• Bifidobacterium breve with α-Linolenic Acid and Linoleic Acid Alters Fatty Acid Metabolism in the Maternal Separation Model of Irritable Bowel Syndrome

      Barrett, Eoin; Fitzgerald, Patrick; Dinan, Timothy G.; Cryan, John F.; Ross, R Paul; Quigley, Eamonn M.; Shanahan, Fergus; Kiely, Barry; Fitzgerald, Gerald F; O'Toole, Paul W.; et al. (PLOS, 20/11/2012)
      The aim of this study was to compare the impact of dietary supplementation with a Bifidobacterium breve strain together with linoleic acid & α-linolenic acid, for 7 weeks, on colonic sensitivity and fatty acid metabolism in rats. Maternally separated and non-maternally separated Sprague Dawley rats (n = 15) were orally gavaged with either B. breve DPC6330 (109 microorganisms/day) alone or in combination with 0.5% (w/w) linoleic acid & 0.5% (w/w) α-linolenic acid, daily for 7 weeks and compared with trehalose and bovine serum albumin. Tissue fatty acid composition was assessed by gas-liquid chromatography and visceral hypersensitivity was assessed by colorectal distension. Significant differences in the fatty acid profiles of the non-separated controls and maternally separated controls were observed for α-linolenic acid and arachidonic acid in the liver, oleic acid and eicosenoic acid (c11) in adipose tissue, and for palmitoleic acid and docosahexaenoic acid in serum (p<0.05). Administration of B. breve DPC6330 to MS rats significantly increased palmitoleic acid, arachidonic acid and docosahexaenoic acid in the liver, eicosenoic acid (c11) in adipose tissue and palmitoleic acid in the prefrontal cortex (p<0.05), whereas feeding B. breve DPC6330 to non separated rats significantly increased eicosapentaenoic acid and docosapentaenoic acid in serum (p<0.05) compared with the NS un-supplemented controls. Administration of B. breve DPC6330 in combination with linoleic acid and α-linolenic acid to maternally separated rats significantly increased docosapentaenoic acid in the serum (p<0.01) and α-linolenic acid in adipose tissue (p<0.001), whereas feeding B. breve DPC6330 with fatty acid supplementation to non-separated rats significantly increased liver and serum docosapentaenoic acid (p<0.05), and α-linolenic acid in adipose tissue (p<0.001). B. breve DPC6330 influenced host fatty acid metabolism. Administration of B. breve DPC6330 to maternally separated rats significantly modified the palmitoleic acid, arachidonic acid and docosahexaenoic acid contents in tissues. The effect was not observed in non-separated animals.
    • Collective unconscious: How gut microbes shape human behavior

      Dinan, Timothy G.; Stilling, Roman M.; STANTON, CATHERINE; Cryan, John F.; Science Foundation Ireland; Health Research Board of Ireland; European Community's Seventh Framework Programme; SFI/12/RC/2273; HRA_POR/2011/23; HRA_POR/2012/32; et al. (Elsevier, 2015-03-03)
      The human gut harbors a dynamic and complex microbial ecosystem, consisting of approximately 1 kg of bacteria in the average adult, approximately the weight of the human brain. The evolutionary formation of a complex gut microbiota in mammals has played an important role in enabling brain development and perhaps sophisticated social interaction. Genes within the human gut microbiota, termed the microbiome, significantly outnumber human genes in the body, and are capable of producing a myriad of neuroactive compounds. Gut microbes are part of the unconscious system regulating behavior. Recent investigations indicate that these microbes majorly impact on cognitive function and fundamental behavior patterns, such as social interaction and stress management. In the absence of microbes, underlying neurochemistry is profoundly altered. Studies of gut microbes may play an important role in advancing understanding of disorders of cognitive functioning and social interaction, such as autism.
    • Collective unconscious: How gut microbes shape human behavior

