The pathophysiology of short bowel syndrome and intestinal failure - deciphering the role of inflammation and host-microbiota interaction in intestinal adaptation.

• Applicant: Dr. Peggy Berlin
• Subject Area: Gastroenterology ; Nutritional Sciences
• Term: since 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 331003022

Short bowel syndrome (SBS) is a rare and complex disease that may occur after massive intestinal resection. Usually a functional small bowel length of less than 200 cm is associated with an insufficient absorption of macronutrients and/or water and electrolytes. The disease course depends on the postsurgical anatomy and individual risk factors that adversely influence intestinal adaptation. In a recent DFG-funded project (BE 6292/1-1), the applicant investigated the Nod2 mutation as a risk factor for intestinal failure. Nod2-knockout mice have worse outcome after bowel resection and develop more severe intestinal insufficiency with higher body weight loss, higher stool water, and impaired electrolyte- and fluid balance compared to wildtype mice. Mechanistically this is due to an impaired barrier function and decreased ion permeability that aggravate sodium recirculation in the villi tip of the remnant small bowel. In patients, maintenance of the ileocecal valve and colon in continuity has a beneficial effect on the SBS outcome. Nevertheless, there are only few mechanistic studies addressing the role of the colon in adaptation. Ileocecal resection induces strong dysbiotic changes in the colon, independent of the extent of resected small bowel. This is accompanied by a loss of mucus degrading and fermenting bacteria. mRNA expression studies reveal changes of ion transporters and mucus components which indicate an impaired mucus barrier function under short bowel conditions. So far, little is known about mucosal function and bacterial-host interaction in SBS. In the proposed project, compensatory mechanisms of the colon will be addressed. Mucus function, transport, microbiome and bacterial metabolites and their interaction will be analysed. Unlike previous studies, comparative analyses will be performed in a Crohn's-like ileitis model (SAMP1/YitFc) to include the influence of disease-specific inflammation on adaptation. As Crohn's disease is a frequent indication for ileocecal resection, the project is expected to provide highly clinically relevant insights into the pathophysiology of intestinal failure, taking into account the patient's underlying disease and providing the basis for new therapeutic strategies.

• DFG Programme: Research Grants
• Co-Investigators: Professor Dr. Georg Lamprecht; Privatdozentin Dr. Maria Witte