Untargeted metabolomics reveal signatures of a healthy lifestyle.

This cross-sectional study investigated differences in the plasma metabolome in two groups of adults that were of similar age but varied markedly in body composition and dietary and physical activity patterns. Study participants included 52 adults in the lifestyle group (LIFE) (28 males, 24 females) and 52 in the control group (CON) (27 males, 25 females). The results using an extensive untargeted ultra high-performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS) metabolomics analysis with 10,535 metabolite peaks identified 486 important metabolites (variable influence on projections scores of VIP ≥ 1) and 16 significantly enriched metabolic pathways that differentiated LIFE and CON groups. A novel metabolite signature of positive lifestyle habits emerged from this analysis highlighted by lower plasma levels of numerous bile acids, an amino acid profile characterized by higher histidine and lower glutamic acid, glutamine, ß-alanine, phenylalanine, tyrosine, and proline, an elevated vitamin D status, higher levels of beneficial fatty acids and gut microbiome catabolism metabolites from plant substrates, and reduced levels of N-glycan degradation metabolites and environmental contaminants. This study established that the plasma metabolome is strongly associated with body composition and lifestyle habits. The robust lifestyle metabolite signature identified in this study is consistent with an improved life expectancy and a reduced risk for chronic disease.

The state of the science on the health benefits of blueberries: a perspective.

Mounting evidence indicates that blueberry consumption is associated with a variety of health benefits. It has been suggested that regular consumption of blueberries can support and/or protect against cardiovascular disease and function, pre-diabetes and type 2 diabetes, and brain and cognitive function in individuals with health conditions and age-related decline. Further, mechanistic investigations highlight the role of blueberry anthocyanins in mediating these health benefits, in part through interactions with gut microbiota. Also, nutritional interventions with blueberries have demonstrated the ability to improve recovery following exercise-induced muscle damage, attributable to anti-inflammatory effects. Despite these advancements in blueberry health research, research gaps persist which affects the generalizability of findings from clinical trials. To evaluate the current state of knowledge and research gaps, a blueberry health roundtable with scientific experts convened in Washington, DC (December 6-7, 2022). Discussions centered around five research domains: cardiovascular health, pre-diabetes and diabetes, brain health and cognitive function, gut health, and exercise recovery. This article synthesizes the outcomes of a blueberry research roundtable discussion among researchers in these domains, offering insights into the health benefits of blueberries and delineating research gaps and future research directions.

Beet supplementation mitigates post-exercise inflammation.

Objectives: This study investigated the efficacy of a mixed beet-based supplement (BEET) versus placebo (PL) in countering inflammation during recovery from 2.25 h of intensive cycling in 20 male and female cyclists. A multi-omics approach was used that included untargeted proteomics and a targeted oxylipin panel. Methods: A randomized, placebo-controlled, double-blind, crossover design was used with two 2-week supplementation periods and a 2-week washout period. Supplementation periods were followed by a 2.25 h cycling bout at close to 70%VO2max. The BEET supplement provided 212 mg of nitrates per day, 200 mg caffeine from green tea extract, 44 mg vitamin C from Camu Camu berry, B-vitamins from quinoa sprouts (40% Daily Value for thiamin, riboflavin, niacin, and vitamin B6), and 2.5 g of a mushroom blend containing Cordyceps sinensis and Inonotus obliquus. Six blood samples were collected before and after supplementation (overnight fasted state), immediately post-exercise, and at 1.5 h-, 3 h-, and 24 h-post-exercise. Results: The 2.25 h cycling bout increased plasma levels of 41 of 67 oxylipins detected. BEET supplementation significantly increased plasma nitrate (NO3 -) and nitrite (NO2 -) (sum, NO3 - + NO2 -) concentrations (interaction effect, p < 0.001) and two anti-inflammatory oxylipins [18-hydroxyeicosapentaenoic acid (18-HEPE) and 4-hydroxy-docosahexanoic acid (4-HDoHE)]. The untargeted proteomics analysis identified 616 proteins (458 across all times points), and 2-way ANOVA revealed a cluster of 45 proteins that were decreased and a cluster of 21 that were increased in the BEET versus PL trials. Functional enrichment supported significant BEET-related reductions in inflammation-related proteins including several proteins related to complement activation, the acute phase response, and immune cell adhesion, migration, and differentiation. Discussion: Intake of a BEET-based supplement during a 2-week period was linked to higher plasma levels of NO3 - + NO2 -, elevated post-exercise levels of two anti-inflammatory oxylipins, and a significant decrease in a cluster of proteins involved in complement activation and inflammation. These data support that 2-weeks intake of nitrate from a mixed beet-based supplement moderated protein biomarkers of exercise-induced inflammation in athletes.

