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Role of Microbiota in the Pathogenesis of Diabetic Neuropathy
(Ann Arbor, MI)
Pilot & Feasibility Program
Metabolic disruption represented by diabetes, dyslipidemia, prediabetes and metabolic syndrome leads to serious neurological complications such as peripheral neuropathy (PN). Much effort has been undertaken to understand the pathophysiology of PN and the link between metabolic dysregulation and peripheral nerve injury. Work by our group and others using the high fat diet (HFD)-mouse model have shown that the microbiota of the HFD-fed mice is significantly different than those of their control littermates. This disruption in microbiota is referred to as dysbiosis which has been correlated with PN. Moreover, dietary reversal of the HFD by a standard diet or oleate-rich diet succeeded in rectifying the disruption of the microbiota and reversal of PN. Apart from a handful of association studies, the role of microbiota in PN has not been well studied or characterized. There is also a gap in our understanding of the mechanisms by which HFD-associated dysbiosis imparts nerve injury and predisposes PN. In the current study, we aim at (1) investigating the role of microbiota in mediating PN and (2) determine the effect of microbiota on fatty acid absorption and metabolism in gut and nerves as a candidate pathway for nerve injury. To achieve our aims, we are going to use C57BL/6J mice (4-week-old) that will be depleted from their microbiota by an antibiotic cocktail (administered for 2 weeks) followed by fecal microbial transplant (FMT) from different sources and phenotyped for any PN abnormalities. After 10 weeks of FMT inoculation (16 weeks of age), feces will be collected from all mice groups for analysis of microbiota by 16S rRNA sequencing and determination of fecal fatty acid content followed by the sacrifice of mice and measurement of metabolic parameters (glucose, lipid profile, fatty acids, fatty acid metabolites). Nerves, colons, ileum will be harvested for the determination of protein expression of signaling proteins involved in fatty acid absorption and metabolism (Mogat2, PLA2g2e, Cyp2c). This study will provide a novel insight into the role of microbiota in PN and the mechanism by which it imparts nerve injury or protection. This will ultimately allow us to optimally target the microbiota to restore nerve function in prediabetic, diabetic, and obese subjects with PN.
Data for this report has not yet been released.
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Please acknowledge all posters, manuscripts or scientific materials that were generated in part or whole using funds from the Diabetic Complications Consortium(DiaComp) using the following text:
Financial support for this work provided by the NIDDK Diabetic Complications Consortium (RRID:SCR_001415, www.diacomp.org), grants DK076169 and DK115255
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