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Lack of association between endocrine disrupting chemicals and male fertility: A systematic review and meta-analysis.
Martínez, MÁ, Marquès, M, Salas-Huetos, A, Babio, N, Domingo, JL, Salas-Salvadó, J
Environmental research. 2023;217:114942
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Exposure to natural or synthetic chemicals is directly related to environmental conditions, dietary and other lifestyle factors. Some of these chemicals are named endocrine disrupting chemicals (EDCs) because of their capability to interfere with the endocrine system. The aim of this study was to summarise and explore the association between exposure to EDCs and human male fertility indicators. This study is a systematic review and meta-analysis of seven studies; 4 assessed bisphenol A (BPA) in urine and sperm quality parameters, while 3 articles evaluated PCB153 [polychlorinated biphenyls] in serum and sperm quality parameters. Results show that there weren’t any positive or inverse associations between BPA or PCB153 and the sperm parameters analysed. Authors conclude that the systematic review showed a high disparity between studies, making difficult a consensus on the possible detrimental effect of the 12 groups of EDCs on male fertility. Thus, no conclusive statements can be drawn. Further studies are needed in order to provide more robust data.
Abstract
The incidence of infertility currently affects about 15% of the world's population. Male factors are estimated to be responsible for up to 40-50% of these cases. While the cause of these reproductive disorders is still unclear, the exposure to a family of ubiquitous compounds in our daily life, named endocrine disrupting chemicals (EDCs) could be involved. This paper was aimed at performing a systematic review and meta-analysis of population studies exploring whether human male exposure to EDCs affects male fertility. Clinical and observational studies assessing the exposure to EDCs along with sperm quality, the most common reproductive disorders, sperm DNA damage, sperm oxidative stress, fertilization rate, implantation rate, clinical pregnancy rate, live birth rate, and miscarriage rate were included. The quality assessment tool from the NHLBI-NIH was used to assure that studies met standardized quality criteria. Sensitivity analysis and heterogeneity among studies was assessed. Overall, the 32 selected articles, including 7825 individuals in the systematic review, explored 12 families of EDCs. The results revealed a high heterogeneity among studies in relation to the association between exposure to EDCs and the endpoints analyzed. Meta-analyses were performed with data from 7 articles including 479 individuals, 4 articles assessing the association between BPA in urine and sperm quality, and 3 articles evaluating PCB153 in serum and sperm quality. In the meta-analysis, we identified an unpredicted significant positive association between PCB153 exposure and sperm concentration. However, it would not be clinically relevant. No positive or inverse associations were found neither for BPA, nor for PCB153 and the rest of sperm parameters analyzed. The high disparity between studies made difficult to draw conclusions on the potential harmful effects of EDCs on male fertility. Consequently, to delineate the potential relationship that EDCs can have on male fertility, an important condition stressing the health system, further investigations are required.
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The effectiveness of interventions during the first 1,000 days to improve energy balance-related behaviors or prevent overweight/obesity in children from socio-economically disadvantaged families of high-income countries: a systematic review.
Lioret, S, Harrar, F, Boccia, D, Hesketh, KD, Kuswara, K, Van Baaren, C, Maritano, S, Charles, MA, Heude, B, Laws, R
Obesity reviews : an official journal of the International Association for the Study of Obesity. 2023;24(1):e13524
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The first 1,000 days is an opportune time to support parents, as primary caregivers and role model, to promote a healthy lifestyle and prevent obesity for their children. The aim of this study was to update the current evidence on the effectiveness of family-based interventions implemented during pregnancy and up to 2 years of age to improve energy balance-related behaviours and growth, or prevent overweight (OW)/ obesity (OB), in children growing up in families experiencing socio-economic disadvantage. This study is a systematic review of thirty-three studies which corresponded to 24 distinct interventions. Of the 24 interventions, nearly all were (cluster) randomised controlled trials; three had a quasi-experimental design. Results show that there is some effectiveness on behavioural and anthropometric outcomes in young children when programmes target and are tailored to families experiencing socioeconomic disadvantage. Authors conclude that a holistic, multilevel and proportionate interventions are likely to more effective and sustainably address the issue of social inequalities and inequities. Additionally, more thorough process evaluation of such complex interventions using mixed methods is needed to better understand why interventions worked or not, by which mechanisms of action (if any), for whom and in which context.
Abstract
This narrative systematic review examined effectiveness of interventions during pregnancy and up to 2 years of age in improving energy balance-related behaviors or prevent overweight/obesity in children from families experiencing socio-economic disadvantage. We identified 24 interventions, from 33 articles, since 1990. Overall, despite their heterogeneity and variability in internal and external validity, there was some evidence of beneficial impact of interventions on obesity risk (4/15), and associated behaviors, e.g.: breastfeeding (9/18), responsive feeding (11/16), diet (7/8), sedentary (1/3) and movement (4/7) behaviors, and sleep (1/2). The most effective interventions aimed at promoting breastfeeding commenced antenatally; this was similar for the prevention of obesity, provided the intervention continued for at least 2 years postnatally and was multi-behavioral. Effective interventions were more likely to target first-time mothers and involve professional delivery agents, multidisciplinary teams and peer groups. Among ethnic/racial minorities, interventions delivered by lay agents had some impact on dietary behavior but not weight outcomes. Co-creation with stakeholders, including parents, and adherence to theoretical frameworks were additional ingredients for more pragmatic, inclusive, non-judgmental, and effective programs. The growing body of evidence on obesity prevention interventions targeting families experiencing socio-economic disadvantage is promising for reducing early inequalities in obesity risk.