The anti-inflammatory effects of exercise on autoimmune diseases: A 20-year systematic review.

BACKGROUND: The anti-inflammatory effect of exercise may be an underlying factor in improving several autoimmune diseases. The aim of this systematic review was to examine the evidence on the role of exercise training in mitigating inflammation in adolescents and adults with autoimmune disease. METHODS: PubMed, Web of Science, and Embase databases were systematically reviewed for related studies published between January 1, 2003, and August 31, 2023. All randomized and non-randomized controlled trials of exercise interventions with autoimmune disease study participants that evaluated inflammation-related biomarkers were included. The quality of evidence was assessed using the Tool for the assEssment of Study qualiTy and reporting in EXercise scale and Cochrane bias risk tool. RESULTS: A total of 14,565 records were identified. After screening the titles, abstracts, and full texts, 87 were eligible for the systematic review. These studies were conducted in 25 different countries and included a total of 2779 participants (patients with autoimmune disease, in exercise or control groups). Overall, the evidence suggests that inflammation-related markers such as C-reactive protein, interleukin 6, and tumor necrosis factor α were reduced by regular exercise interventions. Regular exercise interventions combined with multiple exercise modes were associated with greater benefits. CONCLUSION: Regular exercise training by patients with autoimmune disease exerts an anti-inflammatory influence. This systematic review provides support for the promotion and development of clinical exercise intervention programs for patients with autoimmune disease. Most patients with autoimmune disease can safely adopt moderate exercise training protocols, but changes in inflammation biomarkers will be modest at best. Acute exercise interventions are ineffective or even modestly but transiently pro-inflammatory.

Healthy lifestyle linked to innate immunity and lipoprotein metabolism: a cross-sectional comparison using untargeted proteomics.

This study used untargeted proteomics to compare blood proteomic profiles in two groups of adults that differed widely in lifestyle habits. A total of 52 subjects in the lifestyle group (LIFE) (28 males, 24 females) and 52 in the control group (CON) (27 males, 25 females) participated in this cross-sectional study. Age, education level, marital status, and height did not differ significantly between LIFE and CON groups. The LIFE and CON groups differed markedly in body composition, physical activity patterns, dietary intake patterns, disease risk factor prevalence, blood measures of inflammation, triglycerides, HDL-cholesterol, glucose, and insulin, weight-adjusted leg/back and handgrip strength, and mood states. The proteomics analysis showed strong group differences for 39 of 725 proteins identified in dried blood spot samples. Of these, 18 were downregulated in the LIFE group and collectively indicated a lower innate immune activation signature. A total of 21 proteins were upregulated in the LIFE group and supported greater lipoprotein metabolism and HDL remodeling. Lifestyle-related habits and biomarkers were probed and the variance (> 50%) in proteomic profiles was best explained by group contrasts in indicators of adiposity. This cross-sectional study established that a relatively small number of proteins are associated with good lifestyle habits.

Blueberry intake elevates post-exercise anti-inflammatory oxylipins: a randomized trial.

