Longitudinal Metabolomics Reveals Ornithine Cycle Dysregulation Correlates With Inflammation and Coagulation in COVID-19 Severe Patients

COVID-19 is a severe disease in humans, as highlighted by the current global pandemic. Several studies about the metabolome of COVID-19 patients have revealed metabolic disorders and some potential diagnostic markers during disease progression. However, the longitudinal changes of metabolomics in COVID-19 patients, especially their association with disease progression, are still unclear. Here, we systematically analyzed the dynamic changes of the serum metabolome of COVID-19 patients, demonstrating that most of the metabolites did not recover by 1–3 days before discharge. A prominent signature in COVID-19 patients comprised metabolites of amino acids, peptides, and analogs, involving nine essential amino acids, 10 dipeptides, and four N-acetylated amino acids. The levels of 12 metabolites in amino acid metabolism, especially three metabolites of the ornithine cycle, were significantly higher in severe patients than in mild ones, mainly on days 1–3 or 4–6 since onset. Integrating blood metabolomic, biochemical, and cytokine data, we uncovered a highly correlated network, including 6 cytokines, 13 biochemical parameters, and 49 metabolites. Significantly, five ornithine cycle-related metabolites (ornithine, N-acetylornithine, 3-amino-2-piperidone, aspartic acid, and asparagine) highly correlated with “cytokine storms” and coagulation index. We discovered that the ornithine cycle dysregulation significantly correlated with inflammation and coagulation in severe patients, which may be a potential mechanism of COVID-19 pathogenicity. Our study provided a valuable resource for detailed exploration of metabolic factors in COVID-19 patients, guiding metabolic recovery, understanding the pathogenic mechanisms, and creating drugs against SARS-CoV-2 infection.

Beetroot juice — a suitable post-marathon metabolic recovery supplement?

Background Red beetroot (Beta vulgaris L.) is a multifunctional functional food that reportedly exhibits potent anti-inflammatory, antioxidant, vasodilation, and cellular regulatory properties. This vegetable has gained a fair amount of scientific attention as a possible cost-effective supplement to enhance performance and expedite recovery after physical exercise. To date, no study has investigated the effects of incremental beetroot juice ingestion on the metabolic recovery of athletes after an endurance race. Considering this, as well as the beneficial glucose and insulin regulatory roles of beetroot, this study investigated the effects of beetroot juice supplementation on the metabolic recovery trend of athletes within 48 h after completing a marathon. Methods By employing an untargeted two-dimensional gas chromatography time-of-flight mass spectrometry approach, serum samples (collected pre-, post-, 24 h post-, and 48 h post-marathon) of 31 marathon athletes that ingested a series (n = 7; 250 ml) of either beetroot juice (n = 15 athletes) or isocaloric placebo (n = 16 athletes) supplements within 48 h post-marathon, were analysed and statistically compared. Results The metabolic profiles of the beetroot-ingesting cohort recovered to a pre-marathon-related state within 48 h post-marathon, mimicking the metabolic recovery trend observed in the placebo cohort. Since random inter-individual variation was observed immediately post-marathon, only metabolites with large practical significance (p-value ≤0.05 and d-value ≥0.5) within 24 h and 48 h post-marathon were considered representative of the effects of beetroot juice on metabolic recovery. These (n = 4) mainly included carbohydrates (arabitol and xylose) and odd-chain fatty acids (nonanoate and undecanoate). The majority of these were attributed to beetroot content and possible microbial fermentation thereof. Conclusion Apart from the global metabolic recovery trends of the two opposing cohorts, it appears that beetroot ingestion did not expedite metabolic recovery in athletes within 48 h post-marathon.

Acute melatonin administration improves exercise tolerance and the metabolic recovery after exhaustive effort

The present study investigated the effects of acute melatonin administration on the biomarkers of energy substrates, GLUT4, and FAT/CD36 of skeletal muscle and its performance in rats subjected to exhaustive swimming exercise at an intensity corresponding to the maximal aerobic capacity (tlim). The incremental test was performed to individually determine the exercise intensity prescription and 48 h after, the animals received melatonin (10 mg·kg−1) or vehicles 30 min prior to tlim. Afterwards, the animals were euthanized 1 or 3 h after the exhaustion for blood and muscles storage. The experiment 1 found that melatonin increased the content of glycogen and GLUT4 in skeletal muscles of the animals that were euthanized 1 (p < 0.05; 22.33% and 41.87%) and 3 h (p < 0.05; 37.62% and 57.87%) after the last procedures. In experiment 2, melatonin enhanced the tlim (p = 0.01; 49.42%), the glycogen content (p < 0.05; 40.03%), GLUT4 and FAT/CD36 in exercised skeletal muscles (F = 26.83 and F = 25.28, p < 0.01). In summary, melatonin increased energy substrate availability prior to exercise, improved the exercise tolerance, and accelerated the recovery of muscle energy substrates after the tlim, possibly through GLUT4 and FAT/CD36.

