Impact of probiotic supplementation on exercise endurance among nonelite athletes: a randomized, placebo-controlled, double-blind, clinical trial.

This randomized, placebo-controlled, double-blind, parallel trial investigated whether generally healthy adult, nonelite runners would have a greater time-to-exhaustion during submaximal treadmill running with probiotic versus placebo supplementation. It was hypothesized that the probiotic would impact training progression by reducing gastrointestinal (GI) and cold/flu symptoms. Participants who typically ran ≥24 km/week, ran or cross-trained 3-5 days per week, and had a maximal oxygen intake (V̇O2 max) in the 60-85th percentile were enrolled. V̇O2 max was used to establish individualized workload settings (85% of V̇O2 max) for the submaximal endurance tests at baseline and following 6 weeks of supplementation with a probiotic (Lactobacillus helveticus Lafti L10, 5×109 CFU/capsule/day) or placebo. Participants self-reported GI and cold/flu symptoms and physical activity via daily and weekly questionnaires. Outcomes were tested using a linear model to determine if mean response values adjusted for baseline differed between groups. Twenty-eight participants (n = 14/group), aged 25 ± 5 years (mean ± SD) with a body mass index of 23 ± 3 kg/m2, completed the study. At the final visit the probiotic group had a lower time-to-exhaustion versus the placebo group (P = 0.01) due to an increase in time-to-exhaustion with the placebo (1344 ± 188 to 1565 ± 219 s, P = 0.01) with no change with the probiotic (1655 ± 230 to 1547 ± 215 s, P = 0.23). During the intervention, the probiotic group completed fewer aerobic training sessions per week (P = 0.02) and trained at a lower intensity (P = 0.007) versus the placebo group. Few GI and cold/flu symptoms were reported with no differences between groups. Time-to-exhaustion increased in the placebo group, possibly due to differences in training habits.

Impact of probiotic supplementation on exercise endurance among non-elite athletes: study protocol for a randomized, placebo-controlled, double-blind, clinical trial.

BACKGROUND: Some probiotics appear to improve athletic performance, endurance, and recovery after intense exercise. Other formulations may provide performance-related benefits via immune and gastrointestinal functions in athletic individuals. However, few formulations have been studied for both types of effects among non-elite athletes. The primary objective of this study is to assess the ergogenic effects of a probiotic on high-intensity endurance running performance in non-elite runners. Secondary objectives include assessment of perceived exertion, blood chemistry, immune and stress biomarkers, cold and flu symptoms, and gastrointestinal health after the probiotic intervention. METHODS: This 9-week randomized, placebo-controlled, double-blind, parallel trial will assess the ergogenic effects of a probiotic (5 billion colony-forming units/day, for 6 weeks) in healthy, non-elite runners (N=32; 18-45 years). Participants will be monitored via daily and weekly questionnaires during the 2-week pre-baseline, 6-week intervention, and 1-week washout. Questionnaires will inquire about activity, muscle soreness, gastrointestinal symptoms, cold and flu symptoms, stool form and frequency, and adverse events. During the pre-baseline visit, maximal oxygen uptake (V̇O2 max) is assessed to set appropriate individualized workload settings for the treadmill time-to-exhaustion endurance tests. These time-to-exhaustion endurance running tests will be completed at an intensity of 85% VO2max at baseline and final visits. During these tests, self-perceived exercise effort will be rated via the Borg Rating of Perceived Exertion scale and finger sticks assessing capillary blood glucose and lactate concentrations will be collected every 3 min. Additional questionnaires will assess diet and motivation to exercise. Body composition will be assessed using air displacement plethysmography at the baseline and final visits. Hypotheses will be tested using two-sided tests, and a linear model and with a type I error rate of α=0.05. Primary and secondary outcomes will be tested by comparing results between the intervention groups, adjusting for baseline values. DISCUSSION: These results will build evidence documenting the role of probiotics on running endurance performance and physiological responses to exercise in non-elite athletes. Understanding the potential mechanisms of probiotic effects and how they mitigate the intestinal or immune discomforts caused by running could provide additional strategy means to help runners improve their performance. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT04588142 . Posted on October 19, 2020. PROTOCOL VERSION: July 2, 2021, version 1.2.

Targeted and untargeted metabolomics provide insight into the consequences of glycine-N-methyltransferase deficiency including the novel finding of defective immune function.

Fatty liver disease is increasing along with the prevalence of obesity and type-2 diabetes. Hepatic fibrosis is a major health complication for which there are no efficacious treatment options available. A better understanding of the fundamental mechanisms that contribute to the accumulation of fibrosis is needed. Glycine-N-methyltransferase (GNMT) is a critical enzyme in one-carbon metabolism that serves to regulate methylation and remethylation reactions. GNMT knockout (GNMT-/- ) mice display spontaneous hepatic fibrosis and later develop hepatocellular carcinoma. Previous literature supports the idea that hypermethylation as a consequence of GNMT deletion contributes to the hepatic phenotype observed. However, limited metabolomic information is available and the underlying mechanisms that contribute to hepatic fibrogenesis in GNMT-/- mice are still incomplete. Therefore, our goals were to use dietary intervention to determine whether increased lipid load exacerbates steatosis and hepatic fibrosis in this model and to employ both targeted and untargeted metabolomics to further understand the metabolic consequences of GNMT deletion. We find that GNMT mice fed high-fat diet do not accumulate more lipid or fibrosis in the liver and are in fact resistant to weight gain. Metabolomics analysis confirmed that pan-hypermethylation occurs in GNMT mice resulting in a depletion of nicotinamide intermediate metabolites. Further, there is a disruption in tryptophan catabolism that prevents adequate immune cell activation in the liver. The chronic cellular damage cannot be appropriately cleared due to a lack of immune checkpoint activation. This mouse model is an excellent example of how a disruption in small molecule metabolism can significantly impact immune function.

Disruption of hepatic one-carbon metabolism impairs mitochondrial function and enhances macrophage activity in methionine-choline-deficient mice.

One-carbon metabolism is a collection of metabolic cycles that supports methylation and provides one-carbon bound folates for the de novo synthesis of purine and thymidine nucleotides. The methylation of phosphatidylethanolamine to form choline has been extensively studied in the context of fatty liver disease. However, the role of one-carbon metabolism in supporting nucleotide synthesis during liver damage has not been addressed. The objective of this study is to determine how the disruption of one-carbon metabolism influences nucleotide metabolism in the liver after dietary methionine and choline restriction. Mice (n=8) were fed a methionine-choline-deficient or control diet for 3 weeks. We treated mice with the compound alloxazine (0.5 mg/kg), a known adenosine receptor antagonist, every second day during the final week of feeding to probe the function of adenosine signaling during liver damage. We found that concentrations of several hepatic nucleotides were significantly lower in methionine- and choline-deficient mice vs. controls (adenine: 13.9±0.7 vs. 10.1±0.6, guanine: 1.8±0.1 vs. 1.4±0.1, thymidine: 0.0122±0.0027 vs. 0.0059±0.0027 nmol/mg dry tissue). Treatment of alloxazine caused a specific decrease in thymidine nucleotides, decrease in mitochondrial content in the liver and exacerbation of steatohepatitis as shown by the increased hepatic lipid content and altered macrophage morphology. This study demonstrates a role for one-carbon metabolism in supporting de novo nucleotide synthesis and mitochondrial function during liver damage.