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Acute beetroot juice reduces blood pressure in young Black and White males but not females.
Grosicki, GJ, Flatt, AA, Cross, BL, Vondrasek, JD, Blumenburg, WT, Lincoln, ZR, Chall, A, Bryan, A, Patel, RP, Ricart, K, et al
Redox biology. 2023;63:102718
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Cardiovascular (CV) disease is the leading cause of death in the United States. Out of all ethnic groups, CV disease is particularly common in black Americans. High blood pressure (BP) is one of the main contributors to CV disease, and black Americans exhibit a disproportionally higher incident rate of high BP when compared to other ethnic groups. Partly this is due to genetic and physiological differences, yet is also influenced by social, socioeconomic, and environmental factors. One physiological difference that may contribute to higher BP in black adults appears to be a reduced availability of nitric oxide (NO). NO is a gas that is abundant in the human body. It regulates vascular tone and elasticity of the arteries, and therefore helps to manage blood pressure. Nitrates that occur in foods can be converted to NO and thus contribute to NO levels in the body. Beetroot juice (BRJ) is rich in nitrates. This study examined whether BRJ supplementation can reduce resting BP and cardiovascular reactivity in adults. The randomized, placebo-controlled, crossover-design study was completed by 18 black and 20 white young adults, male and female, with an average age of 21. The study monitored heart rate, BP and arterial stiffness in a variety of settings. The study also assessed socioeconomic status, perceived discrimination, sleep and dietary intake. The main findings from this investigation were that despite young black adults having higher resting BP, acute BRJ supplementation reduced the pressure to a similar extent in young black and white adults, but primarily in males. This reduction correlated with increased levels of circulating nitrites. However, acute BRJ supplementation did not influence resting arterial stiffness. The result also highlighted previously seen racial differences relating to social determinants of health and lifestyle, which may contribute to the elevated BP values seen in black participants. The study demonstrated that dietary nitrate from beetroot juice has the potential to be a cost-effective blood pressure-lowering strategy for young black and white males. Yet the findings also highlighted the complex interplay of social, lifestyle, and underlying physiological factors that influence racial differences when it comes to CV health
Abstract
A complex interplay of social, lifestyle, and physiological factors contribute to Black Americans having the highest blood pressure (BP) in America. One potential contributor to Black adult's higher BP may be reduced nitric oxide (NO) bioavailability. Therefore, we sought to determine whether augmenting NO bioavailability with acute beetroot juice (BRJ) supplementation would reduce resting BP and cardiovascular reactivity in Black and White adults, but to a greater extent in Black adults. A total of 18 Black and 20 White (∼equal split by biological sex) young adults completed this randomized, placebo-controlled (nitrate (NO3-)-depleted BRJ), crossover design study. We measured heart rate, brachial and central BP, and arterial stiffness (via pulse wave velocity) at rest, during handgrip exercise, and during post-exercise circulatory occlusion. Compared with White adults, Black adults exhibited higher pre-supplementation resting brachial and central BP (Ps ≤0.035; e.g., brachial systolic BP: 116(11) vs. 121(7) mmHg, P = 0.023). Compared with placebo, BRJ (∼12.8 mmol NO3-) reduced resting brachial systolic BP similarly in Black (Δ-4±10 mmHg) and White (Δ-4±7 mmHg) adults (P = 0.029). However, BRJ supplementation reduced BP in males (Ps ≤ 0.020) but not females (Ps ≥ 0.299). Irrespective of race or sex, increases in plasma NO3- were associated with reduced brachial systolic BP (ρ = -0.237, P = 0.042). No other treatment effects were observed for BP or arterial stiffness at rest or during physical stress (i.e., reactivity); Ps ≥ 0.075. Despite young Black adults having higher resting BP, acute BRJ supplementation reduced systolic BP in young Black and White adults by a similar magnitude, an effect that was driven by males.
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Early life gut microbiota profiles linked to synbiotic formula effects: a randomized clinical trial in European infants.
Lagkouvardos, I, Intze, E, Schaubeck, M, Rooney, JP, Hecht, C, Piloquet, H, Clavel, T
The American journal of clinical nutrition. 2023;117(2):326-339
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Microbial colonisation of the intestine after birth is a central event that influences infant health with life-long consequences. Although improvement of hygienic conditions reduces infant mortality due to infections, environments with low microbial biomass counteract natural colonisation by commensal microbes. The aim of this study was to assess the effects of a synbiotic intervention formula (IF) on faecal microbiota. This study was a multicentre, randomised, controlled, double-blind intervention trial which enrolled 540 infants. Infants whose parents had chosen not to breastfeed or were not able to breastfeed prior to study inclusion were allocated randomly to 1 of 2 formula groups (n = 230 control formula, n = 230 IF). The infants in the breastfed reference group (n = 80) were mainly fed human milk. Results showed that synbiotic intervention influenced the gut microbiota and milieu parameters during early life to resemble some major characteristics found in breastfed infants (higher relative abundances of bifidobacteria, lower richness, lower faecal pH and butyrate concentrations), and effects depended on the ecosystem profile of the infants. Authors conclude that specific randomised, controlled studies that focus on infants born by Caesarean section and how early nutrition can support the beneficial development of their microbiota are needed.
Expert Review
Conflicts of interest:
None
Take Home Message:
- Infant gut colonisation differs in vaginal versus cesarean section deliveries and between breastfed and infant formula practices.
- Both enriched strain-specific probiotic and standard infant formula were shown to have a marked effect on microbiota colonisation in infants at age 4 months.
