A study to explore novel causes of diabetes neuropathy and dysmotility in the gut
Onesmo Balemba   (Moscow, ID)
Damage to enteric nervous system (ENS) causes gastrointestinal (GI) motility disorders in type two diabetes (T2D) patients and insulin resistance. It is believed that molecules derived from diet-gut microbiota-host interactions—particularly palmitate, lipopolysaccharide (LPS) and lipoteichoic acid act synergistically to damage the ENS neurons and disrupt GI movements in prediabetes and T2D patients. Still, knowledge of the role of molecules derived from diet-gut microbiota-host interactions in causing diabetic ENS neuropathy and GI dysmotility is extremely limited. We have discovered that sterile fluid (supernatants) from of distal ileum and cecum contents of diabetic and nondiabetic C57BL/6 mice restricted to high fat diet (HFD) for 8 weeks (nondiabetic female or diabetic male mice) inhibit intestinal propulsion in vitro. Furthermore, they damage nitrergic and cholinergic myenteric neurons and inhibits the excitability of smooth muscle cells. Supernants with these damaging effects are likely produced before mice develop diabetes phenotype (obesity, hyperglycemia, insulin resistance), because supernatants of 2-week HFD mice (normal glycemic) block muscle contractions. All these changes match the effects of HFD ingestion but are in sharp contrast to results obtained in using supernatants of mice fed standard chow diet (SCD). Palmitate, short chain fatty acids, glucose, LPS and lipoteichoic acid (LTA) do not mimic the antimotility effects of supernatant from HFD mice individually or when mixed together. Our results suggest that ileocecal supernatants of HFD mice contain unknown molecules—that disrupt motility by impairing ENS neurons and smooth muscle cells, before the type two diabetes. We believe that fecal supernants from prediabetes and T2D patients contain such molecules. Our objective here is to test the hypothesis that transplantation of supernatants of feces from mice restricted to HFD for 8 weeks, and prediabetes or T2D humans into healthy mice, will alter gut motility by disrupting neurotransmission in the ENS. We believe that this will confirm our ex vivo results, and the idea that unknown toxins from intestinal contents trigger GI ENS neuropathy and dysmotility before insulin resistance. In future research we will focus our efforts on studying supernatants from 1-2weeks HFD mice, chemical identification of toxins in supernatants and their mechanisms of action. Therefore, our work may have ramifications for understanding the etiology of both neuropathy and T2D, lead to new biomarkers and therapeutic targets for GI dysmotility, diabetic neuropathy and neurodegeneration.
No report available yet.