Carbon Chemist

Tag: Metabolite

  • Pregnant women show significant immune system changes linked to gut microbiome

    Pregnant women show significant immune system changes linked to gut microbiome

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    In a recent study published in Clinical Microbiology, a group of researchers investigated how gut microbiota and metabolite changes relate to immune function during pregnancy by comparing the gut microbiota, fecal and plasma metabolites, and cytokines in pregnant and non-pregnant women.

    Study: Multi-omics analysis reveals the associations between altered gut microbiota, metabolites, and cytokines during pregnancy. Image Credit: Ground Picture/Shutterstock.comStudy: Multi-omics analysis reveals the associations between altered gut microbiota, metabolites, and cytokines during pregnancy. Image Credit: Ground Picture/Shutterstock.com

    Background 

    Pregnancy induces significant changes in hormonal levels, body structure, and immune function, essential for fetal development.

    Initially, the maternal immune system is pro-inflammatory, becoming anti-inflammatory, then shifting back to pro-inflammatory to initiate labor.

    The role of the gut microbiome in immune regulation during pregnancy is increasingly recognized, with studies showing its influence on pregnancy outcomes and conditions like preeclampsia through changes in the microbial composition and interactions with immune cells.

    However, the detailed mechanisms remain unclear. Metabolites, rather than direct microbial interactions, predominantly mediate the relationship between the microbiome and the immune system, highlighting areas for further research to understand pregnancy-related immune adjustments and develop new therapeutic strategies.

    About the study 

    In the study conducted at the First Affiliated Hospital of Jinan University between February 2019 and August 2020, 30 pregnant and 15 non-pregnant women were recruited to explore the interactions between gut microbiota, metabolites, and immune function.

    Eligible pregnant participants were between 18 and 34 years old, had naturally conceived singleton pregnancies, and had pre-pregnancy body mass index (BMI) of 18.5 to 21.9 kg/m2, excluding those with pregnancy complications or immune disorders.

    The control group consisted of healthy females matching the pregnant group in age and BMI, with neither group using probiotics or antibiotics in the six months before the study.

    Fecal and blood samples were collected from pregnant women in the late third trimester and non-pregnant women on the 14th day of their menstrual cycle.

    Fecal samples were obtained using sterile techniques and stored at -80°C, while blood samples were processed to separate the serum for storage under the same conditions.

    The study employed 16S ribosomal ribonucleic acid (rRNA) gene sequencing to analyze the gut microbiota, with deoxyribonucleic acid (DNA) extracted and sequenced to identify microbial species.

    A combination of random forest analysis and Weighted Gene Co-expression Network Analysis (WGCNA) was used to differentiate microbial profiles between groups.

    Untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) metabolomics analyzed the fecal and plasma samples to identify metabolic changes, employing quality control measures to ensure data reliability.

    The metabolomic data were processed and analyzed to determine significant differences and map them to biological pathways using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database.

    Plasma cytokines were measured using a multiplex bead assay to assess immune function differences between the groups.

    Finally, using statistical and visualization tools, multi-omics analysis integrated the data from microbial, metabolomic, and cytokine analyses to explore potential correlations and mediation effects. 

    Study results 

    The study found no significant differences between average age or pre-pregnancy BMI between the two groups. Immune profiling revealed that pregnant participants had lower levels of pro-inflammatory cytokines and higher levels of certain anti-inflammatory cytokines than the controls, indicating a shift towards immunosuppression during pregnancy.

    The study also investigated gut microbiota, finding distinct microbial compositions between pregnant and non-pregnant women.

    Pregnant women had a higher diversity of operational taxonomic units (OTUs) and differences in the abundance of specific bacterial phyla.

    Using random forest models and WGCNA methods, the researchers identified microbial modules that correlated negatively with pro-inflammatory cytokines, suggesting that certain gut bacteria groups have a consistent impact on reducing inflammation during pregnancy.

    Notably, bacteria like Bifidobacterium and Ruminococcus, known for their anti-inflammatory properties, were more abundant in pregnant women and were negatively correlated with pro-inflammatory cytokines.

