Publications by authors named "Conall R Strain"

12 Publications

  • Page 1 of 1

The gut microbiome influences the bioavailability of olanzapine in rats.

EBioMedicine 2021 Apr 1;66:103307. Epub 2021 Apr 1.

APC Microbiome Ireland, University College Cork, Cork, Ireland; School of Pharmacy, University College Cork, Cavanagh Pharmacy Building, Cork, Ireland. Electronic address:

Background: The role of the gut microbiome in the biotransformation of drugs has recently come under scrutiny. It remains unclear whether the gut microbiome directly influences the extent of drug absorbed after oral administration and thus potentially alters clinical pharmacokinetics.

Methods: In this study, we evaluated whether changes in the gut microbiota of male Sprague Dawley rats, as a result of either antibiotic or probiotic administration, influenced the oral bioavailability of two commonly prescribed antipsychotics, olanzapine and risperidone.

Findings: The bioavailability of olanzapine, was significantly increased (1.8-fold) in rats that had undergone antibiotic-induced depletion of gut microbiota, whereas the bioavailability of risperidone was unchanged. There was no direct effect of microbiota depletion on the expression of major CYP450 enzymes involved in the metabolism of either drug. However, the expression of UGT1A3 in the duodenum was significantly downregulated. The reduction in faecal enzymatic activity, observed during and after antibiotic administration, did not alter the ex vivo metabolism of olanzapine or risperidone. The relative abundance of Alistipes significantly correlated with the AUC of olanzapine but not risperidone.

Interpretation: Alistipes may play a role in the observed alterations in olanzapine pharmacokinetics. The gut microbiome might be an important variable determining the systemic bioavailability of orally administered olanzapine. Additional research exploring the potential implication of the gut microbiota on the clinical pharmacokinetics of olanzapine in humans is warranted.

Funding: This research is supported by APC Microbiome Ireland, a research centre funded by Science Foundation Ireland (SFI), through the Irish Government's National Development Plan (grant no. 12/RC/2273 P2) and by Nature Research-Yakult (The Global Grants for Gut Health; Ref No. 626891).
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http://dx.doi.org/10.1016/j.ebiom.2021.103307DOI Listing
April 2021

GG soluble mediators ameliorate early life stress-induced visceral hypersensitivity and changes in spinal cord gene expression.

Neuronal Signal 2020 Dec 23;4(4):NS20200007. Epub 2020 Nov 23.

APC Microbiome Ireland, University College Cork, Cork, Ireland.

Visceral hypersensitivity is a hallmark of many functional and stress-related gastrointestinal disorders, and there is growing evidence that the gut microbiota may play a role in its pathophysiology. It has previously been shown that early life stress-induced visceral sensitivity is reduced by various probiotic strains of bacteria (including Lactobacillus rhamnosus GG (LGG)) alone or in combination with prebiotic fibres in rat models. However, the exact mechanisms underpinning such effects remain unresolved. Here, we investigated if soluble mediators derived from LGG can mimic the bacteria's effects on visceral hypersensitivity and the microbiota-gut-brain axis. Rats were exposed to maternal separation (MS) from postnatal days 2-12. From weaning onwards both non-separated (NS) and MS offspring were provided drinking water with or without supplementation of standardized preparations of the LGG soluble mediators (LSM). Our results show that MS led to increased visceral sensitivity and exaggerated corticosterone plasma levels following restraint stress in adulthood, and both of these effects were ameliorated through LSM supplementation. Differential regulation of various genes in the spinal cord of MS versus NS rats was observed, 41 of which were reversed by LSM supplementation. At the microbiota composition level MS led to changes in beta diversity and abundance of specific bacteria including , which were ameliorated by LSM. These findings support probiotic soluble mediators as potential interventions in the reduction of symptoms of visceral hypersensitivity.
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http://dx.doi.org/10.1042/NS20200007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7726314PMC
December 2020

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

Psychopharmacology (Berl) 2021 Jan 20;238(1):149-163. Epub 2020 Sep 20.

APC Microbiome Ireland, University College Cork, Cork, Ireland.

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.
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http://dx.doi.org/10.1007/s00213-020-05665-yDOI Listing
January 2021

Microbiome Transfer Partly Overrides Lack of IL-1RI Signaling to Alter Hepatic but not Adipose Tissue Phenotype and Lipid Handling following a High-Fat Diet Challenge.

Mol Nutr Food Res 2021 01 12;65(1):e2000202. Epub 2020 Jul 12.

