Previous research has shown antibiotics may increase the risk of immune-related diseases including inflammatory bowel disease (IBD) by disturbing the composition and functions of the gut microbiota. Although the use of antibiotics during the peripartum period (including both the preterm and post-natal periods) has been suggested as a risk factor for IBD development later in life, little is known about the possible underlying mechanisms.
A new rodent study, led by Dr. Eugene Chang from the Department of Medicine at the Knapp Centre for Biomedical Discovery at the University of Chicago (Chicago, USA), has found that antibiotics taken in pregnancy may lead to gut dysbiosis, immune dysfunction and increased IBD risk in genetically susceptible rat offspring.
The researchers examined the impact of the broad-spectrum antibiotic cefoperazone (CPZ) on both maternal and offspring gut microbiota when administered to dams during the peripartum period; they used the interleukin-10 (IL-10)-deficient mouse model of IBD-an experimental model widely used to mirror human intestinal inflammation. Experimental conditions were controlled for cage, gender, age, and the presence of common murine pathobionts as confounding factors.
Maternal CPZ exposure during the peripartum period in IL-10-deficient mice led to an increased susceptibility to developing both spontaneous and chemically-induced (via dextran sodium sulfate, or DSS) colitis in offspring, as observed by differences in histology scores of proximal and distal colons and increased levels of faecal lipocalin-2 (a sensitive marker of intestinal inflammation in mice) between CPZ and non-treatment groups. However, none of the adult mice treated with the antibiotic developed colitis; their offspring exhibited a high risk for developing colitis when compared to those from mothers that were not treated with antibiotics. These results suggest that the timing of antibiotic exposure is crucial, and is especially influential during the post-natal period when the offspring’s immune system is still under development.
Exposure to antibiotics in the peripartum period also induced persistent and significant changes in the gut microbiota in IL-10-deficient dams, which were passed on to their offspring. Indeed, CPZ exposure led to persistent changes in specific bacterial species in IL-10-deficient dams that persisted even 4 to 8 weeks after finishing CPZ treatment. Specifically, the mothers showed a decrease in diversity of the gut microbiota and fewer populations of Bacteroidetes and increased populations of Firmicutes and Verrucomicrobia. Besides this, offspring from CPZ-exposed dams developed gut dysbiosis similar to their mothers that persisted into adulthood (3, 7 and 11 weeks of age) and was associated with a skewing of the host immune system towards an increase in pro-inflammatory genes relevant to IBD and a decrease in anti-inflammatory and mucosal protective mediators. These data reveal that peripartum CPZ maternal exposure may promote increased risk for colitis in genetically susceptible offspring in adulthood through affecting the critical window in early life of microbial assemblage and immune system development.
Faecal microbiota transplantation (FMT) of CPZ-exposed dams’ gut microbiota into germ-free IL-10-deficient mice led to a similar skewing of the host immune response consisting of a pro-inflammatory response in the offspring of FMT-CPZ recipients similar to that observed in the offspring of donor mice. These data show that CPZ-induced dysbiosis observed in dams is sufficient to transfer an inflammatory phenotype in the absence of CPZ exposure.
In conclusion, antibiotic-induced maternal dysbiosis in rats during the peripartum period increases colitis risk in genetically susceptible offspring through gut microbiota dysbiosis and immune dysfunction.
Miyoshi J, Bobe AM, Miyoshi S, et al. Peripartum antibiotics promote gut dysbiosis, loss of immune tolerance, and inflammatory bowel disease in genetically prone offspring. Cell Rep. 2017; 20(2):491-504. doi: 10.1016/j.celrep.2017.06.060.
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