Cluster-specific associations between the gut microbiota and behavioral outcomes in preschool-aged children.

BACKGROUND: The gut microbiota is recognized as a regulator of brain development and behavioral outcomes during childhood. Nonetheless, associations between the gut microbiota and behavior are often inconsistent among studies in humans, perhaps because many host-microbe relationships vary widely between individuals. This study aims to stratify children based on their gut microbiota composition (i.e., clusters) and to identify novel gut microbiome cluster-specific associations between the stool metabolomic pathways and child behavioral outcomes. METHODS: Stool samples were collected from a community sample of 248 typically developing children (3-5 years). The gut microbiota was analyzed using 16S sequencing while LC-MS/MS was used for untargeted metabolomics. Parent-reported behavioral outcomes (i.e., Adaptive Skills, Internalizing, Externalizing, Behavioral Symptoms, Developmental Social Disorders) were assessed using the Behavior Assessment System for Children (BASC-2). Children were grouped based on their gut microbiota composition using the Dirichlet multinomial method, after which differences in the metabolome and behavioral outcomes were investigated. RESULTS: Four different gut microbiota clusters were identified, where the cluster enriched in both Bacteroides and Bifidobacterium (Ba2) had the most distinct stool metabolome. The cluster characterized by high Bifidobacterium abundance (Bif), as well as cluster Ba2, were associated with lower Adaptive Skill scores and its subcomponent Social Skills. Cluster Ba2 also had significantly lower stool histidine to urocanate turnover, which in turn was associated with lower Social Skill scores in a cluster-dependent manner. Finally, cluster Ba2 had increased levels of compounds involved in Galactose metabolism (i.e., stachyose, raffinose, alpha-D-glucose), where alpha-D-glucose was associated with the Adaptive Skill subcomponent Daily Living scores (i.e., ability to perform basic everyday tasks) in a cluster-dependent manner. CONCLUSIONS: These data show novel associations between the gut microbiota, its metabolites, and behavioral outcomes in typically developing preschool-aged children. Our results support the concept that cluster-based groupings could be used to develop more personalized interventions to support child behavioral outcomes. Video Abstract.

Local and Systemic Effects of Bioactive Food Ingredients: Is There a Role for Functional Foods to Prime the Gut for Resilience?

Scientific advancements in understanding the impact of bioactive components in foods on the gut microbiota and wider physiology create opportunities for designing targeted functional foods. The selection of bioactive ingredients with potential local or systemic effects holds promise for influencing overall well-being. An abundance of studies demonstrate that gut microbiota show compositional changes that correlate age and disease. However, navigating this field, especially for non-experts, remains challenging, given the abundance of bioactive ingredients with varying levels of scientific substantiation. This narrative review addresses the current knowledge on the potential impact of the gut microbiota on host health, emphasizing gut microbiota resilience. It explores evidence related to the extensive gut health benefits of popular dietary components and bioactive ingredients, such as phytochemicals, fermented greens, fibres, prebiotics, probiotics, and postbiotics. Importantly, this review distinguishes between the potential local and systemic effects of both popular and emerging ingredients. Additionally, it highlights how dietary hormesis promotes gut microbiota resilience, fostering better adaptation to stress-a hallmark of health. By integrating examples of bioactives, this review provides insights to guide the design of evidence-based functional foods aimed at priming the gut for resilience.

The gut virome is associated with stress-induced changes in behaviour and immune responses in mice.

The microbiota-gut-brain axis has been shown to play an important role in the stress response, but previous work has focused primarily on the role of the bacteriome. The gut virome constitutes a major portion of the microbiome, with bacteriophages having the potential to remodel bacteriome structure and activity. Here we use a mouse model of chronic social stress, and employ 16S rRNA and whole metagenomic sequencing on faecal pellets to determine how the virome is modulated by and contributes to the effects of stress. We found that chronic stress led to behavioural, immune and bacteriome alterations in mice that were associated with changes in the bacteriophage class Caudoviricetes and unassigned viral taxa. To determine whether these changes were causally related to stress-associated behavioural or physiological outcomes, we conducted a faecal virome transplant from mice before stress and autochthonously transferred it to mice undergoing chronic social stress. The transfer of the faecal virome protected against stress-associated behaviour sequelae and restored stress-induced changes in select circulating immune cell populations, cytokine release, bacteriome alterations and gene expression in the amygdala. These data provide evidence that the virome plays a role in the modulation of the microbiota-gut-brain axis during stress, indicating that these viral populations should be considered when designing future microbiome-directed therapies.