- By the age of 2 years, however, there is no significant difference between breastfed and formula fed infants.
Evidence Category:
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A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Introduction
This randomised controlled intervention study compared gut health parameters with the use of a synbiotic pre- and probiotic strain enriched infant formula with human milk and standard formula at three intervals over a period of 2 years.
Methods
This was a double-blinded controlled study of 540 infants from France and Belgium. Participants were randomly allocated to 2 formula groups (n = 230 Control Formula (CF), n = 230 Intervention Formula (IF)) and the breastfed reference group (n = 80) as well as delivery mode (Cesarean and vaginal delivery). The synbiotic IF was a standard infant formula enriched with prebiotic GOS (0.02 g/g) and the probiotic strain L. fermentum CECT5716 (at least 1.0 × 106 cfu/g).
Stool analysis was conducted at three time intervals, 4, 12, and 24 months (infant age). Biomarkers included short chain fatty acids, pH, secretory IgA, calprotectin, and various bacterial phyla via microbiota analysis.
Results
- At 4 months, the IF group tested higher for Bifidobacterium spp., and Lactobacillaceae and lower occurrence of Blautia spp., as well as Ruminoccocus gnavus and relatives compared to CF. They also had lower fecal pH and butyrate levels
- Both the formula cohorts had lower SigA and more basic pH values than the human milk cohort, as well as higher prevalence of anaerobes belonging to the bacterial genera Akkermansia, Collinsella, and Faecalibacterium.
- By age 24 months, the IF cohort exhibited increased levels of Akkermansia, Escherichia-Shigella, and R.gnavus. However there were no significant differences between the formula fed and human milk cohort at this time interval.
- The differences observed at 4 months disappeared over time, except for a significantly higher relative abundance of bifidobacteria and Faecalibacterium spp. in IF infants at 12 months compared with CF infants.
Conclusion:
Although prominent differences between the cohorts were observed at 4 months, it appears that by the age of 2 years, there is little observable difference. This is most likely due to gut ecosystem maturation. The paper draws attention to the fact that changes to microbiota following treatment were more pronounced in infants who tested lower in occurrences of Bacteroides spp at age 4 months. Of note is the prevalence of cesarean birth deliveries in this cohort thereby indicating potential improved alternative feeding options when breastfeeding is not possible for these infants.
Clinical practice applications:
- Probiotic L.fermentum and prebiotic galacto-oligosaccharide enriched infant formula appears to the improve infant microbiome, when compared to that of breastfed infants.
- The most receptive infants were those born via cesarean section.
Limitations to consider:
- The sample groups were from France and Belgium, with no indication as to culture, socio-economic, or sex distribution.
- The two infant formula groups were n=230 each with only 80 infants in the breastfed reference group.
- There was no indication of maternal diet practices pre-, during, and post- pregnancy.
- Stool samples were not collected from the infants at baseline visit prior to formula intervention.
Considerations for future research:
- Future studies need to include more diverse cultural and socio-economic cohorts to ascertain the potential influence of parental diet in baseline infant microbiome.
- It is imperative to establish what role solid food choices, generally introduced at 6 months, might have on gut ecosystem maturation.
- It would be useful to have a larger cesarean section birth cohort to compare to vaginal deliveries for more definitive results.
Abstract
BACKGROUND Microbial colonization of the gastrointestinal tract after birth is an essential event that influences infant health with life-long consequences. Therefore, it is important to investigate strategies to positively modulate colonization in early life. OBJECTIVES This randomized, controlled intervention study included 540 infants to investigate the effects of a synbiotic intervention formula (IF) containing Limosilactobacillus fermentum CECT5716 and galacto-oligosaccharides on the fecal microbiome. METHODS The fecal microbiota from infants was analyzed by 16S rRNA amplicon sequencing at 4, 12, and 24 months of age. Metabolites (e.g., short-chain fatty acids) and other milieu parameters (e.g., pH, humidity, and IgA) were also measured in stool samples. RESULTS Microbiota profiles changed with age, with major differences in diversity and composition. Significant effects of the synbiotic IF compared with control formula (CF) were visible at month 4, including higher occurrence of Bifidobacterium spp. and Lactobacillaceae and lower occurrence of Blautia spp., as well as Ruminoccocus gnavus and relatives. This was accompanied by lower fecal pH and concentrations of butyrate. After de novo clustering at 4 months of age, overall phylogenetic profiles of the infants receiving IF were closer to reference profiles of those fed with human milk than infants fed CF. The changes owing to IF were associated with fecal microbiota states characterized by lower occurrence of Bacteroides compared with higher levels of Firmicutes (valid name Bacillota), Proteobacteria (valid name Pseudomonadota), and Bifidobacterium at 4 months of age. These microbiota states were linked to higher prevalence of infants born by Cesarean section. CONCLUSIONS The synbiotic intervention influenced fecal microbiota and milieu parameters at an early age depending on the overall microbiota profiles of the infants, sharing a few similarities with breastfed infants. This trial was registered at clinicaltrials.gov as NCT02221687.
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The Influence of Vitamin E and Omega-3 Fatty Acids on Reproductive Health Indices Among Male Workers Exposed to Electromagnetic Fields.
