Specific Bacterial Taxa and Their Metabolite, DHPS, Linked to Alzheimers Disease, Parkinsons Disease, and Amyotrophic Lateral Sclerosis.

Neurodegenerative diseases (NDDs) are multifactorial disorders frequently associated with gut dysbiosis, oxidative stress, and inflammation; however, the pathophysiological mechanisms remain poorly understood. We investigated bacterial and metabolic dyshomeostasis in the gut microbiome associated with early disease stages across three NDDs, amyotrophic lateral sclerosis (ALS), Alzheimers Disease (AD), Parkinsons Disease (PD), and healthy controls (HC) and discovered a previously unrecognized link between a microbial-derived metabolite with an unknown role in human physiology, 2,3-dihydroxypropane-1-sulfonate (DHPS), and NDDs. DHPS was downregulated in AD, ALS, and PD, while Eubacterium and Desulfovibrio, capable of metabolizing this metabolite,1-4 were increased in all disease cohorts. Additionally, select taxa within the Clostridia class had strong negative correlations to DHPS suggesting a potential role in DHPS metabolism. Hydrogen sulfide is a catabolic product of DHPS,1,5 and hydrogen sulfide promotes inflammation,6-8 oxidative stress,9 mitochondrial damage,10 and gut dysbiosis,2,11 known hallmarks of NDD. These findings suggest that cryptic sulfur metabolism via DHPS is a missing link in our current understanding of NDD onset and progression. To the best of our knowledge, we are the first to provide evidence of a conserved gut-brain axis linkage of specific bacterial taxa and their metabolism of DHPS shared by three neurodegenerative diseases.