Metabolic recovery after weight loss surgery is reflected in serum microRNAs

IntroductionBariatric surgery offers the most effective treatment for obesity, ameliorating or even reverting associated metabolic disorders, such as type 2 diabetes. We sought to determine the effects of bariatric surgery on circulating microRNAs (miRNAs) that have been implicated in the metabolic cross talk between the liver and adipose tissue.Research design and methodsWe measured 30 miRNAs in 155 morbidly obese patients and 47 controls and defined associations between miRNAs and metabolic parameters. Patients were followed up for 12 months after bariatric surgery. Key findings were replicated in a separate cohort of bariatric surgery patients with up to 18 months of follow-up.ResultsHigher circulating levels of liver-related miRNAs, such as miR-122, miR-885-5 p or miR-192 were observed in morbidly obese patients. The levels of these miRNAs were positively correlated with body mass index, percentage fat mass, blood glucose levels and liver transaminases. Elevated levels of circulating liver-derived miRNAs were reversed to levels of non-obese controls within 3 months after bariatric surgery. In contrast, putative adipose tissue-derived miRNAs remained unchanged (miR-99b) or increased (miR-221, miR-222) after bariatric surgery, suggesting a minor contribution of white adipose tissue to circulating miRNA levels. Circulating levels of liver-derived miRNAs normalized along with the endocrine and metabolic recovery of bariatric surgery, independent of the fat percentage reduction.ConclusionsSince liver miRNAs play a crucial role in the regulation of hepatic biochemical processes, future studies are warranted to assess whether they may serve as determinants or mediators of metabolic risk in morbidly obese patients.

Metabolite Sequestration Enables Rapid Recovery from Fatty Acid Depletion in Escherichia coli

ABSTRACT Microbes adapt their metabolism to take advantage of nutrients in their environment. Such adaptations control specific metabolic pathways to match energetic demands with nutrient availability. Upon depletion of nutrients, rapid pathway recovery is key to release cellular resources required for survival under the new nutritional conditions. Yet, little is known about the regulatory strategies that microbes employ to accelerate pathway recovery in response to nutrient depletion. Using the fatty acid catabolic pathway in Escherichia coli, here, we show that fast recovery can be achieved by rapid release of a transcriptional regulator from a metabolite-sequestered complex. With a combination of mathematical modeling and experiments, we show that recovery dynamics depend critically on the rate of metabolite consumption and the exposure time to nutrients. We constructed strains with rewired transcriptional regulatory architectures that highlight the metabolic benefits of negative autoregulation over constitutive and positive autoregulation. Our results have wide-ranging implications for our understanding of metabolic adaptations, as well as for guiding the design of gene circuitry for synthetic biology and metabolic engineering. IMPORTANCE Rapid metabolic recovery during nutrient shift is critical to microbial survival, cell fitness, and competition among microbiota, yet little is known about the regulatory mechanisms of rapid metabolic recovery. This work demonstrates a previously unknown mechanism where rapid release of a transcriptional regulator from a metabolite-sequestered complex enables fast recovery to nutrient depletion. The work identified key regulatory architectures and parameters that control the speed of recovery, with wide-ranging implications for the understanding of metabolic adaptations as well as synthetic biology and metabolic engineering.