Mohammadi, H, Golbabaei, F, Dehghan, SF, Imani, H, Ramezani Tehrani, F, Khodakarim Ardakani, S
American journal of men's health. 2022;16(1):15579883221074821
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Studies have suggested that low-frequency electromagnetic fields (EMF) may have a detrimental effect on male fertility. Lower hormone levels and higher free radicals in the body damaging sperm cells have been indicated to play a role in this relationship. Supporting the development of sperm cells in individuals who have been subjected to EMF may be an effective therapy. Sperm cells contain large amounts of polyunsaturated fatty acids such as omega-3 and supplementation may be of benefit. Although high amounts of omega-3 can have side effects, which can be limited with the dual supplementation of vitamin E. This randomised control trial aimed to determine the effect of omega-3 and vitamin E supplementation on reproductive indices of individuals who work with EMF. The results showed that EMF exposure affected sperm count, morphology, and motility and that the supplementation of omega-3 and vitamin E in conjunction could limit effects on morphology and motility. It was concluded that simultaneous vitamin E and omega-3 consumption could be of benefit for fertility in men exposed to EMF, however further studies are required to confirm this finding due to study limitations and size. This study could be used by healthcare professionals to understand that EMF is of detriment to fertility in men but there may be ways to limit the effects involving the use of omega-3 and vitamin E supplementation.
Expert Review
Conflicts of interest:
None
Take Home Message:
- Vitamin E and Omega 3 fatty acids have been reported to influence sperm morphology and sperm motility.
- This study reported that the intake of 100 mg of vitamin E accompanied by Omega 3 fatty acids (180 mg eicosatetraenoic acid [EPA] and 120 mg docosahexaenoic acid [DHA]) had a significant improvement in sperm morphology and motility after 3 months.
- In addition, this study also reported that electric magnetic fields may have a negative effect on sperm morphology and motility.
Evidence Category:
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A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Introduction
A block-randomized, double-blind, placebo-controlled study was conducted to investigate the effects of using vitamin E and Omega 3 fatty acid supplementation on reproductive indices among workers in an automobile parts manufacturing facility. The effect of exposure to electromagnetic fields on certain sex hormones and sperm parameters was also assessed.
Methodology
92 married males between the ages of 20-50 were deployed into 4 groups. The first group was given vitamin E (100 mg) accompanied by a placebo capsule. The second group was given Omega 3 fatty acids (180 mg eicosatetraenoic acid [EPA] and 120 mg docosahexaenoic acid [DHA]) accompanied by a placebo capsule. The third group was given vitamin E along with Omega 3 fatty acids. Finally, the fourth group acted as a placebo group and was given 2 placebo capsules.
The semen parameters of the participants were analysed before and after three months of consuming the supplements. Sex hormones within the blood serum were also analysed after the 3-month supplement period. At the endpoint, 80/92 subjects completed the study.
Results
Primary clinical outcomes were:
- Certain demographic parameters had significant effects on sluggish and full sperm motility: age (B = −1.344, p = .034); employment duration (B = −1.863, p = .022); and smoking (B = −94.24, p = .003).
- The difference in the level of testosterone before and after the intervention was not statistically significant for any age group.
- The difference in follicle-stimulating hormone (FSH) and Luteinizing Hormone (LH) before and after the intervention were not statistically significant for any of the supplement groups.
- There was a statistically significant effect on sperm count and sperm with full motility before and after the intervention in the vitamin E + Omega 3 group, p =.016.
- The effect of supplement use on sperm morphology was significant in the vitamin E + Omega 3 group (B = -4.961; p = .001).
- The effect of supplement use on full and sluggish sperm motility was also significant in the vitamin E + Omega 3 group (B = 72.211, p = .021).
Secondary clinical outcomes were:
- Electric fields had the largest effect on the percentage of immotile sperm amongst the exposure variables (B = 9.541; p = .053).
Clinical practice applications:
- Prior studies have reported on the antioxidant effects of vitamin E and the effect of Omega 3 fatty acids on the testicles and the hypothalamic-pituitary-gonadal axis.
- This study concluded that participants increased their normal sperm morphology by 16% and their sperm motility by 12% over a 3-month period by supplementing with vitamin E and Omega 3 fatty acids.
- Based on these findings, a practitioner could therefore consider recommending 100 mg of vitamin E accompanied by Omega 3 fatty acids (180 mg eicosatetraenoic acid [EPA] and 120 mg docosahexaenoic acid [DHA]) for at least 3 months to help support the reproductive health of their male patients struggling with sperm morphology and/or sperm motility.
Considerations for future research:
- In this study vitamin E and Omega 3 did not show significant effects on certain sex hormones (testorterone, FSH and LH) therefore, there is a need to investigate if a higher dosage or longer consumption of the supplements could make a difference to these outcomes.
- There are mixed findings on the potential effects of electric magnetic fields on male reproductive indices and therefore there is a need for further clinical studies to be done using the same type of frequency, intensity, and exposure protocols to draw further conclusions.
Abstract
The present study aims to investigate the effects of using the supplementation of vitamin E and Omega 3 fatty acids on reproductive indices among workers in an automobile parts manufacturing plant. The effect of exposure to electromagnetic fields on certain sex hormones and sperm parameters will also be assessed. The participants were deployed into four groups as per the double-blind block randomization method. Semen parameters and sex hormones of the participants were analyzed before and after 3-month consumption of supplements. The level of workers' exposure to low-frequency magnetic and electrical fields was measured through the recommendation of National Institute for Occupational Safety and Health. Univariate analysis of variance indicated that exposure to electric fields had a statistically significant effect on sperm count, morphology, and motility. The simultaneous consumption of vitamin E + Omega 3 had a statistically significant effect on sperm morphology and motility.
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Dietary macronutrients and the gut microbiome: a precision nutrition approach to improve cardiometabolic health.