Long-term and trimester-specific effects of prenatal stress on the child gut microbiota.

OBJECTIVE: Stress is common among pregnant individuals and is associated with an altered gut microbiota composition in infants. It is unknown if these compositional changes persist into the preschool years when the gut microbiota reaches an adult-like composition. This study aimed to investigate if indicators of prenatal stress (i.e., psychological distress and stress-related physiology) are associated with children's gut microbiota composition and metabolites at 3-4 years of age. METHODS: Maternal-child pairs (n = 131) were from the Alberta Pregnancy Outcomes and Nutrition (APrON) cohort. Each trimester, psychological distress was measured as symptoms of anxiety (Symptom Checklist-90-R) and depressed mood (Edinburgh Postnatal Depression Scale), whereas salivary cortisol was quantified as a measure of stress-related physiology. Child stool samples were collected at 3-4 years to evaluate gut microbiota composition using 16S rRNA gene sequencing and fecal metabolome using liquid chromatography with tandem mass spectrometry (LC-MS/MS). Associations between prenatal distress and cortisol with the gut microbiota were determined using Pearson and Spearman correlations and corrected for multiple testing. Associations between prenatal distress and cortisol with the fecal metabolome were assessed using Metaboanalyst. RESULTS: Symptoms of depressed mood during the 2nd and 3rd trimesters and anxiety during the 2nd trimester of pregnancy were associated with increased alpha diversity of the child's gut microbiota. Cortisol levels during the 1st trimester were also associated with increased Faith PD diversity (r = 0.32), whereas cortisol levels during the 2nd trimester were associated with reduced Shannon diversity (r = -0.27). Depression scores during the 2nd and 3rd trimesters were associated with reductions in the relative abundances of Eggerthella, Parasutterella, and increases in Ruminococcaceae (rs = -0.28, rs = -0.32, rs = 0.32, respectively), as well as the fecal metabolome (e.g., branched-chain amino acid metabolism). Cortisol levels during the 2nd trimester correlated with 7 bacterial taxa, whereas 1st-trimester cortisol levels were associated with the child's fecal metabolome. CONCLUSIONS: Prenatal distress and cortisol were associated with both child gut microbiota composition and fecal metabolome at preschool age. Understanding these associations may allow for the identification of microbiota-targeted interventions to support child developmental outcomes affected by prenatal stress.

Prenatal mental health data and birth outcomes in the pregnancy during the COVID-19 Pandemic dataset.

The COVID-19 pandemic was a substantial stressor, especially for pregnant individuals. We aimed to understand the impact of COVID-19-related stresses on pregnant individuals and their infants and collected survey-based data across Canada as part of the Pregnancy during the COVID-19 Pandemic (PdP) project. The dataset described here provides baseline prenatal data and basic birth outcomes from PdP participants. This data includes information from pregnant individuals as well as their infants. At enrolment and time of completion of the baseline survey, participants were pregnant, ≥17 years of age, ≤35 weeks of gestation, living in Canada, and able to read and write in English or French. Baseline data were collected between April 2020-April 2021. Infant data were collected between May 2020-December 2021. All data were collected via self-report using online questionnaires in REDCAP. Questionnaires were available in both English and French. Data were checked for completeness and plausibility, and duplicates were removed. The dataset described here includes age, education, and household income of the pregnant individuals reported at the baseline/enrollment survey. Raw scores are provided for the Edinburgh Postnatal Depression Scale (EPDS) and the PROMIS Anxiety scale. Ratings are also given for three variables describing fear of the COVID-19 virus. Birth outcomes are provided for infants, including gestational age at birth, birthweight, length, mode of delivery, and whether the infant spent time in the neonatal intensive care unit (NICU). Delivery date is reported as month and year. These data will be beneficial for anyone interested in researching stress during pregnancy or birth outcomes in the context of the COVID-19 pandemic. They will also be useful to researchers interested in examining more general effects of prenatal distress on birth outcomes in children. Data could also be compared to other datasets from the COVID-19 pandemic to establish generalizability, or to pre-pandemic datasets to determine the extent of changes during the COVID-19 pandemic.