This study determined if 18 days of supplementation with blueberries (BL) compared to placebo (PL) could mitigate muscle soreness and damage and improve inflammation resolution in untrained adults (n = 49, ages 18-50 years) after engaging in a 90-min bout of "weekend warrior" eccentric exercise. The BL freeze dried supplement provided 1 cup of fresh blueberries per day equivalent with 805 mg/day total phenolics and 280 mg/day anthocyanins. Urine levels of eight BL gut-derived phenolics increased after 14- and 18-days supplementation with 83% higher concentrations in BL vs. PL (p < 0.001). The 90-min exercise bout caused significant muscle soreness and damage during 4d of recovery and a decrease in exercise performance with no significant differences between PL and BL. Plasma oxylipins were identified (n = 76) and grouped by fatty acid substrates and enzyme systems. Linoleic acid (LA) oxylipins generated from cytochrome P450 (CYP) (9,10-, 12,13-dihydroxy-9Z-octadecenoic acids) (diHOMEs) were lower in BL vs. PL (treatment effect, p = 0.051). A compositive variable of 9 plasma hydroxydocosahexaenoic acids (HDoHEs) generated from docosahexaenoic acid (DHA, 22:6) and lipoxygenase (LOX) was significantly higher in BL vs. PL (treatment effect, p = 0.008). The composite variable of plasma 14-HDoHE, 17-HDoHE, and the eicosapentaenoic acid (EPA)-derived oxylipin 18-hydroxyeicosapentaenoic acid (18-HEPE) (specialized pro-resolving lipid mediators, SPM, intermediates) was significantly higher in BL vs PL (treatment effect, p = 0.014). Pearson correlations showed positive relationships between post-exercise DHA-LOX HDoHEs and SPM intermediates with urine blueberry gut-derived phenolics (r = 0.324, p = 0.023, and r = 0.349, p = 0.015, respectively). These data indicate that 18d intake of 1 cup/day blueberries compared to PL was linked to a reduction in pro-inflammatory diHOMES and sustained elevations in DHA- and EPA-derived anti-inflammatory oxylipins in response to a 90-min bout of unaccustomed exercise by untrained adults.

Effects of High-Intensity Interval Training and Combined High-Intensity Interval Training Programs on Cancer-Related Fatigue and Cancer Pain: A Systematic Review and Meta-analysis.

PURPOSE: This systematic review and meta-analysis assessed the effectiveness of high-intensity interval training (HIIT) alone and combined HIIT programs compared with usual care on cancer-related fatigue (CRF) and pain related to cancer or cancer-related treatments. METHODS: Articles published prior to January 2023 were searched in the following digital databases: PubMed, Cochrane Database of Systematic Reviews and Cochrane Controlled Clinical Trials (CENTRAL), Web of Science, Scopus and ScienceDirect. Randomized controlled trials were included that met the following criteria: (i) adult cancer patients and survivors (>18 yr old); (ii) HIIT or combined HIIT programs versus usual care; (iii) assessment of fatigue and pain. Cochrane tool was used for assessing Risk of Bias (RoB) and Review Manager (RevMan 5.2) was used for data analysis. RESULTS: Based on limited number (12) of studies included, we found HIIT and combined HIIT interventions have significant effect sizes on reducing both CRF (standardized mean difference, 0.63; 95% confidence interval, 0.42-0.84; P < 0.001) and cancer-associated pain (standardized mean difference, 0.44; 95% confidence interval, 0.25-0.63; P < 0.001). CONCLUSIONS: This systematic review and meta-analysis indicate that HIIT and combined HIIT programs can reduce CRF and pain.

Astaxanthin supplementation counters exercise-induced decreases in immune-related plasma proteins.