Jardon, KM, Canfora, EE, Goossens, GH, Blaak, EE
Gut. 2022;71(6):1214-1226
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The global rise in the prevalence of obesity is strongly associated with an increase in the incidence and prevalence of cardiometabolic diseases, including insulin resistance (IR) and type 2 diabetes mellitus. In recent years, advancements have been made in understanding the involvement of the gut microbiome in obesity and related cardiometabolic complications as regulator of host energy and substrate metabolism. This study is a review that discusses the latest research describing interactions between dietary composition, the gut microbiome and host metabolism. Results show that current evidence for developing optimal dietary interventions targeting bodyweight control and IR via the gut microbiota is still in its infancy and does not capture the complexity of the integration of a whole-diet approach, the microbial and the host’s metabolic phenotype. Furthermore, implementation of targeted, precision nutrition intervention strategies or dietary guidelines for individuals or subgroups in public health requires further insight in the mechanisms involved in (non-)response to dietary intervention. Authors conclude that future studies are needed and these should focus on assessing detailed individual phenotyping and gaining insight into the balance between carbohydrate and protein fermentation by the gut microbiota as well as the site of fermentation in the colon.
Abstract
Accumulating evidence indicates that the gut microbiome is an important regulator of body weight, glucose and lipid metabolism, and inflammatory processes, and may thereby play a key role in the aetiology of obesity, insulin resistance and type 2 diabetes. Interindividual responsiveness to specific dietary interventions may be partially determined by differences in baseline gut microbiota composition and functionality between individuals with distinct metabolic phenotypes. However, the relationship between an individual's diet, gut microbiome and host metabolic phenotype is multidirectional and complex, yielding a challenge for practical implementation of targeted dietary guidelines. In this review, we discuss the latest research describing interactions between dietary composition, the gut microbiome and host metabolism. Furthermore, we describe how this knowledge can be integrated to develop precision-based nutritional strategies to improve bodyweight control and metabolic health in humans. Specifically, we will address that (1) insight in the role of the baseline gut microbial and metabolic phenotype in dietary intervention response may provide leads for precision-based nutritional strategies; that (2) the balance between carbohydrate and protein fermentation by the gut microbiota, as well as the site of fermentation in the colon, seems important determinants of host metabolism; and that (3) 'big data', including multiple omics and advanced modelling, are of undeniable importance in predicting (non-)response to dietary interventions. Clearly, detailed metabolic and microbial phenotyping in humans is necessary to better understand the link between diet, the gut microbiome and host metabolism, which is required to develop targeted dietary strategies and guidelines for different subgroups of the population.
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Association of Attention-Deficit/Hyperactivity Disorder Diagnosis With Adolescent Quality of Life.
Kazda, L, McGeechan, K, Bell, K, Thomas, R, Barratt, A
JAMA network open. 2022;5(10):e2236364
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Attention-deficit/hyperactivity disorder (ADHD) is “a persistent pattern of inattention and/or hyperactivity-impulsivity that interferes with functioning…and negatively impacts…social and academic activities”. This negative effect can extend beyond activities directly impacted by hyperactive or inattentive (H/I) behaviours, thus affecting overall quality of life (QOL). The aim of this study was to investigate whether an ADHD diagnosis in childhood or early adolescence is associated with improved QOL in adolescents compared with well-matched individuals without diagnosis. This study is a cohort study which followed an emulated target trial design using prospective, observational data from the Longitudinal Study of Australian Children. Results show that children diagnosed with ADHD reported similar or poorer QOL at age 14 to 15 years compared with children who had grown up experiencing the same levels of H/I behaviours but had not been given an ADHD diagnosis. Furthermore, an ADHD diagnosis did have some negative associations, including an increase in risk of self-harm. Authors conclude that their findings raise important questions about the long-term effectiveness and safety of diagnosing children and adolescents with ADHD, especially for those with low-risk or borderline H/I behaviours.
Abstract
IMPORTANCE Appropriate diagnosis of attention-deficit/hyperactivity disorder (ADHD) can improve some short-term outcomes in children and adolescents, but little is known about the association of a diagnosis with their quality of life (QOL). OBJECTIVE To compare QOL in adolescents with and without an ADHD diagnosis. DESIGN, SETTING, AND PARTICIPANTS This cohort study followed an emulated target trial design using prospective, observational data from the Longitudinal Study of Australian Children, a representative, population-based prospective cohort study with biennial data collection from 2006 to 2018 with 8 years of follow-up (ages 6-7 to 14-15 years). Propensity score matching was used to ensure children with and without ADHD diagnosis were well matched on a wide range of variables, including hyperactive/inattentive (H/I) behaviors. Eligible children were born in 1999 to 2000 or 2003 to 2004 and did not have a previous ADHD diagnosis. All incident ADHD cases were matched with controls. Data were analyzed from July 2021 to January 2022. EXPOSURES Incident parent-reported ADHD diagnosis at age 6 to 7, 8 to 9, 10 to 11, 12 to 13, or 14 to 15. MAIN OUTCOMES AND MEASURES Quality of life at age 14 to 15 was measured with Child Health Utility 9D (CHU9D) and 8 other prespecified, self-reported measures mapped to the World Health Organization's QOL domains. Pooled regression models were fitted for each outcome, with 95% CIs and P values calculated using bootstrapping to account for matching and repeat observations. RESULTS Of 8643 eligible children, a total of 393 adolescents had an ADHD diagnosis (284 [72.2%] boys; mean [SD] age, 10.03 [0.30] years; mean [SD] H/I Strengths and Difficulties Questionnaire score, 5.05 [2.29]) and were age-, sex-, and H/I score-matched with 393 adolescents without ADHD diagnosis at time zero. Compared with adolescents without diagnosis, those with an ADHD diagnosis reported similar QOL on CHU9D (mean difference, -0.03; 95% CI, -0.07 to 0.01; P = .10), general health (mean difference, 0.11; 95% CI, -0.04 to 0.27; P = .15), happiness (mean difference, -0.18; 95% CI, -0.37 to 0.00; P = .05), and peer trust (mean difference, 0.65; 95% CI, 0.00 to 1.30; P = .05). Diagnosed adolescents had worse psychological sense of school membership (mean difference, -2.58; 95% CI, -1.13 to -4.06; P < .001), academic self-concept (mean difference, -0.14; 95% CI, -0.02 to -0.26; P = .02), and self-efficacy (mean difference, -0.20; 95% CI, -0.05 to -0.33; P = .007); displayed more negative social behaviors (mean difference, 1.56; 95% CI, 0.55 to 2.66; P = .002); and were more likely to harm themselves (odds ratio, 2.53; 95% CI, 1.49 to 4.37; P < .001) than adolescents without diagnosis. CONCLUSIONS AND RELEVANCE In this cohort study, ADHD diagnosis was not associated with any self-reported improvements in adolescents' QOL compared with adolescents with similar levels of H/I behaviors but no ADHD diagnosis. ADHD diagnosis was associated with worse scores in some outcomes, including significantly increased risk of self-harm. A large, randomized clinical trial with long-term follow-up is needed.