Exploring associations between the gut microbiota and full-scale intelligence in preschool children.

The relationship between the gut microbiota and neurocognitive outcomes is becoming increasingly recognized; however, findings in humans are inconsistent. In addition, few studies have investigated the gut microbial metabolites that may mediate this relationship. The objective of this study was to investigate associations between full-scale intelligence (FSIQ) and the composition of the gut microbiota and metabolome in preschool children. Stool samples were collected from a community sample of 245 typically developing children (3-5 years) from the Alberta Pregnancy Outcomes and Nutrition (APrON) cohort. The faecal microbiome was assessed using 16S rRNA sequencing and the metabolome using LC-MS/MS. FSIQ and scores on the Verbal Comprehension, Visual Spatial, Working Memory indices of the Wechsler Preschool and Primary Scale of Intelligence-IV were used to assess neurocognition. Associations between the gut microbiota and FSIQ were determined using Pearson and Spearman correlations, which were corrected for multiple testing and relevant covariates. Verbal Comprehension correlated negatively with both Shannon alpha diversity (r = -0.14, p = 0.032) and the caffeine-derived metabolite paraxanthine (r = -0.22, p < 0.001). No other significant correlations were observed. Overall, the weak to modest correlations between Verbal Comprehension with alpha diversity and paraxanthine provide limited evidence of an association between the gut microbiota and neurocognitive outcomes in typically developing preschool children.

Critical windows of early-life microbiota disruption on behaviour, neuroimmune function, and neurodevelopment.

Numerous studies have emphasised the importance of the gut microbiota during early life and its role in modulating neurodevelopment and behaviour. Epidemiological studies have shown that early-life antibiotic exposure can increase an individual's risk of developing immune and metabolic diseases. Moreover, preclinical studies have shown that long-term antibiotic-induced microbial disruption in early life can have enduring effects on physiology, brain function and behaviour. However, these studies have not investigated the impact of targeted antibiotic-induced microbiota depletion during critical developmental windows and how this may be related to neurodevelopmental outcomes. Here, we addressed this gap by administering a broad-spectrum oral antibiotic cocktail (ampicillin, gentamicin, vancomycin, and imipenem) to mice during one of three putative critical windows: the postnatal (PN; P2-9), pre-weaning (PreWean; P12-18), or post-weaning (Wean; P21-27) developmental periods and assessed the effects on physiology and behaviour in later life. Our results demonstrate that targeted microbiota disruption during early life has enduring effects into adolescence on the structure and function of the caecal microbiome, especially for antibiotic exposure during the weaning period. Further, we show that microbial disruption in early life selectively alters circulating immune cells and modifies neurophysiology in adolescence, including altered myelin-related gene expression in the prefrontal cortex and altered microglial morphology in the basolateral amygdala. We also observed sex and time-dependent effects of microbiota depletion on anxiety-related behavioural outcomes in adolescence and adulthood. Antibiotic-induced microbial disruption had limited and subtle effects on social behaviour and did not have any significant effects on depressive-like behaviour, short-term working, or recognition memory. Overall, this study highlights the importance of the gut microbiota during critical windows of development and the subtle but long-term effects that microbiota-targeted perturbations can have on brain physiology and behaviour.

Prebiotic supplementation modulates selective effects of stress on behavior and brain metabolome in aged mice.

