Roan Willson

Major: Biochemistry / Microbiology

Faculty Advisor: Onesmo Balemba

Project Title:

High fat diet disrupts gastrointestinal movement by damaging the enteric nervous system damage before insulin resistance and impaired glucose tolerance in mice

Abstract

Roughly, 34 million Americans suffer from Type 2 diabetes (T2D), 50-70% of which have debilitating gastrointestinal (GI) motility disorder--dysphagia, gastroparesis, diarrhea, constipation, and pain. These GI illnesses are thought to be caused by enteric nervous system (ENS) damage triggered by longstanding T2D. Current research utilizing mice restricted to high fat diet (HFD) for 8 weeks and beyond suggests that ENS damage is initiated by toxins from the gut. The goal of this studywasto test the hypothesis that HFD consumption causes production of toxic/antimotility substances in feces, ENS injury and GI dysmotility before insulin resistance in mice.

Materials and Methods. Male and female C57BL/6 mice were fed 70% kcal HFD or standard chow diet (SCD) for 2 weeks and monitored for T2D conditions (obesity, glucose tolerance, insulin resistance and inflammation). Evan’s blue intragastric gavage was used to analyze GI motility. Duodenums were fixed in 4% paraformaldehyde and stained by immunohistochemistry to reveal all neurons and nitrergic myenteric neurons. Confocal microscopy and morphometry were used to quantify immunoreactivity per ganglionic area. Duodenal muscle preparations were cultured in sterile filtrate from cecum feces to determine whether they contain substances that inhibit GI motility by damaging ENS and reducing muscle contractions.

Results.  HFD ingestion delayed GI transit, increased levels of MCP-1 and IL-6 cytokines in serum without causing glucose intolerance and insulin resistance. The total and nitrergic myenteric neurons per ganglionic area were unchanged but the varicosities of nitrergic myenteric neurons were significantly decreased. Sterile fluid from cecum feces of HFD mice inhibited contractions of duodenal muscle after 6-24 hours and damaged myenteric neurons.

Conclusions. HFD ingestion causes production of toxic/antimotility substances in feces, damage to nitrergic myenteric neurons and GI dysmotility before insulin resistance. This suggests that toxins from GI contents initiate diabetic ENS damage and GI motility disorders.