    Metabolomic analysis of fecal and plasma samples using untargeted LC-MS revealed significant metabolic alterations during pregnancy. Differential metabolites, particularly lipids and bile acids, were identified, with many showing downregulation in pregnant women.

    These included arachidonic acid and various bile acids, known to be associated with inflammation. The analysis highlighted the significant role of bile acid metabolism during pregnancy.

    Correlation studies between metabolites and cytokines indicated that certain metabolites enriched in pregnant women were negatively correlated with pro-inflammatory cytokines, suggesting their involvement in modulating immune responses.

    The study further explored the associations between gut microbiota, metabolites, and cytokines, finding that metabolites might mediate the relationship between microbiota and the immune system.

    Directional mediation analysis identified specific linkages among microbes, metabolites, and cytokines, suggesting that certain gut microbes could influence cytokine levels by modulating metabolite concentrations.

    For example, Ruminococcus callidus and other bacteria could decrease pro-inflammatory cytokines by affecting specific metabolites like deoxycholic acid and arachidonic acid levels.

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  • Resveratrol can combat Alzheimer’s via inflammatory suppression, study shows

    Resveratrol can combat Alzheimer’s via inflammatory suppression, study shows

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    In a recent study published in the journal Antioxidants, researchers investigated the mechanisms by which Resveratrol, a natural phenolic compound, can prevent and attenuate Alzheimer’s Disease (AD). They used the BV2 microglial cell lines established from C57BL/g transgenic murine models to elucidate the mechanistic benefits of Resveratrol against glia activation by proinflammatory monomeric C-reactive protein (mCRP). Their results highlight that Resveratrol inhibits lipopolysaccharides (LPS) and mCRP-induced-cyclooxygenase-2, thereby preventing the release of proinflammatory cytokines. It further upregulates the expression of the antioxidant enzymes, namely Cat and Sod2. Together, these results provide the mechanistic underpinning for the benefits of Resveratrol in combatting and controlling AD.

    Study: Resveratrol Activates Antioxidant Protective Mechanisms in Cellular Models of Alzheimer’s Disease Inflammation. Image Credit: Aimee Lee Studios / ShutterstockStudy: Resveratrol Activates Antioxidant Protective Mechanisms in Cellular Models of Alzheimer’s Disease Inflammation. Image Credit: Aimee Lee Studios / Shutterstock

    What is Resveratrol?

    Resveratrol, commonly found in red grapes and their derivatives (e.g., red wine), is a natural phenolic compound belonging to the stilbene family. Extensive preclinical research into the metabolite has revealed its potent anti-inflammatory, anti-neurodegenerative, antioxidant, and anti-aging properties. It is a common compound synthesized by more than 70 known plant species as a stress-response mechanism.

    Recent Resveratrol studies in animal models have shown that trans-resveratrol is capable of crossing the blood-brain barrier, suggesting that it might perform neuroprotective functions. This is augmented by the fact that older men and women who drink moderately are consistently observed to have lower dementia risk compared to lifetime abstainers. Unfortunately, the human body does not produce Resveratrol, and therapeutic dosages (150-250 mg/d) can only be acquired through oral supplementation.

    Scientists have attempted to elucidate this compound’s impacts on neurodegenerative and non-neural medical conditions to arrive at its mechanistic underpinning. However, Resveratrol’s mechanisms of action in humans remain a mystery, given the inconclusive findings of said studies. The compound is both hormetic and hydrophobic, limiting its absorption and bioavailability. Researchers have circumvented this by developing novel nanocarrier-based delivery systems showing significant promise in cancer- and neurotherapy. Murine models have further suggested that Resveratrol could substantially reduce oxidative stress and improve neurodegenerative outcomes via tumor necrosis factor α (TNFα) downregulation. However, these claims remain to be tested.

    Understanding the mechanisms by which Resveratrol exercises its neurological benefits might allow for the development of new interventions aimed at preventing or managing Alzheimer’s Disease (AD). It would further inform future clinical trials of the safe dosage range, given that the chemical can be cytotoxic in high concentrations.