Aging has a significant impact on physiology with implications for central nervous system function coincident with increased vulnerability to stress exposures. A number of stress-sensitive molecular mechanisms are hypothesized to underpin age-related changes in brain function. Recent cumulative evidence also suggests that aging impacts gut microbiota composition. However, the impact of such effects on the ability of mammals to respond to stress in aging is still relatively unexplored. Therefore, in this study we assessed the ability of a microbiota-targeted intervention (the prebiotic FOS-Inulin) to alleviate age-related responses to stress. Exposure of aged C57BL/6 mice to social defeat led to an altered social interaction phenotype in the social interaction test, which was reversed by FOS-Inulin supplementation. Interestingly, this occured independent of affecting social defeat-induced elevations in the stress hormone corticosterone. Additionally, the behavioral modifications following FOS-Inulin supplementation were also not coincident with improvement of pro-inflammatory markers. Metabolomics analysis was performed and intriguingly, age associated metabolites were shown to be reduced in the prefrontal cortex of stressed aged mice and this deficit was recovered by FOS-Inulin supplementation. Taken together these results suggest that prebiotic dietary intervention rescued the behavioral response to stress in aged mice, not through amelioration of the inflammatory response, but by restoring the levels of key metabolites in the prefrontal cortex of aged animals. Therefore, dietary interventions could be a compelling avenue to improve the molecular and behavioral manifestations of chronic stress exposures in aging via targeting the microbiota-gut brain axis.

Dietary changes among pregnant individuals compared to pre-pandemic: A cross-sectional analysis of the Pregnancy during the COVID-19 Pandemic (PdP) study.

Introduction: Dietary changes are common in pregnancy and may affect pregnancy outcomes, yet these changes and the associated contributory factors during the COVID-19 pandemic have been understudied. We aimed to investigate the association between dietary change and socioeconomic variables, pre-pregnancy BMI, and mental health symptoms; the change in intake of seven food categories and their reasons; and the association between intake of these food categories and mental health symptoms. Materials and methods: In this cross-sectional analysis, we used data from the Pregnancy during the COVID-19 Pandemic (PdP) cohort study that collected data from pregnant Canadian individuals (n = 9,870, gestational age ≤ 35 weeks) on socioeconomic factors, pandemic-related hardships, pre-pregnancy body mass index (BMI), dietary changes compared to pre-pandemic and the reasons for these changes. We assessed depressive and anxiety symptoms using the Edinburgh Postpartum Depression Scale (EPDS) and Patient-Reported Outcomes Measurement Information System (PROMIS)-Anxiety, respectively. Results: 54.3% of the participants reported a change in their diet. Non-white ethnicity (OR = 1.33), job loss (OR = 1.29), clinically elevated depressive and anxiety symptoms (OR = 1.26 and 1.14, respectively), self-isolation (OR = 1.20), pre-pregnancy BMI (OR = 1.19), fear of COVID-19 (OR = 1.15), and pandemic phase at enrolment (OR = 0.90) significantly predicted dietary change. Most participants ate about the same amounts of dairy, meats and canned foods/dried goods as pre-pandemic (61.5, 61.7, and 60.2%, respectively), increased their intake of fresh vegetables/fruits and sweets/snacks (43.2 and 54.5%, respectively), and decreased fast-food and take-out/home delivery (53.2 and 43.1%, respectively). Changes in consumption of the food categories had a curvilinear association with mental health symptoms (except resilience) indicating greater symptoms with either decreased or increased intakes. Changes in craving, having more time for cooking/preparing foods, and being unable to go grocery shopping frequently (but not reduced affordability) were the main reasons driving these dietary changes. Conclusion: Some factors increase the odds of dietary change among pregnant individuals during the pandemic, with some changes toward a healthy and others toward an unhealthy diet. Given the importance of a healthy diet during gestation, identifying the risk and protective factors might be the first essential step in reducing the detrimental effects of unfavorable dietary changes during the pandemic on this vulnerable population.

Inhibition of FKBP51 induces stress resilience and alters hippocampal neurogenesis.

