LAUSR

Brain hypometabolism is a common feature of neurodegenerative disorders [1]. Limited glucose utilization and impaired creatine metabolism characterize neuronal dysfunction in Alzheimer’s and Parkinson’s diseases [2], with hypometabolic brain status correlating with disease progression and severity. Restoring normal brain metabolism thus might be a pertinent target for various brain-specific therapeutics, including gut microbiota-derived short-chain fatty acids (SCFAs). SCFAs are fatty acids with fewer than six carbon atoms (e.g., propionic acid, acetic acid, butyric and isobutyric acid), created naturally after the fermentation of dietary fibers by colonic bacteria. A recent trial suggests that gut-produced SCFAs attenuate Alzheimer’s disease, by serving as substrates for brain energy metabolism and reducing the formation of beta-amyloid aggregates [3]. That being the case, any nutritional compound that can stimulate SCFAs yield from the gut microbiota might be considered as a possible diseasemodifying agent in neurodegenerative diseases (Fig. 1). Water infused with hydrogen gas (hydrogen-rich water, HRW) appeared recently as an innovative functional drink that may exhibit a number of benefits for human health [4]. Specifically, HRW has recently been advocated as a possible nutritional upregulator of SCFAs production by gut microbiota in three pre-clinical trials, all published from 2018 onward. Ad libitum consumption of HRW (hydrogen 0.32 mM) for 4 weeks induced a significant rise in the production of certain SCFAs (such as propionic acid, isobutyric acid, and isovaleric acid) in mouse cecal contents, as compared to the control mice which consumed normal water with no dissolved hydrogen [5]. Another study reported similar effects in piglets fed with a mycotoxincontaminated diet [6], in which 25-day consumption of HRW (0.60 mM) augmented the levels of butyric acid, valeric acid, and total SCFAs in the large intestine. Finally, Bordoni et al. [7] have shown that 15-day treatment with HRW (0.4–0.9 mM) in an animal model of Parkinson’s disease elevated the levels of butyric acid in the feces by inducing a higher abundance of butyrate-producing bacteria (including Lachnospiraceae, Ruminococcaceae, and Papillibacter). Although promising, these preliminary studies have not addressed whether higher levels of gut floragenerated SCFAs after the treatment translate into improved brain bioenergetics. Nevertheless, a randomized, doubleblind, parallel-group clinical trial reported ameliorated patient-reported disease rating scores in patients with levodopa-medicated Parkinson’s disease who drank 1000 mL per day of HRW for 48 weeks [8], suggesting that beneficial effects might be mediated by HRW-driven SCFAs output from the gut flora. These promising findings should be carefully interpreted since this pilot trial was rather small (e.g., nine patients received HRW and eight patients received placebo) and the authors have not tested SCFAs production or any other gut microbiome biomarker. Before recommending water infused with hydrogen to the general public, further robust randomized controlled trials are obligatory, from deciphering possible metabolic role(s) of HRW-driven SCFAs as an alternative energy source for the human brain, to accounting for different HRW treatment protocols and dosing ranges, and pathophysiological features of neurodegenerative disorders. Although HRW is generally considered safe for human consumption [9] the safety surveillance also remains highly justified to detect any rare and/or long-term adverse events over a large patient population and prolonged time period.