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8.
Cadmium exposure and risk of diabetes and prediabetes: A systematic review and dose-response meta-analysis.
Filippini, T, Wise, LA, Vinceti, M
Environment international. 2022;158:106920
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Cadmium is a toxic metal released in the environment after both natural and anthropogenic activities, particularly in contaminated and industrial areas devoted to smelting and refining of metals, and the manufacturing of batteries, coatings, or plastics. Exposure to cadmium may occur through occupational activities, smoking, food, and air pollution. The aim of this study was to provide updated literature on cadmium exposure and the risk of both type 2 diabetes and prediabetes, and to model the shape of these associations using a dose response approach. This study is a systematic review and meta-analysis of forty-two studies. Diabetes was investigated as an outcome in thirty-one studies, prediabetes in four studies, and both diabetes and prediabetes in seven studies. Results show that higher cadmium exposure was associated with increased risks of both diabetes and prediabetes. Diabetes risk increased linearly in studies using urinary cadmium concentrations, while disease risk increased only at the highest exposure levels when assessed using blood concentrations. The analysis for prediabetes also showed a linear increase in risk from low exposure, with a flattening effect at higher urinary cadmium concentrations. Authors conclude that their findings add to the available evidence on potential adverse health effects of environmental exposure to cadmium.
Expert Review
Conflicts of interest:
None
Take Home Message:
- Cadmium exposure through diet, occupational exposure and smoking may increase the risk of type 2 diabetes in affected individuals.
Evidence Category:
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X
A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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B: Systematic reviews including RCTs of limited number
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C: Non-randomized trials, observational studies, narrative reviews
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D: Case-reports, evidence-based clinical findings
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E: Opinion piece, other
Summary Review:
Background
Cadmium exposure might occur through occupational activities, food, air pollution, and smoking. Smokers, in particular, have higher blood cadmium concentrations than non-smokers. Food is the main transmission route for non-smokers, particularly cereals, vegetables, mollusks, and offal. Females and older adults are at a greater risk due to an increased risk of iron deficiency in these population groups, leading to increased absorption, as well as greater age-related bioaccumulation.
Furthermore, cadmium exposure has been associated with an increased risk of diabetes in a number of studies, as referenced in the present manuscript. However, the magnitude and shape of the correlation are uncertain.This systematic review and meta-analysis therefore investigates the relationship between exposure to cadmium and type 2 diabetes and prediabetes risk.
Methods
- The systematic review was conducted and reported in line with the PRISMA 2020 statement. Search strings related to the terms “cadmium” and “diabetes”, or “prediabetes state” in PubMed/MEDLINE, Web of Science and EMBASE databases were employed to search for relevant articles. Latest search date: 1 October 2021.
- Eligibility criteria included: studies evaluating cadmium exposure via biomarker levels with outcomes of interest being type 2 diabetes or prediabetes using WHO criteria and the American Diabetes Association; and reporting of relative risk estimates using the hazard ratio (HR), risk ratio (RR), or odds ratio (OR) with the corresponding 95% confidence interval (CIs). For inclusion in dose-response meta-analysis: reported effect estimates for all exposure categories along with dose in each category.
- Studies were assessed for risk of bias using theROBINS-E tool. Overall certainty of the evidence was assessed using the GRADE approach.
- The meta-analysis involved estimating RRs with corresponding 95% CIs from each study. Generalised least-squares regression with a random effects model and restricted maximum likelihood estimation were used. The highest versus lowest exposure categories were compared. The association between exposure and risk of diabetes or prediabetes was investigated using a one-stage dose-response meta-analysis. Sensitivity analyses were performed and heterogeneity between studies was assessed..
Results
- 42 eligible studies (case-control, cross-sectional, and cohort studies), ranging 65-34, 814 male and female adult participants, were identified investigating the association between cadmium exposure and risk of diabetes or prediabetes. Seven of the included studies were at overall high risk of bias; heterogeneity in the resulting meta-analyses was moderate to substantial. Sensitivity analyses indicated comparable results. Assessment with GRADE found no major inconsistency, indirectness or imprecision for either outcome.