Stress-related psychiatric disorders such as depression are among the leading causes of morbidity and mortality. Considering that many individuals fail to respond to currently available antidepressant drugs, there is a need for antidepressants with novel mechanisms. Polymorphisms in the gene encoding FK506-binding protein 51 (FKBP51), a co-chaperone of the glucocorticoid receptor, have been linked to susceptibility to stress-related psychiatric disorders. Whether this protein can be targeted for their treatment remains largely unexplored. The aim of this work was to investigate whether inhibition of FKBP51 with SAFit2, a novel selective inhibitor, promotes hippocampal neuron outgrowth and neurogenesis in vitro and stress resilience in vivo in a mouse model of chronic psychosocial stress. Primary hippocampal neuronal cultures or hippocampal neural progenitor cells (NPCs) were treated with SAFit2 and neuronal differentiation and cell proliferation were analyzed. Male C57BL/6 mice were administered SAFit2 while concurrently undergoing a chronic stress paradigm comprising of intermittent social defeat and overcrowding, and anxiety and depressive -related behaviors were evaluated. SAFit2 increased neurite outgrowth and number of branch points to a greater extent than brain derived neurotrophic factor (BDNF) in primary hippocampal neuronal cultures. SAFit2 increased hippocampal NPC neurogenesis and increased neurite complexity and length of these differentiated neurons. In vivo, chronic SAFit2 administration prevented stress-induced social avoidance, decreased anxiety in the novelty-induced hypophagia test, and prevented stress-induced anxiety in the open field but did not alter adult hippocampal neurogenesis in stressed animals. These data warrant further exploration of inhibition of FKBP51 as a strategy to treat stress-related disorders.

Sleep and the gut microbiota in preschool-aged children.

Sleep plays a significant role in the mental and physical development of children. Emerging evidence in animals and human adults indicates a relationship between sleep and the gut microbiota; however, it is unclear whether the sleep of preschoolers during a key developmental period, associates with features of their gut microbiota. The objective of this study was to assess the relationship between sleep and gut microbiota in preschool-aged children (4.37 ± 0.48 years, n = 143). Sleep measures included total night-time sleep (TST), sleep efficiency (SE), and wake-time after sleep onset (WASO) assessed using actigraphy. Beta-diversity differences between children with low and high TST (p = .048) suggest gut microbiota community differences. Particularly, relative abundance of Bifidobacterium was higher in the high TST group and Bacteroides, was higher in children who had greater SE and less WASO (LDA score >2). In contrast, some Lachnospiraceae members including Blautia and Coprococcus 1 were associated with shorter night-time sleep duration and less efficiency, respectively. We also found a group of fecal metabolites, including specific neuroactive compounds and immunomodulating metabolites were associated with greater sleep efficiency and less time awake at night. Notably, tryptophan and its metabolizing products were higher in children who had higher SE or lower WASO (LDA score >2); concentration of propionate was higher in children with less WASO (p = .036). Overall, our results reveal a novel association between sleep and gut microbiota in preschool-aged children. Longer night-time sleep and greater sleep efficiency were associated with specific commensal bacteria that may regulate sleep through modulating neurotransmitter metabolism and the immune system.

Associations Between the Gut Microbiota and Internalizing Behaviors in Preschool Children.

OBJECTIVE: Emerging evidence points toward a connection between mental health and the gut microbiota and its metabolites (e.g., short-chain fatty acids). It is unknown whether the gut microbiota is associated with the development of mental health problems (e.g., internalizing or externalizing behaviors) in preschool children. The objective of this study was to evaluate associations between the gut microbiota and internalizing and externalizing behaviors in preschool-aged children. METHODS: A community sample of 248 typically developing children (3-5 years of age) provided a stool sample for gut microbiota and SCFA analysis. Parents reported child internalizing and externalizing behaviors using the Child Behavior Checklist. Associations between child behaviors and gut microbiota measures were analyzed using Spearman correlations followed by an adjustment for multiple testing, with subanalysis conducted in children clinically "at risk" for behavioral problems compared with those who were not. RESULTS: There was a correlation between Shannon alpha diversity with internalizing behaviors (rs = -0.134, p = .035) and its subscale somatic complaints (rs = -0.144, p = .023). In addition, children clinically "at risk" for internalizing problems had decreased alpha diversity (U = 551, p = .017). Internalizing behaviors correlated with valerate and isobutyrate (rs = -0.147, p = .021; rs = -0.140, p = .028, respectively). Furthermore the somatic complaints subscale additionally correlated with acetate and butyrate (rs = -0.219, p = .001; rs = -0.241, p < .001, respectively). These findings were also present in children "at risk" for internalizing problems (U = 569, p = .026; U = 571, p = .028) and somatic complaints (U = 164, p = .004; U = 145, p = .001). CONCLUSIONS: These analyses reveal novel associations between internalizing behaviors and the gut microbiota in preschool children. Furthermore, a relationship between somatic complaints and acetate and butyrate was identified, indicating that interventions that increase SCFA production warrant future investigation.