    About the study

    In the present study, researchers attempt to evaluate the antioxidant protection mechanism of Resveratrol using BV2 microglia, which have been activated by monomeric C-reactive protein (mCRP). mCRP activation and overexpression are vital traits of most inflammation-activated diseases, and its prevention may delay or even reverse conditions like AD that progress in part due to inflammatory stress.

    Schematic representation of the protective mechanisms of resveratrol against the proinflammatory agent mCRP and LPS.Schematic representation of the protective mechanisms of resveratrol against the proinflammatory agent mCRP and LPS.

    The BV2 cell line used herein was established from C57BL/6 transgenic mice microglia, an established model for studying brain inflammation. mCRP was generated from pure CRP protein via urea/ ethylenediaminetetraacetic acid (EDTA) chelation, followed by dialysis. Escherichia coli 026:B26 was used as a lipopolysaccharide (LPS) strain. Resveratrol treatments on these primary cell cultures varied between 10-50 µM. mCRP assays utilized mCRP at 50 µg/mL. To avoid astrocyte damage, primary glial cultures were not subjected to nutrient (serum) starvation.

    Nitric oxide generation by glial cultures was determined using the colorimetric Griess reaction. The Enzyme-Linked Immunosorbent Assay (ELISA) was used to detect and measure tumor necrosis factor-alpha (TNF-α) and interleukin one-beta (IL1 ß) expressed in ng/mL and pg/mL, respectively. Western blotting assays were used to detect and identify other protein products produced by BV2 cells. BV2 cell RNA was then extracted and subjected to Real-Time Quantitative Polymerase Chain Reaction (qPCR) to determine relative gene expression.

    Finally, the immunofluorescence assay was used to measure the impact of Resveratrol on BV2 cell expression. Statistical analyses comprised two-way analysis of variance (ANOVA) and the Shapiro–Wilk test.

    Study findings

    Resveratrol was observed to significantly inhibit and reduce TNF-α production induced by mCRP and LPS, elucidating and validating its anti-inflammatory properties. The compound was further observed to suppress the activation of the nitric oxide pathway, preventing the generation of reactive oxygen species (ROS).

    Activation of the NLR family pyrin domain containing 3 (NLRP3) gene was also observed to be inhibited by Resveratrol. NLRP3 is the gene responsible for producing the cryopyrin protein, a crucial microglia cell sensor inflammasome activated during oxidative stress. Nuclear factor-κB (NF-κB) and Nos2 were observed to be downregulated on the addition of Resveratrol. Finally, Resveratrol was found to induce the expression of antioxidant genes, including Sirt1 and Nfe2I2.

    In summary, Resveratrol’s anti-AD effect was shown to arise due to a combination of oxidation suppression and antioxidant expression.

    Conclusions

    In the present study, researchers investigated the mechanisms by which Resveratrol, a plant metabolite found in over 70 species, can promote positive neurodegenerative outcomes, especially in AD. They used a combination of in vitro cell cultures, ELISAs, western blotting, and qPCR and revealed that Resveratrol both suppresses the generation of ROS and enhances the expression of antioxidant-protecting genes.

    “Resveratrol protected against the polarization of BV2 microglia into an activated phenotype induced by two critical proinflammatory agents, LPS and mCRP. The characterization of mCRP proinflammatory and pro-oxidant mechanisms in BV2 microglia showed the activation of the inflammatory/oxidative cascades of nitric oxide, NLRP3 inflammasome and COX-2 in this novel in vitro model. Resveratrol protective mechanisms against mCRP required the modulation of SIRT1, Nrf2, and NF-ĸB pathways that reduced downstream inflammatory mediators and, most notably, induced antioxidant enzymes. Resveratrol protective mechanisms against activation to proinflammatory phenotype by mCRP was confirmed in primary mixed glial cultures.”

    These findings highlight the potential for Resveratrol in future AD preclinical testing. Resveratrol and similar plant-derived metabolites may allow for the development of future clinical interventions against currently incurable diseases such as AD. However, extensive clinical trials are required to assess the effectiveness of Resveratrol on other oxidation-inducing genes and to arrive at a dosage that is safe for human use.