Objectives: Astaxanthin is a dark red keto-carotenoid found in aquatic animals such as salmon and shrimp, and algae (Haematococcus pluvialis). Astaxanthin has a unique molecular structure that may facilitate anti-oxidative, immunomodulatory, and anti-inflammatory effects during physiological stress. The primary objective of this study was to examine the efficacy of 4-week ingestion of astaxanthin in moderating exercise-induced inflammation and immune dysfunction using a multi-omics approach. Methods: This study employed a randomized, double blind, placebo controlled, crossover design with two 4-week supplementation periods and a 2-week washout period. Study participants were randomized to astaxanthin and placebo trials, with supplements ingested daily for 4 weeks prior to running 2.25 h at close to 70%VO2max (including 30 min of 10% downhill running). After the washout period, participants repeated all procedures using the counterbalanced supplement. The astaxanthin capsule contained 8 mg of algae astaxanthin. Six blood samples were collected before and after supplementation (overnight fasted state), immediately post-exercise, and at 1.5, 3, and 24 h-post-exercise. Plasma aliquots were assayed using untargeted proteomics, and targeted oxylipin and cytokine panels. Results: The 2.25 h running bout induced significant muscle soreness, muscle damage, and inflammation. Astaxanthin supplementation had no effect on exercise-induced muscle soreness, muscle damage, and increases in six plasma cytokines and 42 oxylipins. Notably, astaxanthin supplementation countered exercise-induced decreases in 82 plasma proteins (during 24 h recovery). Biological process analysis revealed that most of these proteins were involved in immune-related functions such as defense responses, complement activation, and humoral immune system responses. Twenty plasma immunoglobulins were identified that differed significantly between the astaxanthin and placebo trials. Plasma levels of IgM decreased significantly post-exercise but recovered after the 24 h post-exercise recovery period in the astaxanthin but not the placebo trial. Discussion: These data support that 4-week astaxanthin versus placebo supplementation did not counter exercise-induced increases in plasma cytokines and oxylipins but was linked to normalization of post-exercise plasma levels of numerous immune-related proteins including immunoglobulins within 24 h. Short-term astaxanthin supplementation (8 mg/day during a 4-week period) provided immune support for runners engaging in a vigorous 2.25 h running bout and uniquely countered decreases in plasma immunoglobulin levels.

Influence of 2 Weeks of Mango Ingestion on Inflammation Resolution after Vigorous Exercise.

Mangoes have a unique nutrient profile (carotenoids, polyphenols, sugars, and vitamins) that we hypothesized would mitigate post-exercise inflammation. This study examined the effects of mango ingestion on moderating exercise-induced inflammation in a randomized crossover trial with 22 cyclists. In random order with trials separated by a 2-week washout period, the cyclists ingested 330 g mango/day with 0.5 L water or 0.5 L of water alone for 2 weeks, followed by a 2.25 h cycling bout challenge. Blood and urine samples were collected pre- and post-2 weeks of supplementation, with additional blood samples collected immediately post-exercise and 1.5-h, 3-h, and 24 h post-exercise. Urine samples were analyzed for targeted mango-related metabolites. The blood samples were analyzed for 67 oxylipins, which are upstream regulators of inflammation and other physiological processes. After 2 weeks of mango ingestion, three targeted urine mango-related phenolic metabolites were significantly elevated compared to water alone (interaction effects, p ≤ 0.003). Significant post-exercise increases were measured for 49 oxylipins, but various subgroup analyses showed no differences in the pattern of change between trials (all interaction effects, p > 0.150). The 2.25 h cycling bouts induced significant inflammation, but no countermeasure effect was found after 2 weeks of mango ingestion despite the elevation of mango gut-derived phenolic metabolites.

Physical activity lowers the risk for acute respiratory infections: Time for recognition.

Physical inactivity is a well-established risk factor for chronic diseases, such as cardiovascular disease, cancer, and diabetes mellitus. There is a growing awareness that physical inactivity should also be regarded as a risk factor for acute respiratory infections (ARIs). ARIs, such as the common cold, influenza, pneumonia, and coronavirus disease 2019 (COVID-19), are among the most pervasive diseases on earth and cause widespread morbidity and mortality. Evidence in support of the linkage between ARIs and physical inactivity has been strengthened during the COVID-19 pandemic because of increased scientific scrutiny. Large-scale studies have consistently reported that the risk for severe COVID-19 outcomes is elevated in cohorts with low physical activity and/or physical fitness, even after adjusting for other risk factors. The lowered risk for severe COVID-19 and other ARIs in physically active groups is attributed to exercise-induced immunoprotective effects, including enhanced surveillance of key immune cells and reduced chronic inflammation. Scientific consensus groups, including those who submitted the Physical Activity Guidelines for Americans, have not yet given this area of research the respect that is due. It is time to add "reduced risk for ARIs" to the "Exercise is Medicine" list of physical activity-related health benefits.