Kefir ameliorates specific microbiota-gut-brain axis impairments in a mouse model relevant to autism spectrum disorder.

Autism spectrum disorder (ASD) is one of the most severe developmental disorders, affecting on average 1 in 150 children worldwide. There is a great need for more effective strategies to improve quality of life in ASD subjects. The gut microbiome has emerged as a potential therapeutic target in ASD. A novel modulator of the gut microbiome, the traditionally fermented milk drink kefir, has recently been shown to modulate the microbiota and decrease repetitive behaviour, one of the hallmarks of ASD, in mice. As such, we hypothesized that kefir could ameliorate behavioural deficits in a mouse model relevant to ASD; the BTBR T+ Itpr3tf/J mouse strain. To this end, adult mice were administered either kefir (UK4) or a milk control for three weeks as treatment lead-in, after which they were assessed for their behavioural phenotype using a battery of tests. In addition, we assessed systemic immunity by flow cytometry and the gut microbiome using shotgun metagenomic sequencing. We found that indeed kefir decreased repetitive behaviour in this mouse model. Furthermore, kefir prolonged stress-induced increases in corticosterone 60 min post-stress, which was accompanied by an ameliorated innate immune response as measured by LY6Chi monocyte levels. In addition, kefir increased the levels of anti-inflammatory Treg cells in mesenteric lymph nodes (MLNs). Kefir also increased the relative abundance of Lachnospiraceae bacterium A2, which correlated with reduced repetitive behaviour and increased Treg cells in MLNs. Functionally, kefir modulated various predicted gut microbial pathways, including the gut-brain module S-Adenosylmethionine (SAM) synthesis, as well as L-valine biosynthesis and pyruvate fermentation to isobutanol, which all correlated with repetitive behaviour. Taken together our data show that kefir modulates peripheral immunoregulation, can ameliorate specific ASD behavioural dysfunctions and modulates selective aspects of the composition and function of the gut microbiome, indicating that kefir supplementation might prove a viable strategy in improving quality of life in ASD subjects.

Protocol for the Pregnancy During the COVID-19 Pandemic (PdP) Study: A Longitudinal Cohort Study of Mental Health Among Pregnant Canadians During the COVID-19 Pandemic and Developmental Outcomes in Their Children.

BACKGROUND: The COVID-19 pandemic and countermeasures implemented by governments around the world have led to dramatically increased symptoms of depression and anxiety. Pregnant individuals may be particularly vulnerable to the negative psychological effects of COVID-19 public health measures because they represent a demographic that is most affected by disasters and because pregnancy itself entails significant life changes that require major psychosocial and emotional adjustments. OBJECTIVE: The PdP study was designed to investigate the associations among exposure to objective hardship caused by the pandemic, perceived stress and psychological distress in pregnant individuals, and developmental outcomes in their offspring. METHODS: The PdP study comprises a prospective longitudinal cohort of individuals who were pregnant at enrollment, with repeated follow-ups during pregnancy and the postpartum period. Participants were eligible if they were pregnant, ≥17 years old, at ≤35 weeks of gestation at study enrollment, living in Canada, and able to read and write in English or French. At enrollment, participants completed an initial survey that assessed demographic and socioeconomic characteristics, previous pregnancies and births, prepregnancy health, health conditions during pregnancy, medications, psychological distress, social support, and hardships experienced because of the COVID-19 pandemic (eg, lost employment or a loved one dying). For the first three months following the initial survey, participants received a monthly email link to complete a follow-up survey that asked about their experiences since the previous survey. After three months, follow-up surveys were sent every other month to reduce participant burden. For each of these surveys, participants were first asked if they were still pregnant and then routed either to the next prenatal survey or to the delivery survey. In the postpartum period, surveys were sent at 3, 6, and 12 months of infant age to assess maternal stress, psychological distress, and infant development. RESULTS: Participant recruitment via social media (Facebook and Instagram) began on April 5, 2020, and is ongoing. As of April 2021, more than 11,000 individuals have started the initial survey. Follow-up data collection is ongoing. CONCLUSIONS: This longitudinal investigation seeks to elucidate the associations among hardships, maternal psychological distress, child development during the COVID-19 pandemic, and risk and resilience factors that amplify or ameliorate these associations. The findings of this study are intended to generate knowledge about the psychological consequences of pandemics on pregnant individuals and point toward prevention and intervention targets. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/25407.

