title: Disturbance of the gut microbiota in early-life selectively affects visceral pain in adulthood without impacting cognitive or anxiety-related behaviors in male rats.
abstract: Disruption of bacterial colonization during the early postnatal period is increasingly being linked to adverse health outcomes. Indeed, there is a growing appreciation that the gut microbiota plays a role in neurodevelopment. However, there is a paucity of information on the consequences of early-life manipulations of the gut microbiota on behavior. To this end we administered an antibiotic (vancomycin) from postnatal days 4-13 to male rat pups and assessed behavioral and physiological measures across all aspects of the brain-gut axis. In addition, we sought to confirm and expand the effects of early-life antibiotic treatment using a different antibiotic strategy (a cocktail of pimaricin, bacitracin, neomycin; orally) during the same time period in both female and male rat pups. Vancomycin significantly altered the microbiota, which was restored to control levels by 8 weeks of age. Notably, vancomycin-treated animals displayed visceral hypersensitivity in adulthood without any significant effect on anxiety responses as assessed in the elevated plus maze or open field tests. Moreover, cognitive performance in the Morris water maze was not affected by early-life dysbiosis. Immune and stress-related physiological responses were equally unaffected. The early-life antibiotic-induced visceral hypersensitivity was also observed in male rats given the antibiotic cocktail. Both treatments did not alter visceral pain perception in female rats. Changes in visceral pain perception in males were paralleled by distinct decreases in the transient receptor potential cation channel subfamily V member 1, the α-2A adrenergic receptor and cholecystokinin B receptor. In conclusion, a temporary disruption of the gut microbiota in early-life results in very specific and long-lasting changes in visceral sensitivity in male rats, a hallmark of stress-related functional disorders of the brain-gut axis such as irritable bowel disorder.
authors.affiliation: Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
authors.forename: S M
authors.initials: SM
authors.lastname: O'Mahony
authors.affiliation: Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
authors.forename: V D
authors.initials: VD
authors.lastname: Felice
authors.affiliation: Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; Department of Biochemistry, University College Cork, Cork, Ireland.
authors.forename: K
authors.initials: K
authors.lastname: Nally
authors.affiliation: Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
authors.forename: H M
authors.initials: HM
authors.lastname: Savignac
authors.affiliation: Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; Department of Microbiology, University College Cork, Cork, Ireland.
authors.forename: M J
authors.initials: MJ
authors.lastname: Claesson
authors.affiliation: Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
authors.forename: P
authors.initials: P
authors.lastname: Scully
authors.affiliation: Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
authors.forename: J
authors.initials: J
authors.lastname: Woznicki
authors.affiliation: Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; Department of Pharmacology & Therapeutics, University College Cork, Cork, Ireland.
authors.forename: N P
authors.initials: NP
authors.lastname: Hyland
authors.affiliation: Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; Department of Medicine, University College Cork, Cork, Ireland.
authors.forename: F
authors.initials: F
authors.lastname: Shanahan
authors.affiliation: Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
authors.forename: E M
authors.initials: EM
authors.lastname: Quigley
authors.affiliation: Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
authors.forename: J R
authors.initials: JR
authors.lastname: Marchesi
authors.affiliation: Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; Department of Microbiology, University College Cork, Cork, Ireland.
authors.forename: P W
authors.initials: PW
authors.lastname: O'Toole
authors.affiliation: Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland; Department of Psychiatry, University College Cork, Cork, Ireland.
authors.forename: T G
authors.initials: TG
authors.lastname: Dinan
authors.affiliation: Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland. Electronic address: j.cryan@ucc.ie.
authors.forename: J F
authors.initials: JF
authors.lastname: Cryan
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001007:Anxiety / Q000503:physiopathology*; D001414:Bacitracin / Q000494:pharmacology; D001522:Behavior, Animal / Q000502:physiology; D003071:Cognition / Q000502:physiology*; D005260:Female; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000382:microbiology*; D006930:Hyperalgesia / Q000503:physiopathology*; D008297:Male; D064307:Microbiota / Q000187:drug effects / Q000502:physiology*; D010866:Natamycin / Q000494:pharmacology; D009355:Neomycin / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D014640:Vancomycin / Q000494:pharmacology; D059265:Visceral Pain / Q000503:physiopathology*
chemical_list: D000900:Anti-Bacterial Agents; D001414:Bacitracin; D014640:Vancomycin; D010866:Natamycin; D009355:Neomycin
keywords: antibiotic; behavior; brain–gut axis; microbiota; neonatal; visceral pain