro studies with primary mixed epithelial cultures and intestinal organoids of both human and murine origin. Transcriptomic, mass-spec-based peptidomic, optical single cell second messenger dynamic and electrophysiological investigations are combined with pharmacological and/or genetic manipulations to identify and characterise signalling mechanisms underlying enteroendocrine hormone release and action.

Funding information

Funding period: 2018-2023

Funding amount: EUR 518663

Grant number: MC_UU_00014/3

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