Acute stress increases monocyte levels and modulates receptor expression in healthy females.

There has been a growing recognition of the involvement of the immune system in stress-related disorders. Acute stress leads to the activation of neuroendocrine systems, which in turn orchestrate a large-scale redistribution of innate immune cells, such as monocytes. Even though acute stress/monocyte interactions have been well-characterized in mice, this is not the case for humans. As such, this study aimed to investigate whether acute stress modulates blood monocyte levels in a subtype-dependent manner and whether the receptor expression of stress-related receptors is affected in humans. Blood was collected from healthy female volunteers at baseline and 1 h after the socially evaluated cold pressor test, after which blood monocyte levels and receptor expression were assessed by flow cytometry. Our results reveal a stress-induced increase in blood monocyte levels, which was independent of monocyte subtypes. Furthermore, colony stimulating factor 1 receptor (CSF-1R) and CD29 receptor expression was increased, while CD62L showed a trend towards increased expression. These results provide novel insights into how acute stress affects the innate immune system.

Bifidobacterium longum counters the effects of obesity: Partial successful translation from rodent to human.

BACKGROUND: The human gut microbiota has emerged as a key factor in the development of obesity. Certain probiotic strains have shown anti-obesity effects. The objective of this study was to investigate whether Bifidobacterium longum APC1472 has anti-obesity effects in high-fat diet (HFD)-induced obese mice and whether B. longum APC1472 supplementation reduces body-mass index (BMI) in healthy overweight/obese individuals as the primary outcome. B. longum APC1472 effects on waist-to-hip ratio (W/H ratio) and on obesity-associated plasma biomarkers were analysed as secondary outcomes. METHODS: B. longum APC1472 was administered to HFD-fed C57BL/6 mice in drinking water for 16 weeks. In the human intervention trial, participants received B. longum APC1472 or placebo supplementation for 12 weeks, during which primary and secondary outcomes were measured at the beginning and end of the intervention. FINDINGS: B. longum APC1472 supplementation was associated with decreased bodyweight, fat depots accumulation and increased glucose tolerance in HFD-fed mice. While, in healthy overweight/obese adults, the supplementation of B. longum APC1472 strain did not change primary outcomes of BMI (0.03, 95% CI [-0.4, 0.3]) or W/H ratio (0.003, 95% CI [-0.01, 0.01]), a positive effect on the secondary outcome of fasting blood glucose levels was found (-0.299, 95% CI [-0.44, -0.09]). INTERPRETATION: This study shows a positive translational effect of B. longum APC1472 on fasting blood glucose from a preclinical mouse model of obesity to a human intervention study in otherwise healthy overweight and obese individuals. This highlights the promising potential of B. longum APC1472 to be developed as a valuable supplement in reducing specific markers of obesity. FUNDING: This research was funded in part by Science Foundation Ireland in the form of a Research Centre grant (SFI/12/RC/2273) to APC Microbiome Ireland and by a research grant from Cremo S.A.

Strain differences in behaviour and immunity in aged mice: Relevance to Autism.

