The Negative Feedback of the Glutamine/Prostatitis Loop Identified Among 1400 Metabolites and Prostatitis via Mendelian Randomization

<b>Background:</b> Prostatitis remains a clinically tricky problem due to its enigmatic etiologies, low cure rates, and relatively high recurrence rates. Therefore, we first employed Mendelian randomization to disclose the causal relationships among 1400 metabolites and prostatitis for a better understanding of the etiologies of prostatitis and thus identifying effective therapeutic targets. <b>Methods:</b> Prostatitis or metabolite-related data were derived from the online FinnGen or genome-wide association study (GWAS) Catalog datasets. Two-sample Mendelian randomization was employed, and sensitivity analyses, including heterogeneity, pleiotropy, and leave-one-out analysis, were applied to evaluate its stability. <b>Results:</b> Four potentially metabolic etiologies were identified for prostatitis, including glutamine degradant levels, adenosine 5'-monophosphate (AMP)-inosine 5'-monophosphate (IMP) ratio, glycolithocholate-glycolithocholate sulfate ratio, and AMP-citrate ratio. Therein, genetic susceptibility to the glutamine degradant levels, the AMP-IMP ratio, or the glycolithocholate-glycolithocholate sulfate ratio could decrease, while the AMP to citrate ratio might increase the risks of prostatitis. Moreover, two potential metabolic phenotypes of prostatitis were also identified, containing glutamine degradant levels and histidine betaine (hercynine) levels, indicating that genetic susceptibility to prostatitis could increase the risks of these two metabolites. Interestingly, we unexpectedly identified the negative feedback of the glutamine/prostatitis loop, showing that not only genetic susceptibility to glutamine degradant levels could decrease the risks of prostatitis but also genetic susceptibility to prostatitis could increase the risks of glutamine degradant levels. <b>Conclusion:</b> Four metabolic etiologies, two metabolic phenotypes, and the glutamine/prostatitis negative feedback loop were first identified by us for prostatitis in the European population to better understand its etiologies and offer novel treatment targets.