IgA Dysfunction Induced by Early-Lifetime Low-Dose Antibiotics Exposure Aggravates Diet-Induced Metabolic Syndrome.

Low-dose antibiotic contamination in animal feed is a persistent global food safety challenge. Transient early-life exposure to low-dose penicillin (LDP) is known to induce metabolic syndrome (MetS) in adult mice, but the underlying mechanisms are unclear. This study investigated the role of gut microbiota (GM) and intestinal immunity in mediating the long-term metabolic effects of early-life LDP exposure. Mice were exposed to LDP transiently during early life. GM composition was analyzed. Intestinal IgA responses were quantified. Bacterial encroachment, systemic and adipose tissue inflammation, and diet-induced MetS were assessed. Germ-free (GF) mice received GM transplants from LDP-exposed or control mice to test causality and persistence. Early-life LDP exposure significantly disrupted GM composition, particularly in the ileum, in 30-day-old mice. These GM alterations caused persistent suppression of intestinal IgA responses, evidenced by reduced IgA-producing cells and sIgA levels. This suppression was constrained to early-life exposure: transferring LDP-modified GM to GF mice produced only a transient reduction in fecal sIgA. The LDP-induced sIgA reduction decreased IgA binding of bacteria, leading to increased bacterial encroachment and systemic and adipose tissue inflammation. These pathological changes exacerbated diet-induced MetS. Our findings demonstrate that early-life LDP exposure induces persistent intestinal IgA deficiency through lasting GM alterations initiated in early development. This deficiency drives bacterial encroachment, inflammation, and ultimately exacerbates MetS. The exacerbation of diet-induced metabolic syndrome by early-life LDP exposure occurs through an intestinal sIgA-dependent pathway triggered by persistent GM disruption. This highlights a critical mechanism linking early-life antibiotic exposure, gut immune dysfunction, and long-term metabolic health, with significant implications for food safety.