Metabolic recovery and compensatory shell growth of juvenile Pacific geoduck Panopea generosa following short-term exposure to acidified seawater

While acute stressors can be detrimental, environmental stress conditioning can improve performance. To test the hypothesis that physiological status is altered by stress conditioning, we subjected juvenile Pacific geoduck, Panopea generosa, to repeated exposures of elevated pCO2 in a commercial hatchery setting followed by a period in ambient common garden. Respiration rate and shell length were measured for juvenile geoduck periodically throughout short-term repeated reciprocal exposure periods in ambient (~550 μatm) or elevated (~2400 μatm) pCO2 treatments and in common, ambient conditions, 5 months after exposure. Short-term exposure periods comprised an initial 10-day exposure followed by 14 days in ambient before a secondary 6-day reciprocal exposure. The initial exposure to elevated pCO2 significantly reduced respiration rate by 25% relative to ambient conditions, but no effect on shell growth was detected. Following 14 days in common garden, ambient conditions, reciprocal exposure to elevated or ambient pCO2 did not alter juvenile respiration rates, indicating ability for metabolic recovery under subsequent conditions. Shell growth was negatively affected during the reciprocal treatment in both exposure histories; however, clams exposed to the initial elevated pCO2 showed compensatory growth with 5.8% greater shell length (on average between the two secondary exposures) after 5 months in ambient conditions. Additionally, clams exposed to the secondary elevated pCO2 showed 52.4% increase in respiration rate after 5 months in ambient conditions. Early exposure to low pH appears to trigger carryover effects suggesting bioenergetic re-allocation facilitates growth compensation. Life stage-specific exposures to stress can determine when it may be especially detrimental, or advantageous, to apply stress conditioning for commercial production of this long-lived burrowing clam.

Methyl-Metabolite Depletion Elicits Adaptive Responses to Support Heterochromatin Stability and Epigenetic Persistence

SummaryS-adenosylmethionine (SAM) is the methyl-donor substrate for DNA and histone methyltransferases that regulate cellular epigenetic states. This metabolism-epigenome link enables the sensitization of chromatin methylation to altered SAM abundance. However, a chromatin-wide understanding of the adaptive/responsive mechanisms that allow cells to actively protect epigenetic information during life-experienced fluctuations in SAM availability are unknown. We identified a robust response to SAM depletion that is highlighted by preferential cytoplasmic and nuclear de novo mono-methylation of H3 Lys 9 (H3K9) at the expense of global losses in histone di- and tri-methylation. Under SAM-depleted conditions, de novo H3K9 mono-methylation preserves heterochromatin stability and supports global epigenetic persistence upon metabolic recovery. This unique chromatin response was robust across the mouse lifespan and correlated with improved metabolic health, supporting a significant role for epigenetic adaptation to SAM depletion in vivo. Together, these studies provide the first evidence for active epigenetic adaptation and persistence to metabolic stress.

Metabolic Recovery and Compensatory Shell Growth of Juvenile Pacific Geoduck Panopea Generosa Following Short-Term Exposure to Acidified Seawater

While acute stressors can be detrimental, environmental stress conditioning can improve performance. To test the hypothesis that physiological status is altered by stress conditioning, we subjected juvenile Pacific geoduck, Panopea generosa, to repeated exposures of elevated pCO2 in a commercial hatchery setting followed by a period in ambient common garden. Respiration rate and shell length were measured for juvenile geoduck periodically throughout short-term repeated reciprocal exposure periods in ambient (~550 µatm) or elevated (~2400 µatm) pCO2 treatments and in common, ambient conditions, five months after exposure. Short-term exposure periods comprised an initial 10-day exposure followed by 14 days in ambient before a secondary 6-day reciprocal exposure. The initial exposure to elevated pCO2 significantly reduced respiration rate by 25% relative to ambient conditions, but no effect on shell growth was detected. Following 14 days in common garden, ambient conditions, reciprocal exposure to elevated or ambient pCO2 did not alter juvenile respiration rates, indicating ability for metabolic recovery under subsequent conditions. Shell growth was negatively affected during the reciprocal treatment in both exposure histories, however clams exposed to the initial elevated pCO2 showed compensatory growth with 5.8% greater shell length (on average between the two secondary exposures) after five months in ambient conditions. Additionally, clams exposed to the secondary elevated pCO2 showed 52.4% increase in respiration rate after five months in ambient conditions. Early exposure to low pH appears to trigger carry-over effects suggesting bioenergetic re-allocation facilitates growth compensation. Life stage-specific exposures to stress can determine when it may be especially detrimental, or advantageous, to apply stress conditioning for commercial production of this long-lived burrowing clam.Lay summaryCommercial shellfish hatcheries provide essential food security, but often production can be hampered by sensitivity of shellfish at early life stages. Repeated short-term exposures can increase tolerance and performance of the geoduck clam with implications for sustainable aquaculture.