Antepartum Antibiotic Treatment Increases Offspring Susceptibility to Experimental Colitis: A Role of the Gut Microbiota

Abstract

Background and aimsPostnatal maturation of the immune system is largely driven by exposure to microbes, and thus the nature of intestinal colonization may be associated with development of childhood diseases that may persist into adulthood. We investigated whether antepartum antibiotic (ATB) therapy can increase offspring susceptibility to experimental colitis through alteration of the gut microbiota.MethodsPregnant C57Bl/6 mice were treated with cefazolin at 160 mg/kg body weight or with saline starting six days before due date. At 7 weeks, fecal samples were collected from male offspring after which they received 4% dextran sulfate sodium (DSS) in drinking water for 5 days. Disease activity index, histology, colonic IL-6, IL-1β and serum C-reactive protein (CRP) were determined. The V3-V4 region of colonic and fecal bacterial 16S rRNA was sequenced. Alpha-, beta-diversity and differences at the phylum and genus levels were determined, while functional pathways of classified bacteria were predicted.ResultsATB influenced fecal bacterial composition and hence bacterial functional pathways before induction of colitis. After induction of colitis, ATB increased onset of clinical disease, histologic score, and colonic IL-6. In addition, ATB decreased fecal microbial richness, changed fecal and colon microbial composition, which was accompanied by a modification of microbial functional pathways. Also, several taxa were associated with ATB at lower taxonomical levels.ConclusionsThe results support the hypothesis that antepartum antibiotics modulate offspring intestinal bacterial colonization and increase susceptibility to develop colonic inflammation in a murine model of colitis, and may guide future interventions to restore physiologic intestinal colonization in offspring born by antibiotic-exposed mothers.

Fetal and early life antibiotics exposure and very early onset inflammatory bowel disease: a population-based study

“…In our study, the highest risk of later VEO-IBD was seen in mothers exposed to antibiotics in the last trimester (aHR 2.57, 95% CI 1.10 to 6.01), that is, just before birth. Recent animal research indicates that antibiotics administered during pregnancy have substantial effects on the offspring microbiome (reduced bacterial diversity), but may also influence the immune response in the offspring45 and increase susceptibility to develop colonic inflammation 46…”

Experimental design considerations in microbiota/inflammation studies

“…For example, Clostridium difficile infection and the inflammatory sequelae are commonly precipitated by the use of antibiotics, 49 and rodent models of the disease have been generated in a similar manner. 50 Similarly, antibiotics have been used to precipitate disease in a number of disease models including those for colitis, 51 obesity 52 and T1D 53 and T2D. 52 Because of the extensive and largely indiscriminate remodelling of the microbiota that occurs following antibiotic use, this approach is not broadly applicable for general studies of the effects of microbiota on inflammation.…”

Involvement of Reduced Microbial Diversity in Inflammatory Bowel Disease

“…IBD has been reported to be caused by a multitude of factors such as genetics, environment, immune system, and gut microbiota. Although its exact pathogenesis remains unclear, dysbiosis of the microbiota in the intestinal tract is widely accepted to initiate or promote intestinal inflammation [1–3]. …”