The BTBR mouse model has been shown to be associated with deficits in social interaction and a pronounced engagement in repetitive behaviours. Autism spectrum disorder (ASD) is the most prevalent neurodevelopmental condition globally. Despite its ubiquity, most research into the disorder remains focused on childhood, with studies in adulthood and old age relatively rare. To this end, we explored the differences in behaviour and immune function in an aged BTBR T + Itpr3tf/J mouse model of the disease compared to a similarly aged C57bl/6 control. We show that while many of the alterations in behaviour that are observed in young animals are maintained (repetitive behaviours, antidepressant-sensitive behaviours, social deficits & cognition) there are more nuanced effects in terms of anxiety in older animals of the BTBR strain compared to C57bl/6 controls. Furthermore, BTBR animals also exhibit an activated T-cell system. As such, these results represent confirmation that ASD-associated behavioural deficits are maintained in ageing, and that that there may be need for differential interventional approaches to counter these impairments, potentially through targeting the immune system.

A specific dietary fibre supplementation improves cognitive performance-an exploratory randomised, placebo-controlled, crossover study.

RATIONALE: The impact of the microbiota on the gut-brain axis is increasingly appreciated. A growing body of literature demonstrates that use of dietary fibre and prebiotics can manipulate the microbiota and affect host health. However, the influence on cognition and acute stress response is less well understood. OBJECTIVES: The objective of this study was to investigate the efficacy of a dietary fibre, polydextrose (PDX), in improving cognitive performance and acute stress responses through manipulation of the gut microbiota in a healthy population. METHODS: In this double-blind, randomised, placebo-controlled, crossover design study, 18 healthy female participants received 12.5 g Litesse®Ultra (> 90% PDX polymer) or maltodextrin for 4 weeks. Cognitive performance, mood, acute stress responses, microbiota composition, and inflammatory markers were assessed pre- and post-intervention. RESULTS: PDX improved cognitive flexibility as evidenced by the decrease in the number of errors made in the Intra-Extra Dimensional Set Shift (IED) task. A better performance in sustained attention was observed through higher number of correct responses and rejections in the Rapid Visual Information Processing (RVP) task. Although there was no change in microbial diversity, abundance of Ruminiclostridium 5 significantly increased after PDX supplementation compared with placebo. PDX supplementation attenuated the increase of adhesion receptor CD62L on classical monocytes observed in the placebo group. CONCLUSIONS: Supplementation with the PDX resulted in a modest improvement in cognitive performance. The results indicate that PDX could benefit gut-to-brain communication and modulate behavioural responses.

Microbiota from young mice counteracts selective age-associated behavioral deficits.

The gut microbiota is increasingly recognized as an important regulator of host immunity and brain health. The aging process yields dramatic alterations in the microbiota, which is linked to poorer health and frailty in elderly populations. However, there is limited evidence for a mechanistic role of the gut microbiota in brain health and neuroimmunity during aging processes. Therefore, we conducted fecal microbiota transplantation from either young (3-4 months) or old (19-20 months) donor mice into aged recipient mice (19-20 months). Transplant of a microbiota from young donors reversed aging-associated differences in peripheral and brain immunity, as well as the hippocampal metabolome and transcriptome of aging recipient mice. Finally, the young donor-derived microbiota attenuated selective age-associated impairments in cognitive behavior when transplanted into an aged host. Our results reveal that the microbiome may be a suitable therapeutic target to promote healthy aging.

Volatility as a Concept to Understand the Impact of Stress on the Microbiome.

The microbiome-gut-brain-axis is a complex phenomenon spanning several dynamic systems in the body which can be parsed at a molecular, cellular, physiological and ecological level. A growing body of evidence indicates that this axis is particularly sensitive to the effects of stress and that it may be relevant to stress resilience and susceptibility. Although stress-induced changes in the composition of the microbiome have been reported, the degree of compositional change over time, which we define as volatility, has not been the subject of in-depth scrutiny. Using a chronic psychosocial stress paradigm in male mice, we report that the volatility of the microbiome significantly correlated with several readouts of the stress response, including behaviour and corticosterone response. We then validated these findings in a second independent group of stressed mice. Additionally, we assessed the relationship between volatility and stress parameters in a cohort of health volunteers who were undergoing academic exams and report similar observations. Finally, we found inter-species similarities in the microbiome stress response on a functional level. Our research highlights the effects of stress on the dynamic microbiome and underscores the informative value of volatility as a parameter that should be considered in all future analyses of the microbiome.