    Journal reference:

    • Bartra, C., Yuan, Y., Vuraić, K., Slevin, M., Pastorello, Y., Suñol, C., & Sanfeliu, C. (2024). Resveratrol Activates Antioxidant Protective Mechanisms in Cellular Models of Alzheimer’s Disease Inflammation. Antioxidants, 13(2), 177, DOI – 10.3390/antiox13020177, https://www.mdpi.com/2076-3921/13/2/177

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  • Ramadan fasting linked to favorable metabolic changes and reduced chronic disease risk

    Ramadan fasting linked to favorable metabolic changes and reduced chronic disease risk

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    In a recent study published in The American Journal of Clinical Nutrition, researchers carried out a metabolomics investigation to elucidate the impacts of Ramadan fasting on health and metabolism. Their study group comprised 72 participants who provided blood shortly before and after Ramadan fasting, based on which researchers generated metabolic scores. Study findings, obtained by comparing participants’ metabolic scores against those maintained by the UK Biobank, reveal that Ramadan fasting significantly reduced the risks of lung, colorectal, and breast cancers.

    Study: Metabolomics of Ramadan fasting and associated risk of chronic diseases. Image Credit: Odua Images / ShutterstockStudy: Metabolomics of Ramadan fasting and associated risk of chronic diseases. Image Credit: Odua Images / Shutterstock

    Can depriving your body of food make you healthier?

    Fasting, the intentional abstention from consuming food and sometimes liquids, is practiced for clinical, religious, political, and fitness reasons, the latter of which is rapidly growing in popularity. Reports reveal that globally, many health-conscious individuals are gravitating toward ‘time-restricted fasting,’ an approach that restricts daily eating to a predetermined period each day (usually six to eight hours). Popularized by the term’ intermittent fasting,’ this trend promises general health improvements, weight loss, and fitness benefits.

    Unfortunately, apart from observational evidence for weight loss, comprehensive metabolic and cohort-based studies into the other benefits of time-restricted fasting remain lacking. Ramadan, the Muslim month of fasting, reflection, prayer, and community, shares every trait of time-restricted fasting except its intent (Ramadan is religious fasting). This provides a ‘natural experiment’ to quantify the positive or negative impacts of time-restricted fasting.

    Two previous works have investigated the impacts of Ramadan fasting on health. However, these studies were small-scale (n = 11, 25) and used dated analytical tools focused on overweight and obese individuals not representative of the fitness-oriented. This presents the need for an updated study using the latest metabolomics techniques and a larger, more generalized sample cohort, the results of which will inform the billions of Muslims and health-minded people worldwide.

    About the study

    In the present study, researchers recorded the metabolomics alterations following Ramadan fasting. Their study cohort was the London Ramadan Study (LORANS), an observational cohort comprising 140 Muslims who observe the Ramadan fast. Study data collection included demographic data, medical records, and two blood samples provided a few days before and a few days following initiation of the fast. Additionally, blood pressure and body composition were recorded during routine blood collection.

    Study inclusion criteria comprised age (above 18 years), intended duration of fast (20 days or more), and completed data records. Pregnant women were excluded from the study. Following exclusions due to unmet criteria requirements, 72 participants were included for data analyses, all providing written informed consent to participate in the study.

    Blood samples were processed to separate and isolate the plasma, which in turn was subjected to high-throughput Nuclear Magnetic Resonance (NMR) spectroscopy using the Nightingale platform. The Nightingale platform was chosen due to its ability to identify and quantify 169 lipids and metabolites. It was also selected because the United Kingdom’s (UK) Biobank dataset includes Nightingale platform readings. The UK Biobank is a country-wide large-cohort prospective study comprising 500,000 English citizens representative of the nation.

    Linear mixed-effects models were used to compare NMR readings from blood samples provided before and after fasting, allowing a one-to-one comparison of the metabolite changes arising as outcomes of the fasting process. Additionally, UK Biobank Nightingale platform metabolite readings were used to compute metabolic risk scores for common chronic diseases, including cancers and cardiometabolic disorders. These values were then applied to NMR readings from this study to measure the relative change in chronic disease risk as a consequence of Ramadan (and, by extension, intermittent) fasting.