Nutrigenomics Research Group and Institute of Food and Health, University College Dublin, Dublin, D04 V1W8, Republic of Ireland.

Scope: IL-1RI-mediated inflammatory signaling alters metabolic tissue responses to dietary challenges (e.g., high-fat diet [HFD]). Recent work suggests that metabolic phenotype is transferrable between mice in a shared living environment (i.e., co-housing) due to gut microbiome exchange. The authors examine whether the metabolic phenotype of IL-1RI mice fed HFD or low-fat diet (LFD) could be transferred to wild-type (WT) mice through gut microbiome exchange facilitated by co-housing.

Methods And Results: Male WT (C57BL/J6) and IL-1RI mice are fed HFD (45% kcal) or LFD (10% kcal) for 24 weeks and housed i) by genotype (single-housed) or ii) with members of the other genotype in a shared microbial environment (co-housed). The IL-1RI  gut microbiome is dominant to WT, meaning that co-housed WT mice adopted the IL-1RI microbiota profile. This is concomitant with greater body weight, hepatic lipid accumulation, adipocyte hypertrophy, and hyperinsulinemia in co-housed WT mice, compared to single-housed counterparts. These effects are most evident following HFD. Primary features of microbiome differences are Lachnospiraceae and Ruminococcaceae (known producers of SCFA).

Conclusion: Transfer of SCFA-producing microbiota from IL-1RI mice highlights a new connection between diet, inflammatory signaling, and the gut microbiome, an association that is dependent on the nature of the dietary fat challenge.
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http://dx.doi.org/10.1002/mnfr.202000202DOI Listing
January 2021

Prebiotics from Seaweeds: An Ocean of Opportunity?

Mar Drugs 2019 Jun 1;17(6). Epub 2019 Jun 1.

Teagasc Food Research Centre, Moorepark, Fermoy, Co. Cork, P61 C996, Ireland.

Seaweeds are an underexploited and potentially sustainable crop which offer a rich source of bioactive compounds, including novel complex polysaccharides, polyphenols, fatty acids, and carotenoids. The purported efficacies of these phytochemicals have led to potential functional food and nutraceutical applications which aim to protect against cardiometabolic and inflammatory risk factors associated with non-communicable diseases, such as obesity, type 2 diabetes, metabolic syndrome, cardiovascular disease, inflammatory bowel disease, and some cancers. Concurrent understanding that perturbations of gut microbial composition and metabolic function manifest throughout health and disease has led to dietary strategies, such as prebiotics, which exploit the diet-host-microbe paradigm to modulate the gut microbiota, such that host health is maintained or improved. The prebiotic definition was recently updated to "a substrate that is selectively utilised by host microorganisms conferring a health benefit", which, given that previous discussion regarding seaweed prebiotics has focused upon saccharolytic fermentation, an opportunity is presented to explore how non-complex polysaccharide components from seaweeds may be metabolised by host microbial populations to benefit host health. Thus, this review provides an innovative approach to consider how the gut microbiota may utilise seaweed phytochemicals, such as polyphenols, polyunsaturated fatty acids, and carotenoids, and provides an updated discussion regarding the catabolism of seaweed-derived complex polysaccharides with potential prebiotic activity. Additional in vitro screening studies and in vivo animal studies are needed to identify potential prebiotics from seaweeds, alongside untargeted metabolomics to decipher microbial-derived metabolites from seaweeds. Furthermore, controlled human intervention studies with health-related end points to elucidate prebiotic efficacy are required.
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http://dx.doi.org/10.3390/md17060327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627129PMC
June 2019

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

EBioMedicine 2019 Jun 18;44:618-638. Epub 2019 Mar 18.

Department of Physiology, School of Medicine, College of Medicine & Health, University College Cork, Cork, Ireland; APC Microbiome Ireland, University College Cork, Cork, Ireland. Electronic address:

Background: 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. FUND: Department of Physiology and APC Microbiome Ireland, University College Cork, Ireland.
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http://dx.doi.org/10.1016/j.ebiom.2019.03.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606895PMC
June 2019

Effects of a polysaccharide-rich extract derived from Irish-sourced Laminaria digitata on the composition and metabolic activity of the human gut microbiota using an in vitro colonic model.

Eur J Nutr 2020 Feb 25;59(1):309-325. Epub 2019 Feb 25.

Nutrition Innovation Centre for Food and Health (NICHE), Ulster University, Coleraine, BT52 1SA, UK.