No effects of a 4-week post-exercise sauna bathing on targeted gut microbiota and intestinal barrier function, and hsCRP in healthy men: a pilot randomized controlled trial.

BACKGROUND: Body temperature fluctuations induced by acute exercise bouts may influence the intestinal barrier with related effects on epithelial permeability, immune responses, and release of metabolites produced by the gut microbiota. This study evaluated the effects of post-exercise sauna bathing in young men undergoing endurance training on gut bacteria inflammation and intestinal barrier function. METHODS: Fifteen (15) untrained males aged 22 ± 1.5 years were randomly assigned to exercise training (ET) with or without post-exercise sauna treatments (S). Participants in the group ET + S (n = 8) exercised 60 min, 3 times per week, on a bicycle ergometer followed by a 30-min dry Finish sauna treatment. The control group (ET, n = 7) engaged in the same exercise training program without the sauna treatments. Blood and stool samples were collected before and after the 4-week training program. Blood samples were analysed for the concentration of high-sensitivity C-reactive protein (hsCRP) and complete blood counts. Stool samples were analysed for pH, quantitative and qualitative measures of targeted bacteria, zonulin, and secretory immunoglobulin A. RESULTS: Interaction effects revealed no differences in the pattern of change over time between groups for the abundance of selected gut microbiome bacteria and stool pH, zonulin, sIgA, and hsCRP. Pre- and post-study fecal concentrations of Bifidobacterium spp., Faecalibacterium prausnitzii, and Akkermansia muciniphila were below reference values for these bacteria in both groups. CONCLUSIONS: The combination of 4-weeks exercise followed by passive heat exposure did not have a measurable influence on targeted gut microbiota, intestinal barrier function, and hsCRP levels in young males. TRIAL REGISTRATION: The study was retrospectively registered in the clinical trials registry (Clinicaltrials.gov) under the trial registration number: NCT05277597. Release Date: March 11, 2022.

Enhancing the Cognitive Effects of Flavonoids With Physical Activity: Is There a Case for the Gut Microbiome?

Age-related cognitive changes can be the first indication of the progression to dementias, such as Alzheimer's disease. These changes may be driven by a complex interaction of factors including diet, activity levels, genetics, and environment. Here we review the evidence supporting relationships between flavonoids, physical activity, and brain function. Recent in vivo experiments and human clinical trials have shown that flavonoid-rich foods can inhibit neuroinflammation and enhance cognitive performance. Improved cognition has also been correlated with a physically active lifestyle, and with the functionality and diversity of the gut microbiome. The great majority (+ 90%) of dietary flavonoids are biotransformed into phytoactive phenolic metabolites at the gut microbiome level prior to absorption, and these prebiotic flavonoids modulate microbiota profiles and diversity. Health-relevant outcomes from flavonoid ingestion may only be realized in the presence of a robust microbiome. Moderate-to-vigorous physical activity (MVPA) accelerates the catabolism and uptake of these gut-derived anti-inflammatory and immunomodulatory metabolites into circulation. The gut microbiome exerts a profound influence on cognitive function; moderate exercise and flavonoid intake influence cognitive benefits; and exercise and flavonoid intake influence the microbiome. We conclude that there is a potential for combined impacts of flavonoid intake and physical exertion on cognitive function, as modulated by the gut microbiome, and that the combination of a flavonoid-rich diet and routine aerobic exercise may potentiate cognitive benefits and reduce cognitive decline in an aging population, via mechanisms mediated by the gut microbiome. Mechanistic animal studies and human clinical interventions are needed to further explore this hypothesis.

Almond intake alters the acute plasma dihydroxy-octadecenoic acid (DiHOME) response to eccentric exercise.

