Prenatal antibiotic exposure and the origins offspring asthma susceptibility. (ORIGIN)

• Applicant: Dr. Melanie Lynn Conrad
• Subject Area: Gynaecology and Obstetrics ; Reproductive Medicine, Urology
• Term: from 2014 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 260349368

• Final Report Year: 2025

Final Report Abstract

Asthma is the most common chronic inflammatory disease of childhood, with approximately 4 million children affected in Germany. Though allergic asthma undoubtedly has a genetic component, a dramatic increase in incidence over the past decades indicates that the environment also plays a fundamental role in disease susceptibility. Many publications have shown that taking antibiotics during pregnancy is associated with increased risk for asthma development in children and we confirmed this association by performing a metaanalysis of 27 studies. It is estimated that 25% of women take antibiotics during pregnancy, and if this has even a small effect on childhood asthma susceptibility it can substantially influence public health. Since it is still unknown how antibiotics taken during pregnancy influence fetal/neonatal development and childhood asthma susceptibility, it is increasingly important to study the mechanisms involved in these processes. To examine these mechanisms, our DFG project ORIGIN used a mouse model in which treatment of mice with antibiotics during pregnancy increases offspring asthma severity. Using this model, we demonstrated that maternal antibiotic use during pregnancy was associated with significantly lower fetal weight (fetal growth restriction) as well as lower weight in the offspring during early life, compared to offspring from control mothers. We further showed that antibiotic use during pregnancy changed the maternal gut bacteria (microbiome), and that these bacteria were passed on to the offspring. The gut bacteria during infancy are very important for the establishment of the immune system, and our mouse model revealed that offspring prenatally exposed to antibiotics also had an altered gut microbiome, which contributed to intestinal inflammation in early life. This gut inflammation in the offspring interfered with the formation of the gut barrier during infancy, resulting in detrimental bacterial components crossing the gut into the bloodstream. These bacterial components activated the immune system in the blood and altered the types of immune cells that reside in the lung and initiate the immune response. Our results show that seeding of the lung with detrimental immune cell types during infancy is associated with severe asthma outcome in early life. This information substantially contributes to our understanding of how antibiotic use during pregnancy can alter immune system development in the offspring and predispose towards a severe asthma phenotype.

Publications

• Relative risk of developing asthma after prenatal antibiotic exposure: Protocol for a systematic review and meta-analysis.
  Cait A.; Wedel A.; Arntz JL; Duinkerken J.; Datye S.; Cait .J; Alhasan MM & Conrad ML
  
• Prenatal antibiotic exposure, asthma, and the atopic march: A systematic review and meta‐analysis. Allergy, 77(11), 3233-3248.
  Cait, Alissa; Wedel, Alexander; Arntz, Jeanne L.; Duinkerken, Jacyra; Datye, Swarali; Cait, Jessica; Alhasan, Moumen M. & Conrad, Melanie L.
  
• Antibiotic use during pregnancy is linked to offspring gut microbial dysbiosis, barrier disruption, and altered immunity along the gut–lung axis. European Journal of Immunology, 53(10).
  Alhasan, Moumen M.; Hölsken, Oliver; Duerr, Claudia; Helfrich, Sofia; Branzk, Nora; Philipp, Alina; Leitz, Dominik; Duerr, Julia; Almousa, Yahia; Barrientos, Gabriela; Mohn, William W.; Gamradt, Stefanie & Conrad, Melanie L.
  
• Low-dose perinatal supplementation with Enterococcus faecalis increases concentrations of short-chain fatty acids in the offspring but does not protect against allergic asthma. International Immunology, 35(10), 475-482.
  Arntz, Jeanne L.; Alhasan, Moumen M.; Datye, Swarali; Kahhaleh, Fariz G.; Almousa, Yahia; Barrientos, Gabriela; Schwiertz, Andreas & Conrad, Melanie L.
  
• Mouse milk immunoglobulin G Fc-linked N-glycosylation nano-LC–MS analysis in a model of vancomycin exposure during pregnancy. Analytical and Bioanalytical Chemistry, 415(12), 2239-2247.
  Alhasan, Moumen M.; Habazin, Siniša; Kahhaleh, Fariz G.; Lauc, Gordan; Conrad, Melanie L. & Novokmet, Mislav
  
• Nutrition during pregnancy: Influence on the gut microbiome and fetal development. American Journal of Reproductive Immunology, 91(1).
  Barrientos, Gabriela; Ronchi, Francesca & Conrad, Melanie L.
  
• Regulatory T cells and their role in allergic disease. Allergy, 80(1), 77-93.
  Conrad, Melanie L.; Barrientos, Gabriela; Cai, Xuejun; Mukherjee, Saikat; Das, Mrinmoy; Stephen‐Victor, Emmanuel & Harb, Hani
  
• The gut‐lung axis and asthma susceptibility in early life. Acta Physiologica, 240(3).
  Kahhaleh, Fariz G.; Barrientos, Gabriela & Conrad, Melanie L.