      Dinan, Timothy G.; Stilling, Roman M.; STANTON, CATHERINE; Cryan, John F.; Science Foundation Ireland; Health Research Board; European Union; SFI/12/RC/2273; HRA_POR/2011/23; HRA_POR/2012/32; et al. (Elsevier, 2015-03-03)
      The human gut harbors a dynamic and complex microbial ecosystem, consisting of approximately 1 kg of bacteria in the average adult, approximately the weight of the human brain. The evolutionary formation of a complex gut microbiota in mammals has played an important role in enabling brain development and perhaps sophisticated social interaction. Genes within the human gut microbiota, termed the microbiome, significantly outnumber human genes in the body, and are capable of producing a myriad of neuroactive compounds. Gut microbes are part of the unconscious system regulating behavior. Recent investigations indicate that these microbes majorly impact on cognitive function and fundamental behavior patterns, such as social interaction and stress management. In the absence of microbes, underlying neurochemistry is profoundly altered. Studies of gut microbes may play an important role in advancing understanding of disorders of cognitive functioning and social interaction, such as autism.
    • Collective unconscious: How gut microbes shape human behavior

      Dinan, Timothy G.; Stilling, Roman M.; STANTON, CATHERINE; Cryan, John F.; Science Foundation Ireland; Health Research Board of Ireland; European Union; SFI/12/RC/2273; HRA_POR/2011/23; HRA_POR/2012/32 (Elsevier BV, 2015-04)
      The human gut harbors a dynamic and complex microbial ecosystem, consisting of approximately 1 kg of bacteria in the average adult, approximately the weight of the human brain. The evolutionary formation of a complex gut microbiota in mammals has played an important role in enabling brain development and perhaps sophisticated social interaction. Genes within the human gut microbiota, termed the microbiome, significantly outnumber human genes in the body, and are capable of producing a myriad of neuroactive compounds. Gut microbes are part of the unconscious system regulating behavior. Recent investigations indicate that these microbes majorly impact on cognitive function and fundamental behavior patterns, such as social interaction and stress management. In the absence of microbes, underlying neurochemistry is profoundly altered. Studies of gut microbes may play an important role in advancing understanding of disorders of cognitive functioning and social interaction, such as autism.
    • Food for thought: The role of nutrition in the microbiota-gut–brain axis

      Oriach, Clara Seira; Robertson, Ruairi C.; STANTON, CATHERINE; Cryan, John F.; Dinan, Timothy G.; Science Foundation Ireland; Health Research Board of Ireland; Sea Change Strategy, NutraMara programme; Department of Agriculture, Food and the Marine; SFI/12/RC/2273; et al. (Elsevier, 2016-01-21)
      Recent research has provided strong evidence for the role of the commensal gut microbiota in brain function and behaviour. Many potential pathways are involved in this bidirectional communication between the gut microbiota and the brain such as immune mechanisms, the vagus nerve and microbial neurometabolite production. Dysbiosis of gut microbial function has been associated with behavioural and neurophysical deficits, therefore research focused on developing novel therapeutic strategies to treat psychiatric disorders by targeting the gut microbiota is rapidly growing. Numerous factors can influence the gut microbiota composition such as health status, mode of birth delivery and genetics, but diet is considered among the most crucial factors impacting on the human gut microbiota from infancy to old age. Thus, dietary interventions may have the potential to modulate psychiatric symptoms associated with gut–brain axis dysfunction. Further clinical and in vivo studies are needed to better understand the mechanisms underlying the link between nutrition, gut microbiota and control of behaviour and mental health.
    • Food for thought: The role of nutrition in the microbiota-gut–brain axis

