Adolescent dietary manipulations differentially affect gut microbiota composition and amygdala neuroimmune gene expression in male mice in adulthood

peer-reviewedAdolescence is a critical developmental period that is characterised by growth spurts and specific neurobiological, neuroimmune and behavioural changes. In tandem the gut microbiota, which is a key player in the regulation of health and disease, is shaped during this time period. Diet is one of the most important regulators of microbiota composition. Thus, we hypothesised that dietary disturbances of the microbiota during this critical time window result in long-lasting changes in immunity, brain and behaviour. C57BL/6 male mice were exposed to either high fat diet or cafeteria diet during the adolescent period from postnatal day 28 to 49 and were tested for anxiety-related and social behaviour in adulthood. Our results show long-lasting effects of dietary interventions during the adolescent period on microbiota composition and the expression of genes related to neuroinflammation or neurotransmission. Interestingly, changes in myelination-related gene expression in the prefrontal cortex following high fat diet exposure were also observed. However, these effects did not translate into overt behavioural changes in adulthood. Taken together, these data highlight the importance of diet-microbiota interactions during the adolescent period in shaping specific outputs of the microbiota-gut-brain axis in later life.Science Foundation Irelan

Prebiotic administration modulates gut microbiota and faecal short-chain fatty acid concentrations but does not prevent chronic intermittent hypoxia-induced apnoea and hypertension in adult rats

peer-reviewedBackground Evidence is accruing to suggest that microbiota-gut-brain signalling plays a regulatory role in cardiorespiratory physiology. Chronic intermittent hypoxia (CIH), modelling human sleep apnoea, affects gut microbiota composition and elicits cardiorespiratory morbidity. We investigated if treatment with prebiotics ameliorates cardiorespiratory dysfunction in CIH-exposed rats. Methods Adult male rats were exposed to CIH (96 cycles/day, 6.0% O2 at nadir) for 14 consecutive days with and without prebiotic supplementation (fructo- and galacto-oligosaccharides) beginning two weeks prior to gas exposures. Findings CIH increased apnoea index and caused hypertension. CIH exposure had modest effects on the gut microbiota, decreasing the relative abundance of Lactobacilli species, but had no effect on microbial functional characteristics. Faecal short-chain fatty acid (SCFA) concentrations, plasma and brainstem pro-inflammatory cytokine concentrations and brainstem neurochemistry were unaffected by exposure to CIH. Prebiotic administration modulated gut microbiota composition and diversity, altering gut-metabolic (GMMs) and gut-brain (GBMs) modules and increased faecal acetic and propionic acid concentrations, but did not prevent adverse CIH-induced cardiorespiratory phenotypes. Interpretation CIH-induced cardiorespiratory dysfunction is not dependant upon changes in microbial functional characteristics and decreased faecal SCFA concentrations. Prebiotic-related modulation of microbial function and resultant increases in faecal SCFAs were not sufficient to prevent CIH-induced apnoea and hypertension in our model. Our results do not exclude the potential for microbiota-gut-brain axis involvement in OSA-related cardiorespiratory morbidity, but they demonstrate that in a relatively mild model of CIH, sufficient to evoke classic cardiorespiratory dysfunction, such changes are not obligatory for the development of morbidity, but may become relevant in the elaboration and maintenance of cardiorespiratory morbidity with progressive disease. Funding Department of Physiology and APC Microbiome Ireland, University College Cork, Ireland. APC Microbiome Ireland is funded by Science Foundation Ireland, through the Government's National Development Plan

Protein quality and quantity influence the effect of dietary fat on weight gain and tissue partitioning via host-microbiota changes

ACKNOWLEDGMENTS This work was supported by a research grant from Science Foundation Ireland (SFI) under grant SFI/16/BBSRC/3389, BBSRC under grant number BB/ P009875/1 (to K.N.N. and J.R.S.), and in part by SFI and the Department of Agriculture, Food and Marine under grant 16/RC/3835 (to VistaMilk). We thank Conall Strain, David Mannion, and John Leech for contributing to the metabolomics analysis. We thank Alina Kondrashina for help with the Milliplex system.Peer reviewedPublisher PD