Background: Brown seaweeds are known to be a rich source of fiber with the presence of several non-digestible polysaccharides including laminarin, fucoidan and alginate. These individual polysaccharides have previously been shown to favorably alter the gut microbiota composition and activity albeit the effect of the collective brown seaweed fiber component on the microbiota remains to be determined.

Methods: This study investigated the effect of a crude polysaccharide-rich extract obtained from Laminaria digitata (CE) and a depolymerized CE extract (DE) on the gut microbiota composition and metabolism using an in vitro fecal batch culture model though metagenomic compositional analysis using 16S rRNA FLX amplicon pyrosequencing and short-chain fatty acid (SCFA) analysis using GC-FID.

Results: Selective culture analysis showed no significant changes in cultured lactobacilli or bifidobacteria between the CE or DE and the cellulose-negative control at any time point measured (0, 5, 10, 24, 36, 48 h). Following metagenomic analysis, the CE and DE significantly altered the relative abundance of several families including Lachnospiraceae and genera including Streptococcus, Ruminococcus and Parabacteroides of human fecal bacterial populations in comparison to cellulose after 24 h. The concentrations of acetic acid, propionic acid, butyric acid and total SCFA were significantly higher for both the CE and DE compared to cellulose after 10, 24, 36 and 48 h fermentation (p < 0.05). Furthermore, the acetate:propionate ratio was significantly reduced (p < 0.05) for both CD and DE following 24, 36 and 48 h fermentation.

Conclusion: The microbiota-associated metabolic and compositional changes noted provide initial indication of putative beneficial health benefits of L. digitata in vitro; however, research is needed to clarify if L. digitata-derived fiber can favorably alter the gut microbiota and confer health benefits in vivo.
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http://dx.doi.org/10.1007/s00394-019-01909-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7000515PMC
February 2020

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

EBioMedicine 2018 Dec 13;38:191-205. Epub 2018 Nov 13.

Department of Physiology, School of Medicine, College of Medicine & Health, University College Cork, Cork, Ireland; APC Microbiome Ireland, University College Cork, Cork, Ireland. Electronic address:

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% O at nadir, 6 cycles.hour) for 8 h.day 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.

Funding: The Department of Physiology, and APC Microbiome Ireland, UCC.
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http://dx.doi.org/10.1016/j.ebiom.2018.11.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6306383PMC
December 2018

Differential effects of psychotropic drugs on microbiome composition and gastrointestinal function.

Psychopharmacology (Berl) 2019 May 28;236(5):1671-1685. Epub 2018 Aug 28.

APC Microbiome Ireland, University College Cork, Cork, Ireland.

Rationale: Growing evidence supports a role for the microbiota in regulating gut-brain interactions and, thus, psychiatric disorders. Despite substantial scientific efforts to delineate the mechanism of action of psychotropic medications at a central nervous system (CNS) level, there remains a critical lack of understanding on how these drugs might affect the microbiota and gut physiology.

Objectives: We investigated the antimicrobial activity of psychotropics against two bacterial strain residents in the human gut, Lactobacillus rhamnosus and Escherichia coli. In addition, we examined the impact of chronic treatment with these drugs on microbiota and intestinal parameters in the rat.

Results: In vitro fluoxetine and escitalopram showed differential antimicrobial effects. Lithium, valproate and aripiprazole administration significantly increased microbial species richness and diversity, while the other treatments were not significantly different from controls. At the genus level, several species belonging to Clostridium, Peptoclostridium, Intestinibacter and Christenellaceae were increased following treatment with lithium, valproate and aripiprazole when compared to the control group. Animals treated with escitalopram, venlafaxine, fluoxetine and aripiprazole exhibited an increased permeability in the ileum.

Conclusions: These data show that psychotropic medications differentially influence the composition of gut microbiota in vivo and that fluoxetine and escitalopram have specific antimicrobial activity in vitro. Interestingly, drugs that significantly altered gut microbial composition did not increase intestinal permeability, suggesting that the two factors are not causally linked. Overall, unravelling the impact of psychotropics on gastrointestinal and microbiota measures offers the potential to provide critical insight into the mechanism of action and side effects of these medications.
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http://dx.doi.org/10.1007/s00213-018-5006-5DOI Listing
May 2019

Maternal omega-3 fatty acids regulate offspring obesity through persistent modulation of gut microbiota.

Microbiome 2018 05 24;6(1):95. Epub 2018 May 24.