      Oriach, Clara Seira; Robertson, Ruairi C.; STANTON, CATHERINE; Cryan, John F.; Dinan, Timothy G.; Science Foundation Ireland; Health Research Board of Ireland; Sea Change Strategy; NutraMara programme; SMART FOOD project; et al. (Elsevier BV, 2016-04)
      Recent research has provided strong evidence for the role of the commensal gut microbiota in brain function and behaviour. Many potential pathways are involved in this bidirectional communication between the gut microbiota and the brain such as immune mechanisms, the vagus nerve and microbial neurometabolite production. Dysbiosis of gut microbial function has been associated with behavioural and neurophysical deficits, therefore research focused on developing novel therapeutic strategies to treat psychiatric disorders by targeting the gut microbiota is rapidly growing. Numerous factors can influence the gut microbiota composition such as health status, mode of birth delivery and genetics, but diet is considered among the most crucial factors impacting on the human gut microbiota from infancy to old age. Thus, dietary interventions may have the potential to modulate psychiatric symptoms associated with gut–brain axis dysfunction. Further clinical and in vivo studies are needed to better understand the mechanisms underlying the link between nutrition, gut microbiota and control of behaviour and mental health.
    • Food for thought: The role of nutrition in the microbiota-gut–brain axis

      Oriach, Clara Seira; Robertson, Ruairi C; STANTON, CATHERINE; Cryan, John F.; Dinan, Timothy G.; Science Foundation Ireland; Health Research Board of Ireland; Sea Change Strategy NutraMara programme; SMART FOOD project; Department of Agriculture, Food and the Marine; et al. (Elsevier, 2016-01-21)
      Recent research has provided strong evidence for the role of the commensal gut microbiota in brain function and behaviour. Many potential pathways are involved in this bidirectional communication between the gut microbiota and the brain such as immune mechanisms, the vagus nerve and microbial neurometabolite production. Dysbiosis of gut microbial function has been associated with behavioural and neurophysical deficits, therefore research focused on developing novel therapeutic strategies to treat psychiatric disorders by targeting the gut microbiota is rapidly growing. Numerous factors can influence the gut microbiota composition such as health status, mode of birth delivery and genetics, but diet is considered among the most crucial factors impacting on the human gut microbiota from infancy to old age. Thus, dietary interventions may have the potential to modulate psychiatric symptoms associated with gut–brain axis dysfunction. Further clinical and in vivo studies are needed to better understand the mechanisms underlying the link between nutrition, gut microbiota and control of behaviour and mental health.
    • Influence of GABA and GABA-producing Lactobacillus brevis DPC 6108 on the development of diabetes in a streptozotocin rat model

      Marques, T. M.; Patterson, E.; Wall, Rebecca; O'Sullivan, Orla; Fitzgerald, Gerald F; Cotter, Paul D.; Dinan, Timothy G.; Cryan, John F.; Ross, R Paul; STANTON, CATHERINE; et al. (Wageningen Academic Publishers, 26/05/2016)
      The aim of this study was to investigate if dietary administration of γ-aminobutyric acid (GABA)-producing Lactobacillus brevis DPC 6108 and pure GABA exert protective effects against the development of diabetes in streptozotocin (STZ)-induced diabetic Sprague Dawley rats. In a first experiment, healthy rats were divided in 3 groups (n=10/group) receiving placebo, 2.6 mg/kg body weight (bw) pure GABA or L. brevis DPC 6108 (~109microorganisms). In a second experiment, rats (n=15/group) were randomised to five groups and four of these received an injection of STZ to induce type 1 diabetes. Diabetic and non-diabetic controls received placebo [4% (w/v) yeast extract in dH2O], while the other three diabetic groups received one of the following dietary supplements: 2.6 mg/kg bw GABA (low GABA), 200 mg/kg bw GABA (high GABA) or ~109 L. brevis DPC 6108. L. brevis DPC 6108 supplementation was associated with increased serum insulin levels (P<0.05), but did not alter other metabolic markers in healthy rats. Diabetes induced by STZ injection decreased body weight (P<0.05), increased intestinal length (P<0.05) and stimulated water and food intake. Insulin was decreased (P<0.05), whereas glucose was increased (P<0.001) in all diabetic groups, compared with non-diabetic controls. A decrease (P<0.01) in glucose levels was observed in diabetic rats receiving L. brevis DPC 6108, compared with diabetic-controls. Both the composition and diversity of the intestinal microbiota were affected by diabetes. Microbial diversity in diabetic rats supplemented with low GABA was not reduced (P>0.05), compared with non-diabetic controls while all other diabetic groups displayed reduced diversity (P<0.05). L. brevis DPC 6108 attenuated hyperglycaemia induced by diabetes but additional studies are needed to understand the mechanisms involved in this reduction.
    • Marked elevations in pro-inflammatory polyunsaturated fatty acid metabolites in females with irritable bowel syndrome

