Low-dose penicillin in early life induces long-term changes in murine gut microbiota, brain cytokines and behavior

Abstract

There is increasing concern about potential long-term effects of antibiotics on children's health. Epidemiological studies have revealed that early-life antibiotic exposure can increase the risk of developing immune and metabolic diseases, and rodent studies have shown that administration of high doses of antibiotics has long-term effects on brain neurochemistry and behaviour. Here we investigate whether low-dose penicillin in late pregnancy and early postnatal life induces long-term effects in the offspring of mice. We find that penicillin has lasting effects in both sexes on gut microbiota, increases cytokine expression in frontal cortex, modifies blood–brain barrier integrity and alters behaviour. The antibiotic-treated mice exhibit impaired anxiety-like and social behaviours, and display aggression. Concurrent supplementation with Lactobacillus rhamnosus JB-1 prevents some of these alterations. These results warrant further studies on the potential role of early-life antibiotic use in the development of neuropsychiatric disorders, and the possible attenuation of these by beneficial bacteria.

Prenatal stress disrupts social behavior, cortical neurobiology and commensal microbes in adult male offspring

“…In addition, treating animals with antibiotics to disrupt the microbiome led to changes in social behavior [49]. Stress during gestation alters the composition of the maternal microbiome and these changes are transmitted to the offspring [3,5,6].…”

Gutsy Moves: The Amygdala as a Critical Node in Microbiota to Brain Signaling

“…[90,96] Finally, different probiotic strains have been shown to reduce symptoms of anxiety and depression across several studies in clinical and healthy populations. [97,98] While there have also [5,9,10,88,90] Anxiolytic effects, sometimes sex-specific, in mice (light-dark box, elevated-plus maze) [72,113] Anxiolytic effects in mice (open field, defensive marble burying, elevated-plus maze, light-dark box) [91,93] Strain-specific anxiolytic effects in humans (e.g., Beck Anxiety Index, Hospital Anxiety & Depression Scale) and rodents (defensive marble burying, elevated-plus maze, open field) [11,62,133,134] Transplant from humans with depression or comorbid IBS and anxiety increases anxietylike behavior in mice (open field, step-down test, light-dark box) [96,125] Heightened anxiety in rats (open field) [89] Depression Increased depressive-like behavior in mice (forced swim) [90] Increased depressive-like behavior in rats (forced swim) [94] Antidepressant effects in mice and rats (forced swim, tail suspension, learned helplessness after inescapable shock) [91,92] Strain-specific antidepressant effects in humans (e.g. Beck Depression Inventory, Hospital Anxiety & Depression Scale) and rodents (tail suspension test, forced swim, sucrose preference) [11,97,98,133,134] Transplant from depressed human donors induces depressive-like behavior in mice (sucrose preference, forced swim [varied results], tail suspension test) [90,96] Learned fear Impaired fear recall in adult mice [101] Acute administration enhances fear extinction in rodents and exposure therapy in humans, [103,104] reduces fear recall in huma...…”

“…Social deficits in mice (less interest in social interaction, poor memory for social partners) [110,113] Reversal of social deficits in murine models of ASD [111,115] Reversal of antibiotic-induced social deficits in mice [113] Reduced risk for ASD [116] , reduced symptom severity in children with ASD (open pilot) [117] Transplant of standardized human gut microbiota to children with ASD improved ASD symptoms in open-label pilot [118] Pain Visceral hypersensitivity in mice [119] Visceral hypersensitivity in healthy mice [94,120,135] Reversal of visceral hypersensitivity in stressed mice [122] Increased risk for IBS in humans [51] Positive effects on pain in IBS patients [127] Reversal of stressinduced visceral hypersensitivity in rats [121] Reversal of antibiotic-induced visceral hypersensitivity in mice [135] Positive effects on IBS symptoms in humans [127] Transplant from IBS donors increases GI symptoms (accelerated gastrointestinal transit, increased intestinal permeability) in mice [125,126] Transplant from healthy donors reduces GI symptoms (constipation, diarrhea, indigestion, abdominal pain) in children with ASD (open-label pilot) [118] www.advancedsciencenews.com www.bioessays-journal.com been several studies reporting no effect of probiotics on these measures, [99] these disparate results may be explained by straindependent effects or a moderating effect of symptom severity because it has been reported that the beneficial effects are greatest for those with the most negative symptoms at baseline. [100] …”

“…[89,[110][111][112] Deficits in social behavior are also observed following antibiotic-induced depletion of the microbiota. [72,113] The microbiota also plays a role in murine models of ASD, where treatment with specific bacteria has been shown to reverse many of the social deficits observed in these animals. [111,114] There is some promising early evidence that this approach may translate to clinical settings.…”

Microbiota and Neurodevelopmental Trajectories: Role of Maternal and Early-Life Nutrition

“…Longitudinal clinical studies support the idea that early-life exposure to antibiotics perturbs the natural trajectory of the microbial communities by altering their stability [140]. Furthermore, neonatal exposure to antibiotics in rodents not only altered the microbiota but also induced increased visceral sensitivity and long-lasting changes in brain cytokines and behaviour [141, 142]. …”