- Comparing the highest versus lowest cadmium exposure concentrations associated with type 2 diabetes resulted in a RR of 1.24 (95% CI 0.96–1.59), RR 1.21 (CI 95% 1.00–1.45), and RR 1.47 (CI 95% 1.01–2.13) for blood, urinary, and toenail matrices, respectively. Concurrently, there was an elevated risk of prediabetes for cadmium levels in urine of RR 1.41 (95% CI: 1.15–1.73) and blood RR 1.38 (95% CI: 1.16–1.63), respectively.
- In the dose-response meta-analysis, a linear positive correlation between increasing urinary cadmium levels and diabetes risk was observed, with a RR 1.25 (95% CI 0.90–1.72) at concentration 2.0 µg/g of creatinine compared with no exposure. Conversely, for blood cadmium concentrations, the diabetes risk seemed to rise above 1 µg/L compared with no exposure. Moreover, prediabetes risk increased up to approximately 2 µg/g creatinine beyond which a plateau was reached with RR 1.40 (95% CI 1.12–1.76) at 2 µg/g creatinine.
- The meta-regression showed a negligible correlation between blood cadmium levels and diabetes risk. However, a positive yet imprecise association was found with increasing urinary cadmium concentrations. Similarly, no association was observed between blood cadmium concentrations and risk of prediabetes, whereas a positive relationship with urinary cadmium levels was observed. However, these findings were based on a limited cohort of studies.
Conclusions
- A positive linear correlation between cadmium concentration (measured in multiple matrices) and risk of both type 2 diabetes and prediabetes with a dose-response relationship (moderate-certainty evidence) were observed in this systematic review and meta-analysis. Diabetes risk increased linearly in studies using urinary cadmium concentrations, whereas disease risk increased only at the highest exposure levels when assessed using blood levels. The analysis for prediabetes also demonstrated a linear increase in risk from low exposure, which plateaued at higher urinary cadmium concentrations.
Clinical practice applications:
- To inform practitioners and clients of the risks of cadmium exposure in the diet, through occupational exposure, and through smoking.
- To motivate practitioners to educate themselves and their clients regarding the foods which may pose a higher risk of cadmium exposure (not reviewed in the present article).
- To advise clients on prediabetes and type 2 diabetes risk from cadmium exposure through smoking.
Considerations for future research:
- As cited by the authors, future studies could incorporate stratified analysis in specific subgroups, e.g., non-smokers, or could be restricted to prospective cohort studies with more sufficient data,
- Large-scale observational studies could be conducted investigating cadmium exposure in smokers versus non-smokers.
- Clinical trials could be performed to evaluate the effect of reduction or cessation of tobacco smoking on total body cadmium concentrations .
- Continuous surveillance of dietary cadmium exposure and other heavy metals should be prioritised to inform public health.
- Dietary interventions could assess the possibility to attenuate the risk of cadmium exposure.
Abstract
BACKGROUND Cadmium exposure has been associated with increased diabetes risk in several studies, though there is still considerable debate about the magnitude and shape of the association. OBJECTIVE To perform a systematic review and meta-analysis of observational studies investigating the relation between cadmium exposure and risk of type 2 diabetes and prediabetes, and to summarize data on the magnitude and shape of the association. DATA SOURCE After conducting an online literature search through October 1, 2021, we identified 42 eligible studies investigating the association between cadmium exposure and risk of diabetes and prediabetes. STUDY ELIGIBILITY CRITERIA We included studies that assessed cadmium exposure through biomarker levels; examined type 2 diabetes or prediabetes among outcomes; and reported effect estimates for cadmium exposure for meta-analysis only. STUDY APPRAISAL AND SYNTHESIS METHODS Studies were evaluated using ROBINS-E risk of bias tool. We quantitively assessed the relation between exposure and study outcomes using one-stage dose-response meta-analysis with a random effects meta-analytical model. RESULTS In the meta-analysis, comparing highest-versus-lowest cadmium exposure levels, summary relative risks (RRs) for type 2 diabetes were 1.24 (95% confidence interval 0.96-1.59), 1.21 (1.00-1.45), and 1.47 (1.01-2.13) for blood, urinary, and toenail matrices, respectively. Similarly, there was an increased risk of prediabetes for cadmium concentrations in both urine (RR = 1.41, 95% CI: 1.15-1.73) and blood (RR = 1.38, 95% CI: 1.16-1.63). In the dose-response meta-analysis, we observed a consistent linear positive association between cadmium exposure and diabetes risk, with RRs of 1.25 (0.90-1.72) at 2.0 µg/g of creatinine. Conversely for blood cadmium, diabetes risk appeared to increase only above 1 µg/L. Prediabetes risk increased up to approximately 2 µg/g creatinine above which it reached a plateau with RR of 1.42 (1.12-1.76) at 2 µg/g creatinine. LIMITATIONS AND CONCLUSIONS This analysis provides moderate-certainty evidence for a positive association between cadmium exposure (measured in multiple matrices) and risk of both diabetes and prediabetes.
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9.
Effects of early-life antibiotics on the developing infant gut microbiome and resistome: a randomized trial.