      Clarke, Gerard; Fitzgerald, Peter; Hennessy, Alan A.; Cassidy, Eugene M.; Quigley M., Eamonn M.; Ross, Paul; STANTON, CATHERINE; Cryan, John F.; Dinan, Timothy G. (Elsevier, 2021-01-04)
      Irritable bowel syndrome (IBS) is the most common functional gastrointestinal disorder referred to gastroenterologists. Although the pathophysiology remains unclear, accumulating evidence points to the presence of low-level immune activation both in the gut and systemically. Circulating polyunsaturated fatty acids (PUFA) have recently attracted attention as being altered in a variety of disease states. Arachidonic acid (AA), in particular, has been implicated in the development of a pro-inflammatory profile in a number of immune-related disorders. AA is the precursor of a number of important immunomodulatory eicosanoids, including prostaglandin E2 (PGE2) and leukotriene B4 (LTB4). We investigated the hypothesis that elevated plasma AA concentrations in plasma contribute to the proposed pro-inflammatory profile in IBS. Plasma AA and related PUFA were quantified by gas chromatography analysis in IBS patients and controls. Both PGE2 and LTB4 were measured in serum using commercially available ELISA assays. AA concentrations were elevated in our patient cohort compared with healthy controls. Moreover, we demonstrated that this disturbance in plasma AA concentrations leads to downstream elevations in eicosanoids. Together, our data identifies a novel proinflammatory mechanism in irritable bowel syndrome and also suggests that elevated arachidonic acid levels in plasma may serve as putative biological markers in this condition.
    • Metabolome and microbiome profiling of a stress-sensitive rat model of gut-brain axis dysfunction

      Bassett, Shalome A.; Young, Wayne; Fraser, Karl; Dalziel, Julie E.; Webster, Jim; Ryan, Leigh; Fitzgerald, Patrick; Stanton, Catherine; Dinan, Timothy G.; Cryan, John F.; et al. (Springer Science and Business Media LLC, 2019-10-01)
      Stress negatively impacts gut and brain health. Individual diferences in response to stress have been linked to genetic and environmental factors and more recently, a role for the gut microbiota in the regulation of stress-related changes has been demonstrated. However, the mechanisms by which these factors infuence each other are poorly understood, and there are currently no established robust biomarkers of stress susceptibility. To determine the metabolic and microbial signatures underpinning physiological stress responses, we compared stress-sensitive Wistar Kyoto (WKY) rats to the normoanxious Sprague Dawley (SD) strain. Here we report that acute stress-induced strain-specifc changes in brain lipid metabolites were a prominent feature in WKY rats. The relative abundance of Lactococcus correlated with the relative proportions of many brain lipids. In contrast, plasma lipids were signifcantly elevated in response to stress in SD rats, but not in WKY rats. Supporting these fndings, we found that the greatest diference between the SD and WKY microbiomes were the predicted relative abundance of microbial genes involved in lipid and energy metabolism. Our results provide potential insights for developing novel biomarkers of stress vulnerability, some of which appear genotype specifc.
    • Microbiota and Neurodevelopmental Trajectories: Role of Maternal and Early-Life Nutrition

