The Prolonged Impact of Early-Life Antibiotics Exposure on 81 Common Diseases: Evidence from Epidemiology, Genetics, and Causality

Abstract

Background: The widespread administration of antibiotics to children has prompted concerns regarding the potential adverse effects associated with their use. Early-life exposure to antibiotics has been linked with various health issues, including gastrointestinal disorders, dermatological conditions, and asthma. However, previous studies exhibit certain constraints regarding its scope and ability to establish causal relationships between early-life antibiotics exposure and health complications. This study aimed to systematically investigate the long-lasting effects of antibiotics on various systemic diseases, providing epidemiological and genetic evidence. Methods: Leveraging electronic hospital records, questionnaire data, and genotype data in UK Biobank, we examined 158,391 individuals with documented early-life antibiotics exposure to comprehensively analyze the associations between early antibiotics exposure and systemic diseases. We initiated an observational study scrutinizing the links between antibiotics usage and various diseases. Subsequently, eight Mendelian randomization methods were employed to meticulously account for confounding variables and investigate potential causality. Moreover, genetic correlation analyses were conducted to validate these associations from a genetic perspective. Eventually, colocalization analyses were performed to identify shared genetic structures among them. Results: In our observational study involving 81 common diseases, our findings revealed significnat associations between the exposure to antibiotics during early life and 45 diseases, after correcting the false discovery rate. Among these, 11 diseases demonstrated causal evidence. These diseases include type-2 diabetes (OR = 1.27 [1.18,1.36], P = 4.8×10− 11), depression (OR = 1.77 [1.67,1.89], P = 2.2×10− 72), inflammatory bowel disease (OR = 1.28 [1.14,1.45], P = 6.2×10− 5), polymyalgia rheumatica (OR = 1.28 [1.07,1.53], P = 6.4×10− 3), giant cell arteritis (OR = 1.55 [1.12, 2.14], P = 7.5×10− 3), chronic tonsil and adenoid diseases (OR = 2.13 [1.73, 2.62], P = 1.3×10− 12), other upper respiratory conditions (OR = 1.4 [1.24,1.59], P = 9.7×10− 8), hordeolum and other deep inflammation of the eyelid (OR = 2.13 [1.32,3.41], P = 1.80×10− 3), sciatica (OR = 1.54 [1.35,1.76], P = 8.30×10− 11), cystitis (OR = 1.51 [1.31,1.74], P = 8.10×10− 9), and bronchiectasis (OR = 2.7 [2.37,3.06], P = 9.7×10− 52), and 5 of these had genetic correlations. Additionally, we identified common pleiotropic genetic loci linking antibiotics exposure to these 5 diseases. Conclusions: The study unveiled the enduring and detrimental effects of prolonged antibiotic usage during early life, which can potentially result in the development of diseases across multiple bodily systems, either directly or indirectly.