Microbiome composition in response to serine/glycine deficiency under high-fat diet

Non-mendelian disease mechanisms are challenging to understand mechanistically due to their variable penetrance and complex genetics but offer great potential in understanding the pathophysiology of more common diseases and co-morbidities. Peripheral neuropathy and macular telangiectasia are recent examples that have been associated with alterations in serine and sphingolipid metabolism at the genometabolic level but lack a defined genetic cause. To dissect the molecular drivers of these neurodegenerative phenotypes we induced thermal hypoalgesia in mice through dietary nutrient modulation and conducted metabolic tracing, lipid profiling, functional tests, and neuroimaging. Specifically, we independently modulated dietary serine and glycine (SG) or fat. By combining high-fat diet with SG-deficiency we greatly accelerated the induction of PN in mice, while SG-free, low-fat diets failed to induce PN during this time. Notably, 1-deoxysphingolipids accumulated in all SG-free diets, indicating that their endogenous production and accumulation is not sufficient to drive PN. On the other hand, SG-free HFDs induced PN that was mitigated by treatment with the serine palmityoltransferase inhibitor, myriocin. Lipid flux profiling in diet-fed mice administered myriocin demonstrated that high lipid turnover is required for 1-deoxysphingolipids to drive PN in mice. Notably, since SG-free HFDs failed to induce obesity and insulin resistance, these results suggest that some diabetics could have SL-mediated neuropathy in the absence of glucose intolerance