NEUROPLASTICITY OF MYENTERIC PLEXUS IN DIFFERENT ANIMAL MODELS OF DISEASES: POSSIBLE INTERVENTIONS WITH PROBIOTIC SUPPLEMENTATION

Background: An altered functional innervation of the intestine by the enteric nervous system (ENS) has been demonstrated in different pathologies. Pathological changes in histological features confirm neuronal plasticity in metabolic syndrome and related obesity conditions, in gastrointestinal disorders like Inflammatory bowel diseases, (IBD), and among other pathologies also in Alzheimer’s disease (AD). Changes in functionality and composition of gut microbiota and intestinal dysbiosis seem closely linked to the degeneration of myenteric plexus in the ENS. Aims: Here, we investigated the potential properties of different probiotic strains or multi-strain probiotic formulations in different animal models of pathologies. Animal models of genetic obesity (Zucker’s Rat), and Diet-induced obesity (DIO Rats) were studied to appreciate the temporal progression of changes in glial cells and neurons along the innervation of the gut. Western diet - induced obesity (Cafeteria Rats) was used to investigate the impact of Lactiplantibacillus (Lp) plantarum IMC 510 on the neuroplasticity of the enteric plexus of ENS. The potential properties of Pediocuccus acidilactici 46A (Pa) were evaluated on a murine model of Dextran sulfate sodium (DSS)-induced colitis as models of chemically induced IBD. A hypocaloric cookie with prebioticrich ingredients (red lentils) coated with a multi-strain probiotic (SLAB51®) enriched chocolate was tested on 3xTg-AD mice, a murine model of AD, to evaluate the protective effects on the colonic mucosa and ENS. Methods: Using different markers through immunohistochemical and immunochemical techniques, the morphological and functional modulations of the heterogeneous neuronal population of the gut wall were evaluated and the histological damage, neurodegeneration, and pro-inflammatory cytokines expression, and oxidative stress status were detected on the proximal and distal colon. Results: Concerning the results in obese conditions, myenteric neurons showed a reduction in neuronal marker staining, suggesting a degeneration associated with obesity. An altered immunoreactivity of enteric glial cells (EGCs) was found in the obese rats, which pointed out a suffering condition of nervous tissue suggesting a neuronal degeneration related to lipotoxicity. Also, the cholinergic and nitrergic networks appear affected by dysmetabolic conditions. The physiological status of the myenteric plexus in Lp-supplemented groups seems to be restored. Regarding the outcomes of chemically induced IBD, defects of EGCs function and localization, barrier integrity dysfunction, and immune cell infiltrations were observed in colitis-induced groups, and an improvement was evidenced in Pa-supplemented groups. Morphological modification of neurons of the myenteric plexus was assessed by evaluating HuC/D pan-neuronal marker, then colonic nitrergic and cholinergic pathways were focused, and a neurodegeneration was appreciated in DSS-mice. The results demonstrate that Pa seems to counteract colonic mucosal degeneration and neuronal alteration. Relating to the ENS of the 3xTg-AD mouse model, the SLAB51® administered in water or inside the formulation of the functional prebiotic enriched cookies, appeared to decrease gliosis, without modulation of the neuronal markers of the enteric cholinergic and nitrergic neurons and the oxidative stress conditions. Moreover, seems to be useful to reduce mucus secretion and to enhance the intestinal barrier integrity. Conclusion: In conclusion, the obesity establishment seems to induce myenteric neurodegeneration. Also, gut dysbiosis promoted by an increment of intestinal permeability and related pro-inflammatory microenvironment makes an alteration of EGCs and neurons along the innervation of the gut in animal models of IBD and AD. Although it is difficult to establish the mechanism and the synergistic effects of this symbiotic association, the data, in addition to previous evidence, supports the hypothesis of gut neuronal health- promotion by probiotic supplementation. However, further studies are needed to better understand the use of specific bacterial strains in the management of intestinal disorders and the resulting modulation of the ENS in the different pathologies considered.