      Codagnone, Martin G.; STANTON, CATHERINE; O'Mahony, Siobhain M.; Dinan, Timothy G.; Cryan, John F.; Science Foundation Ireland; European Union; Nestlé Nutrition Institute; 754535; 12/RC/2273 (S. Karger AG, 2019-06-24)
      Pregnancy and early life are characterized by marked changes in body microbial composition. Intriguingly, these changes take place simultaneously with neurodevelopmental plasticity, suggesting a complex dialogue between the microbes that inhabit the gastrointestinal tract and the brain. The purpose of this chapter is to describe the natural trajectory of microbiota during pregnancy and early life, as well as review the literature available on its interaction with neurodevelopment. Several lines of evidence show that the gut microbiota interacts with diet, drugs and stress both prenatally and postnatally. Clinical and preclinical studies are illuminating how these disruptions result in different developmental outcomes. Understanding the role of the microbiota in neurodevelopment may lead to novel approaches to the study of the pathophysiology and treatment of neuropsychiatric disorders.
    • Microbiota-related Changes in Bile Acid & Tryptophan Metabolism are Associated with Gastrointestinal Dysfunction in a Mouse Model of Autism

      Golubeva, Anna V.; Joyce, Susan A.; Moloney, Gerard; Burokas, Aurelijus; Sherwin, Eoin; Arboleya, Silvia; Flynn, Ian; Khochanskiy, Dmitry; Moya-Pérez, Angela; Peterson, Veronica; et al. (Elsevier, 2017-09-21)
      Autism spectrum disorder (ASD) is one of the most prevalent neurodevelopmental conditions worldwide. There is growing awareness that ASD is highly comorbid with gastrointestinal distress and altered intestinal microbiome, and that host-microbiome interactions may contribute to the disease symptoms. However, the paucity of knowledge on gut-brain axis signaling in autism constitutes an obstacle to the development of precision microbiota-based therapeutics in ASD. To this end, we explored the interactions between intestinal microbiota, gut physiology and social behavior in a BTBR T+ Itpr3tf/J mouse model of ASD. Here we show that a reduction in the relative abundance of very particular bacterial taxa in the BTBR gut – namely, bile-metabolizing Bifidobacterium and Blautia species, - is associated with deficient bile acid and tryptophan metabolism in the intestine, marked gastrointestinal dysfunction, as well as impaired social interactions in BTBR mice. Together these data support the concept of targeted manipulation of the gut microbiota for reversing gastrointestinal and behavioral symptomatology in ASD, and offer specific plausible targets in this endeavor.
    • Microbiota-related Changes in Bile Acid & Tryptophan Metabolism are Associated with Gastrointestinal Dysfunction in a Mouse Model of Autism

      Golubeva, Anna B.; Joyce, Susan; Moloney, Gerard; Burokas, Aurelijus; Sherwin, Eoin; Arboleya, Silvia; Flynn, Ian; Khochanskiy, Dmitry; Perez, Angela M.; Peterson, Veronica; et al. (15/09/2017)
      Autism spectrum disorder (ASD) is one of the most prevalent neurodevelopmental conditions worldwide. There is growing awareness that ASD is highly comorbid with gastrointestinal distress and altered intestinal microbiome, and that host-microbiome interactions may contribute to the disease symptoms. However, the paucity of knowledge on gut-brain axis signaling in autism constitutes an obstacle to the development of precision microbiota-based therapeutics in ASD. To this end, we explored the interactions between intestinal microbiota, gut physiology and social behavior in a BTBR T+ Itpr3tf/J mouse model of ASD. Here we show that a reduction in the relative abundance of very particular bacterial taxa in the BTBR gut – namely, bile-metabolizing Bifidobacterium and Blautia species, - is associated with deficient bile acid and tryptophan metabolism in the intestine, marked gastrointestinal dysfunction, as well as impaired social interactions in BTBR mice. Together these data support the concept of targeted manipulation of the gut microbiota for reversing gastrointestinal and behavioral symptomatology in ASD, and offer specific plausible targets in this endeavor.
    • N-3 Polyunsaturated Fatty Acids (PUFAs) Reverse the Impact of Early-Life Stress on the Gut Microbiota