Introduction: This investigation determined if 4-weeks ingestion of nutrient-dense almonds mitigated post-exercise inflammation and muscle soreness and damage. Methods: An acute 90-min of eccentric exercise (90-EE) was used to induce muscle damage in 64 non-obese adults not engaging in regular resistance training (ages 30-65 years, BMI < 30 kg/m2). Using a parallel group design, participants were randomized to almond (AL) (57 g/d) or cereal bar (CB) (calorie matched) treatment groups for a 4-week period prior to the 90-EE (17 exercises). Blood and 24-h urine samples were collected before and after supplementation, with additional blood samples collected immediately post-90-EE, and then daily during 4 additional days of recovery. Changes in plasma oxylipins, urinary gut-derived phenolics, plasma cytokines, muscle damage biomarkers, mood states, and exercise performance were assessed. Results: The 90-EE protocol induced significant muscle damage, delayed onset of muscle soreness (DOMS), inflammation, reduced strength and power performance, and mood disturbance. Interaction effects (2 group × 7 time points) supported that AL vs. CB was associated with reduced post-exercise fatigue and tension (p = 0.051, 0.033, respectively) and higher levels of leg-back strength (p = 0.029). No group differences were found for post-90-EE increases in DOMS and six cytokines. AL was associated with lower levels of serum creatine kinase immediately- and 1-day post-exercise (p = 0.034 and 0.013, respectively). The 90-EE bout increased plasma levels immediately post-exercise for 13 oxylipins. Interaction effects revealed significantly higher levels for AL vs. CB for 12,13-DiHOME (p < 0.001) and lower levels for 9,10-DiHOME (p < 0.001). Urine levels increased in AL vs. CB for seven gut-derived phenolics including 5-(3',4'-dihydroxyphenyl)-γ-valerolactone that was inversely related to changes in plasma 9,10-DiHOME (r = -0.029, p = 0.021). Discussion: These data support some positive effects of almond intake in improving mood state, retaining strength, decreasing muscle damage, increasing the generation of gut-derived phenolic metabolites, and altering the plasma oxylipin DiHOME response to unaccustomed eccentric exercise in untrained adults. The elevated post-exercise plasma levels of 12,13-DiHOME with almond intake support positive metabolic outcomes for adults engaging in unaccustomed eccentric exercise bouts.

Multiomics Approach to Precision Sports Nutrition: Limits, Challenges, and Possibilities.

Most sports nutrition guidelines are based on group average responses and professional opinion. Precision nutrition for athletes aims to improve the individualization of nutrition practices to optimize long-term performance and health. This is a 2-step process that first involves the acquisition of individual-specific, science-based information using a variety of sources including lifestyle and medical histories, dietary assessment, physiological assessments from the performance lab and wearable sensors, and multiomics data from blood, urine, saliva, and stool samples. The second step consists of the delivery of science-based nutrition advice, behavior change support, and the monitoring of health and performance efficacy and benefits relative to cost. Individuals vary widely in the way they respond to exercise and nutritional interventions, and understanding why this metabolic heterogeneity exists is critical for further advances in precision nutrition. Another major challenge is the development of evidence-based individualized nutrition recommendations that are embraced and efficacious for athletes seeking the most effective enhancement of performance, metabolic recovery, and health. At this time precision sports nutrition is an emerging discipline that will require continued technological and scientific advances before this approach becomes accurate and practical for athletes and fitness enthusiasts at the small group or individual level. The costs and scientific challenges appear formidable, but what is already being achieved today in precision nutrition through multiomics and sensor technology seemed impossible just two decades ago.

Exercise Is Medicine for Immune Function: Implication for COVID-19.

ABSTRACT: This review supports that physical activity improves immunosurveillance and has the potential to counter COVID-19 infection and symptomatology at three prevention levels. At the primary prevention level, several lines of evidence support that physical activity is an immune system adjuvant in combating infectious diseases. Recent epidemiological studies indicate that regular physical activity is associated with a reduced risk for COVID-19, similar to what has been reported for other respiratory infections. Although specific COVID-19-related studies are needed, data from investigations with other types of infectious agents, such as influenza, support the potential role of physical activity in augmenting COVID-19 vaccine efficacy (secondary prevention level). There is a growing awareness that COVID-19 can cause sustained morbidity in some patients, and physical training and rehabilitation (tertiary prevention level) can be directed toward improvement in physical fitness, quality of life, and immune health.