Reyman, M, van Houten, MA, Watson, RL, Chu, MLJN, Arp, K, de Waal, WJ, Schiering, I, Plötz, FB, Willems, RJL, van Schaik, W, et al
Nature communications. 2022;13(1):893
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Plain language summary
Disturbances of the gut microbial community composition after birth are associated with a broad spectrum of health problems in early infancy and later in life. The ecological side effects of antibiotics may be even more pronounced and persistent when administered in the early assembly phase of the neonatal gut microbiome in the first weeks of life. The aim of this study was to identify the antibiotic regimen with the least ecological and antimicrobial resistance (AMR) gene selection effects. This study was a randomised controlled study in 147 infants who required broad-spectrum antibiotics for treatment of (suspected) early-onset neonatal sepsis (sEONS) in their first week of life. Infants were randomly allocated 1:1:1 to three most commonly prescribed intravenous antibiotic combinations. Results showed that antibiotic-treated infants show temporarily reduced gut microbial diversity, and major and prolonged ecological perturbations, compared with healthy term-born controls. Furthermore, there was also a shift in AMR gene profile. Authors conclude that there are significant long-term effects of broad-spectrum antibiotic treatment. In fact, their findings suggest that more emphasis should be put on reducing the number of neonates that receive broad-spectrum antibiotics for sEONS.
Abstract
Broad-spectrum antibiotics for suspected early-onset neonatal sepsis (sEONS) may have pronounced effects on gut microbiome development and selection of antimicrobial resistance when administered in the first week of life, during the assembly phase of the neonatal microbiome. Here, 147 infants born at ≥36 weeks of gestational age, requiring broad-spectrum antibiotics for treatment of sEONS in their first week of life were randomized 1:1:1 to receive three commonly prescribed intravenous antibiotic combinations, namely penicillin + gentamicin, co-amoxiclav + gentamicin or amoxicillin + cefotaxime (ZEBRA study, Trial Register NL4882). Average antibiotic treatment duration was 48 hours. A subset of 80 non-antibiotic treated infants from a healthy birth cohort served as controls (MUIS study, Trial Register NL3821). Rectal swabs and/or faeces were collected before and immediately after treatment, and at 1, 4 and 12 months of life. Microbiota were characterized by 16S rRNA-based sequencing and a panel of 31 antimicrobial resistance genes was tested using targeted qPCR. Confirmatory shotgun metagenomic sequencing was executed on a subset of samples. The overall gut microbial community composition and antimicrobial resistance gene profile majorly shift directly following treatment (R2 = 9.5%, adjusted p-value = 0.001 and R2 = 7.5%, adjusted p-value = 0.001, respectively) and normalize over 12 months (R2 = 1.1%, adjusted p-value = 0.03 and R2 = 0.6%, adjusted p-value = 0.23, respectively). We find a decreased abundance of Bifidobacterium spp. and increased abundance of Klebsiella and Enterococcus spp. in the antibiotic treated infants compared to controls. Amoxicillin + cefotaxime shows the largest effects on both microbial community composition and antimicrobial resistance gene profile, whereas penicillin + gentamicin exhibits the least effects. These data suggest that the choice of empirical antibiotics is relevant for adverse ecological side-effects.
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Intestinal Microbial Composition of Children in a Randomized Controlled Trial of Probiotics to Treat Acute Gastroenteritis.
Horne, RG, Freedman, SB, Johnson-Henry, KC, Pang, XL, Lee, BE, Farion, KJ, Gouin, S, Schuh, S, Poonai, N, Hurley, KF, et al
Frontiers in cellular and infection microbiology. 2022;12:883163
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Plain language summary
During the first few years of life the diversity of the gut microbiome increases with increasing age. Many factors influence the colonisation after birth and during infancy. There are some studies that have looked at the use of probiotics as a treatment for gastrointestinal distresses in children with some success. These studies however focus on the outcome. They do not consider the differences in gut microbiota in children and do not look at individual responses to probiotics. The purpose of this randomized, double-blinded, placebo-controlled trial was to understand the effect of a probiotic treatment on children under 4 years old admitted to the emergency department of hospital with acute diarrhea. 70 children were included (30 in the probiotic group, 32 placebo). Stool analyses were done on admission (day 0), then 5 days after administration of a probiotic or placebo and then again at day 28. The results showed that participants younger than 1 year had lower bacterial diversity than older children. The age of the child is a dominant factor in determining the overall diversity of the gut microbiome. Probiotic treatment for 5 days did not alter the composition of the gut microbiota. However, there was lower diversity in the presence of enteric bacterial pathogens; in particular, with C. difficile in stool samples. This study highlights that base line measurements should be included and that age is a key factor when designing future studies of this kind.
Abstract
UNLABELLED Compositional analysis of the intestinal microbiome in pre-schoolers is understudied. Effects of probiotics on the gut microbiota were evaluated in children under 4-years-old presenting to an emergency department with acute gastroenteritis. Included were 70 study participants (n=32 placebo, n=38 probiotics) with stool specimens at baseline (day 0), day 5, and after a washout period (day 28). Microbiota composition and deduced functions were profiled using 16S ribosomal RNA sequencing and predictive metagenomics, respectively. Probiotics were detected at day 5 of administration but otherwise had no discernable effects, whereas detection of bacterial infection (P<0.001) and participant age (P<0.001) had the largest effects on microbiota composition, microbial diversity, and deduced bacterial functions. Participants under 1 year had lower bacterial diversity than older aged pre-schoolers; compositional changes of individual bacterial taxa were associated with maturation of the gut microbiota. Advances in age were associated with differences in gut microbiota composition and deduced microbial functions, which have the potential to impact health later in life. CLINICAL TRIAL REGISTRATION www.ClinicalTrials.gov, identifier: NCT01853124.