      Pusceddu, Matteo M; El Aidy, Sahar; Crispie, Fiona; O'Sullivan, Orla; Cotter, Paul D.; STANTON, CATHERINE; Kelly, Philip; Cryan, John F.; Dinan, Timothy G.; Department of Agriculture, Food and the Marine; et al. (PLOS, 01/10/2015)
      Background Early life stress is a risk factor for many psychiatric disorders ranging from depression to anxiety. Stress, especially during early life, can induce dysbiosis in the gut microbiota, the key modulators of the bidirectional signalling pathways in the gut-brain axis that underline several neurodevelopmental and psychiatric disorders. Despite their critical role in the development and function of the central nervous system, the effect of n-3 polyunsaturated fatty acids (n-3 PUFAs) on the regulation of gut-microbiota in early-life stress has not been explored. Methods and Results Here, we show that long-term supplementation of eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA) (80% EPA, 20% DHA) n-3 PUFAs mixture could restore the disturbed gut-microbiota composition of maternally separated (MS) female rats. Sprague-Dawley female rats were subjected to an early-life stress, maternal separation procedure from postnatal days 2 to 12. Non-separated (NS) and MS rats were administered saline, EPA/DHA 0.4 g/kg/day or EPA/DHA 1 g/kg/day, respectively. Analysis of the gut microbiota in adult rats revealed that EPA/DHA changes composition in the MS, and to a lesser extent the NS rats, and was associated with attenuation of the corticosterone response to acute stress. Conclusions In conclusion, EPA/DHA intervention alters the gut microbiota composition of both neurodevelopmentally normal and early-life stressed animals. This study offers insights into the interaction between n-3 PUFAs and gut microbes, which may play an important role in advancing our understanding of disorders of mood and cognitive functioning, such as anxiety and depression.
    • Recombinant Incretin-Secreting Microbe Improves Metabolic Dysfunction in High-Fat Diet Fed Rodents

      Ryan, Paul M; Patterson, Elaine; Kent, Robert M.; Stack, Helena; O’Connor, Paula M.; Murphy, Kiera; Peterson, Veronica L.; Mandal, Rupasri; Wishart, David S.; Dinan, Timothy G.; et al. (Springer Nature, 2017-10-19)
      The gut hormone glucagon-like peptide (GLP)-1 and its analogues represent a new generation of anti-diabetic drugs, which have also demonstrated propensity to modulate host lipid metabolism. Despite this, drugs of this nature are currently limited to intramuscular administration routes due to intestinal degradation. The aim of this study was to design a recombinant microbial delivery vector for a GLP-1 analogue and assess the efficacy of the therapeutic in improving host glucose, lipid and cholesterol metabolism in diet induced obese rodents. Diet-induced obese animals received either Lactobacillus paracasei NFBC 338 transformed to express a long-acting analogue of GLP-1 or the isogenic control microbe which solely harbored the pNZ44 plasmid. Short-term GLP-1 microbe intervention in rats reduced serum low-density lipoprotein cholesterol, triglycerides and triglyceride-rich lipoprotein cholesterol substantially. Conversely, extended GLP-1 microbe intervention improved glucose-dependent insulin secretion, glucose metabolism and cholesterol metabolism, compared to the high-fat control group. Interestingly, the microbe significantly attenuated the adiposity associated with the model and altered the serum lipidome, independently of GLP-1 secretion. These data indicate that recombinant incretin-secreting microbes may offer a novel and safe means of managing cholesterol metabolism and diet induced dyslipidaemia, as well as insulin sensitivity in metabolic dysfunction.