| Summary: | <i>Drosophila</i> are widely used to study neural development, immunity, and inflammatory pathways and processes associated with the gut–brain axis. Here, we examine the response of adult <i>Drosophila</i> given an inactive bacteriologic (IAB; proprietary lysate preparation of <i>Lactobacillus bulgaricus</i>, ReseT<sup>®</sup>) and a probiotic (<i>Lactobacillus rhamnosus</i>, LGG). In vitro, the IAB activates a subset of conserved Toll-like receptor (TLR) and nucleotide-binding, oligomerization domain-containing protein (NOD) receptors in human cells, and oral administration slowed the age-related decline of adult <i>Drosophila</i> locomotor behaviors. On average, IAB-treated flies lived significantly longer (+23%) and had lower neural aggregate profiles. Different IAB dosages also improved locomotor function and longevity profiles after traumatic brain injury (TBI) exposure. Mechanistically, short-term IAB and LGG treatment altered baseline nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κβ) signaling profiles in neural and abdominal tissues. Overall, at select dosages, IAB and LGG exposure has a positive impact on <i>Drosophila</i> longevity, neural aging, and mild traumatic brain injury (TBI)-related responses, with IAB showing greater benefit. This includes severe TBI (sTBI) responses, where IAB treatment was protective and LGG increased acute mortality profiles. This work shows that <i>Drosophila</i> are an effective model for testing bacterial-based biologics, that IAB and probiotic treatments promote neuronal health and influence inflammatory pathways in neural and immune tissues. Therefore, targeted IAB treatments are a novel strategy to promote the appropriate function of the gut–brain axis.
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