Laboratory for Lipid Medicine and Technology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Background: The early-life gut microbiota plays a critical role in host metabolism in later life. However, little is known about how the fatty acid profile of the maternal diet during gestation and lactation influences the development of the offspring gut microbiota and subsequent metabolic health outcomes.

Results: Here, using a unique transgenic model, we report that maternal endogenous n-3 polyunsaturated fatty acid (PUFA) production during gestation or lactation significantly reduces weight gain and markers of metabolic disruption in male murine offspring fed a high-fat diet. However, maternal fatty acid status appeared to have no significant effect on weight gain in female offspring. The metabolic phenotypes in male offspring appeared to be mediated by comprehensive restructuring of gut microbiota composition. Reduced maternal n-3 PUFA exposure led to significantly depleted Epsilonproteobacteria, Bacteroides, and Akkermansia and higher relative abundance of Clostridia. Interestingly, offspring metabolism and microbiota composition were more profoundly influenced by the maternal fatty acid profile during lactation than in utero. Furthermore, the maternal fatty acid profile appeared to have a long-lasting effect on offspring microbiota composition and function that persisted into adulthood after life-long high-fat diet feeding.

Conclusions: Our data provide novel evidence that weight gain and metabolic dysfunction in adulthood is mediated by maternal fatty acid status through long-lasting restructuring of the gut microbiota. These results have important implications for understanding the interaction between modern Western diets, metabolic health, and the intestinal microbiome.
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http://dx.doi.org/10.1186/s40168-018-0476-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5968592PMC
May 2018

The effect of consuming Palmaria palmata-enriched bread on inflammatory markers, antioxidant status, lipid profile and thyroid function in a randomised placebo-controlled intervention trial in healthy adults.

Eur J Nutr 2016 Aug 8;55(5):1951-62. Epub 2015 Aug 8.

Northern Ireland Centre for Food and Health, School of Biomedical Sciences, University of Ulster, Cromore Road, Coleraine, BT52 1SA, Northern Ireland, UK.

Purpose: Palmaria palmata (P. Palmata) is reported to contain anti-inflammatory and antioxidant compounds albeit no study has investigated these effects in humans.

Methods: A randomised parallel placebo-controlled human intervention study was carried out to investigate the effect of consuming P. Palmata (5 g/day) incorporated into a bread on serum markers of inflammation [C-reactive protein (CRP); cytokine analysis] with secondary analysis investigating changes in lipids (cholesterol, triglycerides), thyroid function [thyroid-stimulating hormone (TSH)] and antioxidant status ferric reducing antioxidant power. ANCOVA with baseline values as covariates, controlling for age, BMI, sex and smoking status, was used to compare differences between treatment groups over time . In vitro studies investigated the inflammatory activity of P. Palmata extracts (hot water, cold water and ethanol extract), protein extracts and associated protein hydrolysates using a Caco-2 inflammation cell model.

Results: Consumption of P. Palmata-enriched bread significantly increased serum CRP (+16.1 %, P = 0.011), triglycerides (+31.9 %, P = 0.001) and TSH (+17.2 %, P = 0.017) when compared to the control group. In vitro evaluation of P. palmata extracts and protein hydrolysates identified a significant induction of IL-8 secretion by Caco-2 cells, and the hot water P. palmata extract was shown to increase adipocyte glycerol release (P < 0.05).

Conclusion: Evidence from this human study suggests that P. palmata stimulates inflammation, increases serum triglycerides and alters thyroid function; however, these changes are not likely to impact health as changes remained within the normal clinical range. The data from the in vitro study provided indications that IL-8 may contribute to the apparent immunostimulation noted in the human study.
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http://dx.doi.org/10.1007/s00394-015-1011-1DOI Listing
August 2016

Seaweed and human health.

Nutr Rev 2014 Mar;72(3):205-16

Seaweeds may have an important role in modulating chronic disease. Rich in unique bioactive compounds not present in terrestrial food sources, including different proteins (lectins, phycobiliproteins, peptides, and amino acids), polyphenols, and polysaccharides, seaweeds are a novel source of compounds with potential to be exploited in human health applications. Purported benefits include antiviral, anticancer, and anticoagulant properties as well as the ability to modulate gut health and risk factors for obesity and diabetes. Though the majority of studies have been performed in cell and animal models, there is evidence of the beneficial effect of seaweed and seaweed components on markers of human health and disease status. This review is the first to critically evaluate these human studies, aiming to draw attention to gaps in current knowledge, which will aid the planning and implementation of future studies.
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http://dx.doi.org/10.1111/nure.12091DOI Listing
March 2014