    Study findings

    Demographic analyses revealed that the mean age of the 72-strong study cohort was 45.7 years, 48.6% (n = 35) of whom were male. Body assessments during blood collection visits showed that, on average, participants lost 1.7 kg and 1.1% of their body fat in the two to three weeks between measurements. Nightingale platform analyses show that of the 169 measured metabolites, 14 were observed to change significantly when comparing blood collections.

    These included one inflammation marker, one amino acid, two glycolysis-related metabolites, two ketone bodies, two triglycerides, and six lipoprotein subclasses. The most significant differences before/after Ramadan were observed for lactate (β = -0.31, P <0.001), acetate (β= -0.22, P <0.001), tyrosine (β= – 0.10, P=0.019) (all inverse) and acetone (β= 0.10, P=0.019) (direct).

    For establishing the metabolic risk scores, baseline characteristics of 117,981 UK Biobank participants were used to establish seven scores, including diabetes (using 46 metabolites), coronary heart disease (16), hypertension (25), renal failure (12), lung cancer (nine), colorectal cancer (two), and breast cancer (one). Applying these scores to present study participants reveals that the relative risk of lung, colorectal, and breast cancers decreased by 9.6%, 2.4%, and 1.1%, respectively. In contrast, the other measured outcomes observed no changes in metabolic risk scores.

    Conclusions

    The present study uses Ramadan fasting as a natural experiment to investigate the effects of time-restricted fasting on people’s health and chronic illness risk. It used cutting-edge, high-throughput NRM spectroscopy via the Nightingale platform to compute chronic disease metabolite risk scores.

    When applied to the 72 included study participants, the metabolic risk scores highlight the beneficial role of Ramadan fasting in reducing the risk of certain cancers such as lung (-9.6%), colorectal (-2.4%), and breast (-1.1%), while having no measurable effects on cardiovascular disease risk.

    Ramadan fasting is associated with short-term favorable changes in the metabolic profile concerning the risk of some chronic diseases. These findings should be further investigated in future, larger studies of longer follow-up with clinical outcomes.

    Journal reference:

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  • New study recommends 2000 IU daily vitamin D supplementation

    New study recommends 2000 IU daily vitamin D supplementation

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    In a recent narrative review published in Nutrients, researchers discuss the evidence arguing for the efficiency and safety of 2000 international units (IU), i.e., 50 micrograms (µg) of vitamin D supplementation per day to prevent and treat vitamin D deficiency in the general adult population.

    Study: Vitamin D Supplementation: A Review of the Evidence Arguing for a Daily Dose of 2000 International Units (50 µg) of Vitamin D for Adults in the General Population. Image Credit: FotoHelin/Shutterstock.comStudy: Vitamin D Supplementation: A Review of the Evidence Arguing for a Daily Dose of 2000 International Units (50 µg) of Vitamin D for Adults in the General Population. Image Credit: FotoHelin/Shutterstock.com

    Background

    Vitamin D deficiency has many adverse clinical consequences, including poor musculoskeletal health, manifesting as diseases like rickets and osteomalacia.

    Moreover, vitamin D may be crucial for preventing extra skeletal diseases like cancer and diabetes.

    Vitamin D is biologically inactive in the human body; thus, in laboratory detection of vitamin D deficiency, they measure serum concentrations of 25-hydroxyvitamin D (25(OH)D), a vitamin D metabolite utilized by the body and that reflects the overall supply from different sources, including ultraviolet-B (sunlight) and food sources, such as fish or mushrooms.

    Worldwide, the prevalence of low serum levels of 25(OH)D, i.e., below 25-30 nmol/L and 50 nmol/L, occurs in ~5-18% and 24-49% of people, respectively, underscoring the need for prompt action to reduce vitamin D deficiency burden globally.

    At a dosage of 50µg per day, the whole 25(OH)D distribution of a given population could rise to higher levels; however, there are safety concerns with such dosage as it may also increase the risk of vitamin D overdosing for those at the higher end of the distribution.

