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The Gut Microbiome in Early Life Stress: A Systematic Review.
Agusti, A, Lamers, F, Tamayo, M, Benito-Amat, C, Molina-Mendoza, GV, Penninx, BWJH, Sanz, Y
Nutrients. 2023;15(11)
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Children exposed to early life stress (ELS) show alterations in brain development and are at increased risk of developing mental illness. This study aims to clarify whether ELS influences the gut microbiome and whether this can be a predictor for the development of mental disorders. 13 articles were included in this systemic review. 4 looked at pre-natal stress and 9 at post-natal stress. Prenatal stress (via maternal stress) may be associated with an increase in Proteobacteria phylum and with a lower abundance of Bifidobacterium and lactic acid bacteria. In the postnatal group, greater microbiome diversity was related to lower depression and anxiety. In boys scores for adaptive skills were higher in those with good levels of Bifidobacterium. A positive association was found between EA (early adversity) experiences and gastrointestinal symptoms and anxiety. This review demonstrates links between ELS and gut microbiome changes. Further research will be necessary to draw more robust conclusions.
Expert Review
Conflicts of interest:
None
Take Home Message:
- This systematic review consolidated and discussed existing evidence on the link between early life stress (ELS) and changes to the human microbiome
- Exposure to ELS, prenatal or postnatal during childhood and adolescence, may impact mental and physical health.
Evidence Category:
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A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)
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X
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 systematic review was conducted to consolidate clinical evidence examining the impact of early life stress (ELS) on the human intestinal microbiome.
Method
Thirteen observational studies were included in the review, sourced from Pubmed, Scopus, Web of Science, and EMBASE. Methodological quality was assessed using the Newcastle-Ottawa Assessment Scale (NOS), with most studies scoring seven or eight out of nine stars.
Study designs varied, including prospective prenatal studies, postnatal longitudinal studies, case-control studies, and cross-sectional studies. Four prenatal studies were prospective in design. The other nine postnatal studies included one longitudinal study, five case-control studies, and three cross-sectional studies. All 13 studies were published between 2015 and 2022. Because study designs and outcome assessments varied, the results were presented in a narrative form. Data was extracted by 2 independent authors.
Results
The primary findings from the review were as follows:
- Four longitudinal stress studies indicated that pregnant mothers experiencing psychological stress, increased cortisol levels, HIV, and lack of social support exhibited a lower abundance of beneficial Bifidobacterium and an increased abundance of Enterobacter genus.
- One postnatal stress longitudinal study (n=260) demonstrated lower depression and anxiety and improved internalising behaviour in patients with high microbiome diversity.
- . One postnatal stress case-control study (n=344) showed changes in the microbiome and an abundance of several bacterial taxa in stressed groups, including genera Prevotella, Bacteroides (Bacteroidetes), Coprococcus, Streptococcus, and Escherichia.
- One cross-sectional study of 128 adults without psychiatric conditions revealed that higher stress correlated with increased levels of Bacteroides, Parabacteroides, Rhodococcus, Methanobrevibacter, and Roseburia at the genus level, as well as lower Phascolarcto bacterium and Firmicutes at the phylum level.
- One large prospective study (n=446) found infants exposed to higher cumulative stress exhibited an increased relative abundance of Proteobacteria groups and lower Bifidobacterium.
Conclusion:
Due to the inconsistency of study designs and their results this review failed to find consensus microbiome signatures associated with pre- or postnatal stress, or both.
Clinical practice applications:
- Early life stress, and alterations in the gut microbiome, have been linked to mental health conditions
- Maternal prenatal stress may be linked to emotional, behavioural, and cognitive outcomes in infants.
Considerations for future research:
- Future research should standardise questionnaires, to ensure consistency and comparability across studies
- Additionally, future studies should consider using standard procedures and specific species and strain resolution shotgun metagenomics sequencing
- Consideration should be given to the influence of environmental variables (diet, physical activity, etc.) and sex in gut microbiome analysis.
Abstract
Exposure to early life stress (ELS), prenatal or postnatal during childhood and adolescence, can significantly impact mental and physical health. The role of the intestinal microbiome in human health, and particularly mental health, is becoming increasingly evident. This systematic review aims to summarize the clinical data evaluating the effect of ELS on the human intestinal microbiome. The systematic review (CRD42022351092) was performed following PRISMA guidelines, with ELS considered as exposure to psychological stressors prenatally and during early life (childhood and adolescence). Thirteen articles met all inclusion criteria, and all studies reviewed found a link between ELS and the gut microbiome in both prenatal and postnatal periods. However, we failed to find consensus microbiome signatures associated with pre- or postnatal stress, or both. The inconsistency of results is likely attributed to various factors such as different experimental designs, ages examined, questionnaires, timing of sample collection and analysis methods, small population sizes, and the type of stressors. Additional studies using similar stressors and validated stress measures, as well as higher-resolution microbiome analytical approaches, are needed to draw definitive conclusions about the links between stress and the human gut microbiome.
