Early-life exposure to environmental stressors can mould adult immune systems and potentially increase the risk of age-related diseases. Epidemiological studies in humans have linked childhood infections to adult inflammatory diseases, such as cardiovascular disease, and can also affect mortality. However, owing to myriad environmental exposures during development and childhood, it is challenging to dissect any direct causal relationships. Drosophila have previously been used as a model organism to delineate how diet, hypoxia and antioxidant intake during development affect lifespan and other related physiological outcomes.
In our current issue, Dr Fumiaki Obata and colleagues have explored the effects of early-life innate immune activation on adult gut health and lifespan in Drosophila. These flies have an innate immune pathway known as the immune deficiency (Imd) pathway, which resembles the human tumour necrosis factor receptor (TNFR) pathway. The Imd pathway is activated in response to certain bacteria but can also be spontaneously induced during ageing, with overactivation linked to neurodegeneration and age-related conditions in organs beyond the gut. In this study, the authors used precise genetic manipulation to activate the Imd pathway in Drosophila specifically during development. Although immune activation was very mild and transient, it resulted in decreased lifespan, increased starvation resistance and decreased food intake in adult flies. Characteristic features of gut inflammation were also observed in these adults, with altered microbiota, increased expression of antimicrobial peptide genes, and decreased intestinal alkaline phosphatases that would normally inhibit the Imd pathway.
Treating adult Drosophila that had experienced Imd activation during development with antibiotics prevented gut inflammation and shortening of lifespan. This suggests that expansion of immuno-stimulative bacteria in the gut is, at least partially, a causal factor of the adult inflammatory gut. The authors also challenged adult flies with an oral pathogen and found that Imd activation during early life did not confer protection against future infections, implying that adult inflammation is rather a pathological outcome.
This study shows that even mild, transient inflammation in early life can induce a sustained effect on Drosophila physiology and lifespan, which impacts our understanding of the effect of childhood infections on inflammatory diseases in later life. Delineating this further could help researchers to develop methods to predict and potentially prevent certain age-related human diseases.