gut reactions: antibiotics, microbial diversity and T1D
By: Shruthi Kandalai
It has previously been shown that children with T1D have lower gut microbial diversity in their gut microbiome than healthy control children. While antibiotic treatments have also been associated with reduced microbial diversity following treatment, it is not certain whether early antibiotic treatment plays a role in T1D pathogenesis.
A research group set out to explore this question through a study administering pulsed antibiotic therapy (PAT) to non-obese diabetic (NOD) mice, mimicking antibiotic treatments given to children who may have a genetic predisposition to T1D.
- T1D incidence was significantly higher in PAT mice than those not exposed to antibiotics (controls).
- PAT males had reduced levels of regulatory T cells and TH-17 (T-helper) cells.
- Pathways specific to sterol, lipid, steroid and cholesterol metabolic processes were most significantly upregulated in PAT males.
- For all PAT mice, microbial diversity was significantly reduced compared to controls, though partial recovery occurred seven weeks after antibiotic cessation.
- PAT mice had lower levels of Bifidobacterium, higher levels of Akkermansia and initially lower levels of S24-7 family bacteria, but recovered following cessation.
- In PAT mice that developed T1D, S24-7 family bacteria was lower and Akkermansia was higher than PAT mice that did not develop T1D.
- Fecal transfer from PAT and control mice to new pups lead to higher levels of Akkermansia and lower levels of S24-7 family bacteria, and similarly lowered levels of regulatory T cells and TH-17 (T-helper) cells.
Another study explored the effect of a single course (1PAT) of antibiotics, compared to multiple courses (3PAT) of antibiotics on NOD mice.
- T1D development was significantly accelerated and enhanced in 1PAT and 3PAT mice compared to NOD mice not exposed to antibiotics (controls).
- By postnatal day 70, both PAT groups showed more islet inflammation than controls.
- There was a significantly increased presence of Enterococcus, Blautia, Enterobacteriaceae and Akkermansia and significantly decreased presence of S24-7, Clostridiales, Oscillospira and Ruminococcus bacteria in the gut microbiomes of PAT mice, compared to controls.
- Pathways involving carbohydrate degradation, amino acid biosynthesis and bacterial cell structural components were increased in 1PAT mice compared to controls.
A nationwide study in Sweden also recently explored this question using information from their national medical register. Swedish children were studied for prenatal antibiotic exposure (730, 221 children) and early life antibiotic exposure (797,318 children), as well as to see the effect antibiotics had on T1D diagnosis within the first 10 years. This study aimed to include a much larger patient population than previous studies.
- Exposure to any antibiotics prenatally was associated with a 15% increased risk of developing T1D, while exposure prenatally to urinary tract, skin or soft tissue infection antibiotics was associated with a 29% increased risk of developing T1D.
- Exposure to antibiotics within the first year of life was associated with a 19% increased risk of developing T1D.
- Children delivered vaginally were associated with a 10% increased risk of developing T1D, while children delivered through cesarean section were associated with a 60% increased risk of developing T1D.
- There was no dose-dependent relationship between antibiotic prescriptions and T1D diagnosis.
- The researchers propose that antibiotics early in life could lead to delays in maturation of microbiome, leading to increased susceptibility in developing T1D. Similarly, this effect may be more pronounced in children delivered through cesarean section, who already have lower microbial diversity.
- While there is an association between antibiotic exposure and T1D development, it is not significant and likely makes only a small contribution to total risk.
The takeaway: Data from the mice studies seem to support that antibiotics affect gut microbiome and can lead to accelerated T1D progression in mice predisposed to developing diabetes. However, human studies show a slight non-significant increase in T1D development following antibiotic exposure prenatally or early in life, though this is most pronounced in children delivered through cesarean section, who already have lower microbial diversity.
- Livanos, A. E., Greiner, T. U., Vangay, P., Pathmasiri, W., Stewart, D., Mcritchie, S., . . . Blaser, M. J. (2016). Antibiotic-mediated gut microbiome perturbation accelerates development of type 1 diabetes in mice. Nature Microbiology, 1(11).
- Zhang, X., Li, J., Krautkramer, K. A., Badri, M., Battaglia, T., Borbet, T. C., . . . Blaser, M. J. (2018). Antibiotic-induced acceleration of type 1 diabetes alters maturation of innate intestinal immunity. eLife.
- Wernroth, M., Fall, K., Svennblad, B., Ludvigsson, J. F., Sjölander, A., Almqvist, C., & Fall, T. (2020). Early Childhood Antibiotic Treatment for Otitis Media and Other Respiratory Tract Infections Is Associated With Risk of Type 1 Diabetes: A Nationwide Register-Based Study With Sibling Analysis. Diabetes Care, 43(5), 991-999.