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Four weeks of probiotic supplementation reduces GI symptoms during a marathon race.
Pugh, JN, Sparks, AS, Doran, DA, Fleming, SC, Langan-Evans, C, Kirk, B, Fearn, R, Morton, JP, Close, GL
European journal of applied physiology. 2019;119(7):1491-1501
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Gastrointestinal (GI) symptoms are common in athletes participating in marathon running. The purpose of this study was to evaluate the effects of probiotic supplementation on GI symptoms and markers of GI permeability and damage during marathon training and racing. 24 runners took part in this double-blind, randomised trial. Participants took a probiotic supplement containing 25 billion organisms (Lactobacilli and bifidobacterial) or placebo for 4 weeks prior to the marathon race. Blood samples were taken before supplementation, pre and post marathon. Participants also completed a questionnaires regarding GI symptoms. All runners experienced GI symptoms during the marathon. Runners supplementing with probiotics reported fewer and less severe GI symptoms, both in training and during the race, and also showed increased performance during the race compared to the placebo group. There was no association between GI symptoms and markers of GI permeability and damage, although both were increased post-race in all participants. The authors conclude that athletes participating in endurance events, where GI symptoms are common and likely to affect performance, could consider probiotic supplementation in the weeks prior to competition.
Abstract
PURPOSE To evaluate the effects of probiotic supplementation on gastrointestinal (GI) symptoms, circulatory markers of GI permeability, damage, and markers of immune response during a marathon race. METHODS Twenty-four recreational runners were randomly assigned to either supplement with a probiotic (PRO) capsule [25 billion CFU Lactobacillus acidophilus (CUL60 and CUL21), Bifidobacterium bifidum (CUL20), and Bifidobacterium animalis subs p. Lactis (CUL34)] or placebo (PLC) for 28 days prior to a marathon race. GI symptoms were recorded during the supplement period and during the race. Serum lactulose:rhamnose ratio, and plasma intestinal-fatty acid binding protein, sCD14, and cytokines were measured pre- and post-races. RESULTS Prevalence of moderate GI symptoms reported were lower during the third and fourth weeks of the supplement period compared to the first and second weeks in PRO (p < 0.05) but not PLC (p > 0.05). During the marathon, GI symptom severity during the final third was significantly lower in PRO compared to PLC (p = 0.010). The lower symptom severity was associated with a significant difference in reduction of average speed from the first to the last third of the race between PLC (- 14.2 ± 5.8%) and PRO (- 7.9 ± 7.5%) (p = 0.04), although there was no difference in finish times between groups (p > 0.05). Circulatory measures increased to a similar extent between PRO and PLC (p > 0.05). CONCLUSION Probiotics supplementation was associated with a lower incidence and severity of GI symptoms in marathon runners, although the exact mechanisms are yet to be elucidated. Reducing GI symptoms during marathon running may help maintain running pace during the latter stages of racing.
3.
Crosstalk between the microbiome and epigenome: messages from bugs.
Qin, Y, Wade, PA
Journal of biochemistry. 2018;163(2):105-112
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Trillions of microbes live symbiotically in and on an individual human being, most of them inside the digestive tract and communally known as the gut microbiome. The gut microbiome plays a vital role in the individual host’s health, not only by helping digest food and harvest energy, but also by regulating immune development and influencing gene expression. Diet and factors, such as infections and the use of antibiotics, can alter the balance of the microbiome and lead to various outcomes. This paper reviewed the current understanding of the ways in which the gut microbiome is capable of altering the host’s gene expression through microbial signals, including metabolites, bile acids, inflammation and altered composition. The studies highlighted in the paper show that gut microbes communicate both with local cells in the intestines and with more distant organs, such as the liver and the cardiovascular system. Through this communication, they can regulate the expression of immune cells, cancer cells, enzymes and inflammation-related molecules. The authors concluded that these interactions, or the crosstalk between the microbes and the host, demonstrate a crucial role of the gut microbiome in the host’s response to environmental signals. However, many of the mechanisms are still unclear, so further studies are needed to explain specific microbe-derived signals, affecting host gene expression, and to deepen our understanding of how lifestyle, health status and environmental exposures, such as antibiotics, regulate the microbiome and its influence.