Altered stress responses in adults born by Caesarean section

peer-reviewedBirth by Caesarean-section (C-section), which increases the risk for metabolic and immune disorders, disrupts the normal initial microbial colonisation of the gut, in addition to preventing early priming of the stress and immune-systems.. Animal studies have shown there are enduring psychological processes in C-section born mice. However, the long-term impact of microbiota-gut-brain axis disruptions due to birth by C-section on psychological processes in humans is unknown. Forty age matched healthy young male university students born vaginally and 36 C-section delivered male students were recruited. Participants underwent an acute stressor, the Trier social stress test (TSST), during a term-time study visit. A subset of participants also completed a study visit during the university exam period, representing a naturalistic stressor. Participants completed a battery of cognitive tests and self-report measures assessing mood, anxiety, and perceived stress. Saliva, blood, and stool samples were collected for analysis of cortisol, peripheral immune profile, and the gut microbiota. Young adults born by C-section exhibit increased psychological vulnerability to acute stress and a prolonged period of exam-related stress. They did not exhibit an altered salivary cortisol awakening response to the TSST, but their measures of positive affect were significantly lower than controls throughout the procedure. Both C-section and vaginally-delivered participants performed equally well on cognitive assessments. Most of the initial effects of delivery mode on the gut microbiome did not persist into adulthood as the gut microbiota profile showed modest changes in composition in adult vaginally-delivered and C-sectioned delivered subjects. From an immune perspective, concentrations of IL-1β and 1L-10 were higher in C-section participants. These data confirm that there is a potential enduring effect of delivery mode on the psychological responses to acute stress during early adulthood. The mental health implications of these observations require further study regarding policies on C-section use

The microbe-heart-brain dialogue: Vagal activity is associated with gut-microbiome patterns in women

Introduction: A functional reciprocity between the gut microbiome and vagal nerve activity has been suggested, however, human studies addressing this phenomenon are limited. Methods: 24- hour cardiac vagal activity (CVA) was assessed from 73 female participants (aged 24.5±4.3 years). Additionally, stool samples were subjected to 16SrRNA gene analysis (V1–V2). Quantitative Insights Into Microbial Ecology (QIIME) was used to analyze microbiome data. Additionally, inflammatory parameters (such as CRP and IL-6) were derived from serum samples. Results: Daytime CVA correlated significantly with gut microbiota diversity (r=0.254, p=0.030), CRP (r=-0.348, p= 0.003), and IL-6 (r=-0.320, p=0.006). When the group was divided at the median of 24 hour CVA (Mdn=1.322), the following features were more abundant in the high CVA group: Clostridia (Linear discriminant analysis effect size (LDA)= 4.195, p= 0.029), Clostridiales (LDA=4.195, p= 0.029), Lachnospira (LDA=3.489, p=0.004), Ruminococcaceae (LDA=4.073, p=0.010), Faecalibacterium (LDA=3.982, p= 0.042), Lactobacillales (LDA=3.317, p=0.029), Bacilli (LDA=3.294, p=0.0350), Streptococcaceae (LDA=3.353, p= 0.006), Streptococcus (LDA=3.332, p=0.011). Based on Dirichlet multinomial mixtures two enterotypes could be detected, which differed significantly in CVA, age, BMI, CRP, IL-6 and diversity. Conclusions: As an indicator of gut-brain communication, gut microbiome analysis could be extended by measurements of CVA to enhance our understanding of signalling via microbiota-gut-brain-axis and its alterations through psychobiotics

Chronic intermittent hypoxia disrupts cardiorespiratory homeostasis and gut microbiota composition in adult male guinea-pigs

