title: Prenatal stress-induced alterations in major physiological systems correlate with gut microbiota composition in adulthood.
abstract: Early-life adverse experiences, including prenatal stress (PNS), are associated with a higher prevalence of neurodevelopmental, cardiovascular and metabolic disorders in affected offspring. Here, in a rat model of chronic PNS, we investigate the impact of late gestational stress on physiological outcomes in adulthood. Sprague-Dawley pregnant dams were subjected to repeated restraint stress from embryonic day 14 to day 20, and their male offspring were assessed at 4 months of age. PNS induced an exaggeration of the hypothalamic-pituitary-adrenal (HPA) axis response to stress, as well as an elevation of blood pressure and impairment of cognitive function. Altered respiratory control was also observed, as demonstrated by increased variability in basal respiratory frequency and abnormal frequency responses to both hypoxic and hypercapnic challenges. PNS also affected gastrointestinal neurodevelopment and function, as measured by a decrease in the innervation density of distal colon and an increase in the colonic secretory response to catecholaminergic stimulation. Finally, PNS induced long lasting alterations in the intestinal microbiota composition. 16S rRNA gene 454 pyrosequencing revealed a strong trend towards decreased numbers of bacteria in the Lactobacillus genus, accompanied by elevated abundance of the Oscillibacter, Anaerotruncus and Peptococcus genera in PNS animals. Strikingly, relative abundance of distinct bacteria genera significantly correlated with certain respiratory parameters and the responsiveness of the HPA axis to stress. Together, these findings provide novel evidence that PNS induces long-term maladaptive alterations in the gastrointestinal and respiratory systems, accompanied by hyper-responsiveness to stress and alterations in the gut microbiota.
authors.affiliation: Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
authors.forename: Anna V
authors.initials: AV
authors.lastname: Golubeva
authors.affiliation: Department of Anatomy & Neuroscience, University College Cork, Cork, Ireland.
authors.forename: Sean
authors.initials: S
authors.lastname: Crampton
authors.affiliation: Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
authors.forename: Lieve
authors.initials: L
authors.lastname: Desbonnet
authors.affiliation: Department of Physiology, University College Cork, Cork, Ireland.
authors.forename: Deirdre
authors.initials: D
authors.lastname: Edge
authors.affiliation: Teagasc Food Research Centre, Moorepark Fermoy, County Cork, Ireland.
authors.forename: Orla
authors.initials: O
authors.lastname: O'Sullivan
authors.affiliation: Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; Department of Pharmacology & Therapeutics, University College Cork, Cork, Ireland.
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Lomasney
authors.affiliation: School of Biochemistry & Cell Biology, University College Cork, Cork, Ireland.
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Zhdanov
authors.affiliation: Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; Teagasc Food Research Centre, Moorepark Fermoy, County Cork, Ireland.
authors.forename: Fiona
authors.initials: F
authors.lastname: Crispie
authors.affiliation: Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
authors.forename: Rachel D
authors.initials: RD
authors.lastname: Moloney
authors.affiliation: Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
authors.forename: Yuliya E
authors.initials: YE
authors.lastname: Borre
authors.affiliation: Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; Teagasc Food Research Centre, Moorepark Fermoy, County Cork, Ireland.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Cotter
authors.affiliation: Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; Department of Pharmacology & Therapeutics, University College Cork, Cork, Ireland.
authors.forename: Niall P
authors.initials: NP
authors.lastname: Hyland
authors.affiliation: Department of Physiology, University College Cork, Cork, Ireland.
authors.forename: Ken D
authors.initials: KD
authors.lastname: O'Halloran
authors.affiliation: Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; Department of Psychiatry, University College Cork, Cork, Ireland.
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Dinan
authors.affiliation: Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; Department of Anatomy & Neuroscience, University College Cork, Cork, Ireland; Irish Centre for Foetal and Neonatal Translational Research (INFANT), CUMH, Cork, Ireland. Electronic address: g.okeeffe@ucc.ie.
authors.forename: Gerard W
authors.initials: GW
authors.lastname: O'Keeffe
authors.affiliation: Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; Department of Anatomy & Neuroscience, University College Cork, Cork, Ireland. Electronic address: j.cryan@ucc.ie.
authors.forename: John F
authors.initials: JF
authors.lastname: Cryan
mesh_terms: D000818:Animals; D001794:Blood Pressure; D003071:Cognition; D003106:Colon / Q000382:microbiology* / Q000503:physiopathology*; D005260:Female; D000069196:Gastrointestinal Microbiome; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology; D008297:Male; D009043:Motor Activity; D010913:Pituitary-Adrenal System / Q000503:physiopathology; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000503:physiopathology* / Q000523:psychology; D012329:RNA, Bacterial / Q000032:analysis; D012336:RNA, Ribosomal, 16S / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015656:Respiratory Mechanics; D012149:Restraint, Physical; D012919:Social Behavior; D013315:Stress, Psychological / Q000382:microbiology* / Q000503:physiopathology*
chemical_list: D012329:RNA, Bacterial; D012336:RNA, Ribosomal, 16S
keywords: Gut microbiota; HPA axis; Intestinal innervation; Maternal stress; Respiratory control