Abstract
Mammals exist in a complicated symbiotic relationship with their gut microbiome, which is postulated to have broad impacts on host health and disease. As omics-based technologies have matured, the potential mechanisms by which the microbiome affects host physiology are being addressed. The gut microbiome, which provides environmental cues, can modify host cell responses to stimuli through alterations in the host epigenome and, ultimately, gene expression. Increasing evidence highlights microbial generation of bioactive compounds that impact the transcriptional machinery in host cells. Here, we review current understanding of the crosstalk between gut microbiota and the host epigenome, including DNA methylation, histone modification and non-coding RNAs. These studies are providing insights into how the host responds to microbial signalling and are predicted to provide information for the application of precision medicine.
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Dietary fructooligosaccharides affect intestinal barrier function in healthy men.
Ten Bruggencate, SJ, Bovee-Oudenhoven, IM, Lettink-Wissink, ML, Katan, MB, van der Meer, R
The Journal of nutrition. 2006;136(1):70-4
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Fructooligosaccharides (FOS) are nondigestible carbohydrates assumed beneficial because they stimulate the protective colonic microflora (bifidobacteria, lactobacilli) that produce organic acids that, in turn, increase host defence against invasive pathogens. However, studies show that FOS increases cytotoxicity of intestinal contents (fecal water), mucin excretion, and intestinal permeability in rats, reducing resistance to infection (since host defence depends on barrier function). This study aims to prove whether the adverse adverse effects of FOS that occurred before infection in rats would occur in humans. This is important because FOS has been added to a variety of products including dairy products and infant formulas. This is a double-blind, placebo-controlled crossover study design with 2 supplement periods of 2 wk. separated by 1 washout period of 2 wks. 34 healthy men were randomly divided in 2 groups. Subjects consumed either lemonade with 20g of FOS or 6g of sucrose (placebo) per day in 3 divided doses (morning, afternoon, and evening). They avoided dairy products and calcium rich foods (since FOS-induced adverse effects in rats is inhibited by calcium intake), foods high in fermentable nondigestible carbohydrates and pro- or prebiotics. Alcohol consumption was restricted. Habitual diet was otherwise maintained. The lemonade also contained the intestinal permeability marker chromium EDTA (CrEDTA). On the last 2 days of both supplement periods, quantitative food intake (self-reported) was measured, 24-h urine samples taken, and gastrointestinal symptoms rated (visual analogue scale). 24-h fecal samples were also collected. Dietary FOS consumption increased bifidobacteria, lactobacilli, lactic acid and decreased fecal pH. Cytotoxicity of fecal water and urinary and fecal CrEDTA excretion were not affected by FOS. Frequency of flatulence, bloating, abdominal pain and cramps were increased in the FOS period. The concept of stimulating endogenous microflora and intestinal organic acid production by rapid fermentation of nondigestible carbohydrates is beneficial for the intestinal barrier in humans is not supported.
Abstract
In contrast to most expectations, we showed previously that dietary fructooligosaccharides (FOS) stimulate intestinal colonization and translocation of invasive Salmonella enteritidis in rats. Even before infection, FOS increased the cytotoxicity of fecal water, mucin excretion, and intestinal permeability. In the present study, we tested whether FOS has these effects in humans. A double-blind, placebo-controlled, crossover study of 2 x 2 wk, with a washout period of 2 wk, was performed with 34 healthy men. Each day, subjects consumed lemonade containing either 20 g FOS or placebo and the intestinal permeability marker chromium EDTA (CrEDTA). On the last 2 d of each supplement period, subjects scored their gastrointestinal complaints on a visual analog scale and collected feces and urine for 24 h. Fecal lactic acid was measured using a colorimetric enzymatic kit. The cytotoxicity of fecal water was determined with an in vitro bioassay, fecal mucins were quantified fluorimetrically, and intestinal permeability was determined by measuring urinary CrEDTA excretion. In agreement with our animal studies, FOS fermentation increased fecal wet weight, bifidobacteria, lactobacilli, and lactic acid. Consumption of FOS increased flatulence and intestinal bloating. In addition, FOS consumption doubled fecal mucin excretion, indicating mucosal irritation. However, FOS did not affect the cytotoxicity of fecal water and intestinal permeability. The FOS-induced increase in mucin excretion in our human study suggests mucosal irritation in humans, but the overall effects are more moderate than those in rats.