Background: Carotid body (peripheral oxygen sensor) sensitisation is pivotal in the development of chronic intermittent hypoxia (CIH)-induced hypertension. We sought to determine if exposure to CIH, modelling human sleep apnoea, adversely affects cardiorespiratory control in guinea-pigs, a species with hypoxia-insensitive carotid bodies. We reasoned that CIH-induced disruption of gut microbiota would evoke cardiorespiratory morbidity. Methods: Adult male guinea-pigs were exposed to CIH (6.5% O2 at nadir, 6 cycles.hour−1) for 8 h.day−1 for 12 consecutive days. Findings: CIH-exposed animals established reduced faecal microbiota species richness, with increased relative abundance of Bacteroidetes and reduced relative abundance of Firmicutes bacteria. Urinary corticosterone and noradrenaline levels were unchanged in CIH-exposed animals, but brainstem noradrenaline concentrations were lower compared with sham. Baseline ventilation was equivalent in CIH-exposed and sham animals; however, respiratory timing variability, sigh frequency and ventilation during hypoxic breathing were all lower in CIH-exposed animals. Baseline arterial blood pressure was unaffected by exposure to CIH, but β-adrenoceptor-dependent tachycardia and blunted bradycardia during phenylephrine-induced pressor responses was evident compared with sham controls. Interpretation: Increased carotid body chemo-afferent signalling appears obligatory for the development of CIH-induced hypertension and elevated chemoreflex control of breathing commonly reported in mammals, with hypoxia-sensitive carotid bodies. However, we reveal that exposure to modest CIH alters gut microbiota richness and composition, brainstem neurochemistry, and autonomic control of heart rate, independent of carotid body sensitisation, suggesting modulation of breathing and autonomic homeostasis via the microbiota-gut-brainstem axis. The findings have relevance to human sleep-disordered breathing

The microbiota drives diurnal rhythms in tryptophan metabolism in the stressed gut

Summary: Chronic stress disrupts microbiota-gut-brain axis function and is associated with altered tryptophan metabolism, impaired gut barrier function, and disrupted diurnal rhythms. However, little is known about the effects of acute stress on the gut and how it is influenced by diurnal physiology. Here, we used germ-free and antibiotic-depleted mice to understand how microbiota-dependent oscillations in tryptophan metabolism would alter gut barrier function at baseline and in response to an acute stressor. Cecal metabolomics identified tryptophan metabolism as most responsive to a 15-min acute stressor, while shotgun metagenomics revealed that most bacterial species exhibiting rhythmicity metabolize tryptophan. Our findings highlight that the gastrointestinal response to acute stress is dependent on the time of day and the microbiome, with a signature of stress-induced functional alterations in the ileum and altered tryptophan metabolism in the colon

Manipulation of gut microbiota blunts the ventilatory response to hypercapnia in adult rats

peer-reviewedBackground: It is increasingly evident that perturbations to the diversity and composition of the gut microbiota have significant consequences for the regulation of integrative physiological systems. There is growing interest in the potential contribution of microbiota-gut-brain signalling to cardiorespiratory control in health and disease. Methods: In adult male rats, we sought to determine the cardiorespiratory effects of manipulation of the gut microbiota following a 4-week administration of a cocktail of antibiotics. We subsequently explored the effects of administration of faecal microbiota from pooled control (vehicle) rat faeces, given by gavage to vehicle- and antibiotic-treated rats. Findings: Antibiotic intervention depressed the ventilatory response to hypercapnic stress in conscious animals, owing to a reduction in the respiratory frequency response to carbon dioxide. Baseline frequency, respiratory timing variability, and the expression of apnoeas and sighs were normal. Microbiota-depleted rats had decreased systolic blood pressure. Faecal microbiota transfer to vehicle- and antibiotic-treated animals also disrupted the gut microbiota composition, associated with depressed ventilatory responsiveness to hypercapnia. Chronic antibiotic intervention or faecal microbiota transfer both caused significant disruptions to brainstem monoamine neurochemistry, with increased homovanillic acid:dopamine ratio indicative of increased dopamine turnover, which correlated with the abundance of several bacteria of six different phyla. Interpretation: Chronic antibiotic administration and faecal microbiota transfer disrupt gut microbiota, brainstem monoamine concentrations and the ventilatory response to hypercapnia. We suggest that aberrant microbiota-gut-brain axis signalling has a modulatory influence on respiratory behaviour during hypercapnic stress