Treatment with Bacterial Biologics Promotes Healthy Aging and Traumatic Brain Injury Responses in Adult Drosophila, Modeling the Gut–Brain Axis and Inflammation Responses

Abstract

Drosophila 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 Drosophila given an inactive bacteriologic (IAB; proprietary lysate preparation of Lactobacillus bulgaricus, ReseT®) and a probiotic (Lactobacillus rhamnosus, 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 Drosophila 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-kβ) signaling profiles in neural and abdominal tissues. Overall, at select dosages, IAB and LGG exposure has a positive impact on Drosophila 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 Drosophila 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.

Drosophila as a model to study autophagy in neurodegenerative diseases and digestive tract

“…Emerging evidence suggests that autophagy may also be involved in gut-brain axis function that has been associated with GI and neuronal disease. 227,228 It was reported that the autophagy inducer trehalose may exert neuroprotective effects through microbiota-gut-brain signaling. 229 In Drosophila, feeding AD flies with acid bacteria can reverse AD phenotype and improve gut microbiota profiles.…”

Potential of Probiotics as an Adjunct for Patients with Major Depressive Disorder

“…In addition, the LAB showed greater benefits in regulating mild TBI-related responses than probiotics, given that different treatments lead to different pathogen associated molecular pattern (PAMP) activity in adults fly. [66] Postbiotics has also been subjected to clinical trials in humans with some encouraging results. Heat-inactivated Lactobacillus gasseri CP2305 significantly ameliorates anxiety and sleep disturbance, and regulates stress-related microbiota on chronic stress responses adults in Japan.…”

“…In addition, the LAB showed greater benefits in regulating mild TBI‐related responses than probiotics, given that different treatments lead to different pathogen associated molecular pattern (PAMP) activity in adults fly. [ 66 ]…”

A pilot study: Innate immune modulation reduces F2‐Isoprostanes and improves psychological health in a chronically stressed cohort

“…10,11 Previously, in vivo Drosophila studies also showed lower basal levels of NF-κB gene targets upon IAB administration, further supporting this conclusion. 12…”

“…10,11 Recently, it has been demonstrated through in vivo Drosophila studies that an inactive bacterial biologic (IAB), accompanied with confirmed pathogen molecular associated patterns (PAMPs) to select Toll-like receptors (TLR) and nucleotide-binding oligomerization domain-containing protein (NOD) receptors, lowered the inflammatory targets of the NF-κB signaling cascade. 12 A pilot study was conducted to determine the effect of oral administration of IAB on the systemic OS levels in humans using the OS biomarker, urinary F2-isoprostane (F2-IsoP). F2-IsoP is a stable noninvasive biomarker and an end-stage metabolite of prostaglandin oxidation, present in all fluids and tissues, and has been reported to increase during the oxidative injury (Mayo Clinic Labs; Cleveland Heart Lab, Inc.).…”