    Moreover, given the extra skeletal health effects of vitamin D, it is crucial to focus on the attainment of 25(OH)D levels needed to prevent them rather than safety concerns for targeting 75 nmol/L (30 ng/mL), which are optimal target serum 25(OH)D concentrations for skeletal health.

    So, researchers additionally investigated whether attaining serum 25(OH)D levels ≥50 nmol/L should be the target.

    Current Vitamin D supplementation guidelines

    Guidelines for vitamin D intake establish target serum 25(OH)D concentrations and recommend the required doses to achieve those levels, assuming adequate intake of other nutrients and seasons (winters or summers).

    Accordingly, current guidelines recommend a daily vitamin D intake of 400-800 IU; however, individuals from different ethnicities or regions may require even higher intakes of 2008-2672 IUs for attaining 25(OH)D serum levels of ≥50 nmol/L.

    What should be the target serum 25(OH)D levels: 75 nmol/L (30 ng/mL) or 2000 IU (50 µg)?

    Many observational studies have suggested that while ≥50 nmol/L serum 25(OH)D levels can prevent rickets and osteomalacia, concentrations ≥75 nmol/L are needed for improved health outcomes in diabetes and cancer.

    The optimal concentration needed may also vary depending on the study population and outcome of interest.

    Further, the authors noted that randomized controlled trials (RCTs) testing 25(OH)D needs may be biased towards healthy people who may not accurately represent the general population, especially those with obesity.

    In fact, optimal serum 25(OH)D concentrations for most chronic diseases are slightly above 75 nmol/L (30 ng/mL).

    Thus, obese individuals, individuals with higher body mass index (BMI), and patients with malabsorption syndromes may require higher doses of vitamin D to increase their serum 25(OH)D levels. 

    Some may not meet the threshold even after supplementing with daily 2000 IUs of vitamin D, like patients with inflammatory bowel disease during episodes of high disease activity.

    Even medications, like antiepileptic drugs, can affect lower serum 25(OH)D concentrations by modulating its metabolism.

    When serum 25(OH)D concentrations exceed 150 ng/mL, vitamin D toxicity may lead to hypercalcemia; thus, clinicians advise caution for those on vitamin D supplements.

    Recent RCTs like the Vitamin D and OmegA-3 Trial (VITAL) gathered safety data on using 2000 IU of vitamin D/day in general adult populations who showed no signs of vitamin D toxicity for 5.3 years, indicating the safety of this daily dosage.

    Further, a meta-analysis of 15 vitamin D RCTs found no increase in kidney stones when supplementing with ≥70 µg of vitamin D for at least one year.

    Another meta-analysis found that daily vitamin D supplementation of 3200-4000 IUs for six months increased the risk of hypercalcemia, hospitalizations, and falls; however, this did not occur in chronic kidney disease patients.

    Conclusions

    Adherence to conservative dosing regimens not exceeding 800 IU (20 µg) of vitamin D per day may not sufficiently treat vitamin D deficiency, considering the heterogeneity in inter-individual dose-response and accounting for the multiple clinical factors involved, such as obesity, malabsorption syndromes, and medications that impair vitamin D metabolism.

    This review revealed that daily vitamin D supplementation was more effective than intermittent bolus dosing in adults. However, precaution is needed for older and diseased individuals, who are more prone to adverse effects of vitamin D overdosing. 

    In real-world settings, clinicians should consider tailoring the vitamin D dosage according to the patient’s needs and characteristics.

    Instead of following the ‘one-size fits all’ approach, they may adopt a personalized treatment approach and prescribe a dosing range from 800-2000 IUs (20-50 µg). 

    It is a narrative review lacking a pre-registered systematic review. Yet, based on the evidence outlined in this review, the authors argue in favor of a daily vitamin D supplement dose of 2000 IU (50 µg) to raise and maintain serum 25(OH)D concentrations >50 nmol/L (20 ng/mL) and >75 nmol/L (30 ng/mL) in >99% and >90% of the general adult population, respectively.

    Furthermore, they found no significant safety concerns in supplementing such a dose for several years, even in individuals with a sufficient vitamin D status at baseline. 

    This could be the perfect remedy for addressing the vitamin D pandemic in the general adult population.

    Journal reference:

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