Increasing evidence suggests that intestinal dysfunctions may represent early events in Alzheimer’s disease and contribute to brain pathology. This study examined the relationship between onset of cognitive impairment and colonic dysfunctions in a spontaneous AD model before the full development of brain pathology. SAMP8 mice underwent Morris water maze and assessment of faecal output at four, six and eight months of age. In vitro colonic motility was examined. Faecal and colonic Aβ, tau proteins, α-synuclein and IL-1β were assessed by ELISA. Colonic citrate synthase activity was assessed by spectrophotometry. Colonic NLRP3, caspase-1 and ASC expression were evaluated by Western blotting. Colonic eosinophil density and claudin-1 expression were evaluated by immunohistochemistry. The effect of Aβ on NLRP3 signalling and mitochondrial function was tested in cultured cells. Cognitive impairment and decreased faecal output occurred in SAMP8 mice from six months. When compared with SAMR1, SAMP8 animals displayed: (1) impaired in vitro colonic contractions; (2) increased enteric AD-related proteins, IL-1β, active-caspase-1 expression and eosinophil density; and (3) decreased citrate synthase activity and claudin-1 expression. In THP-1 cells, Aβ promoted IL-1β release, which was abrogated upon incubation with caspase-1 inhibitor or in ASC^-/- cells. Aβ decreased mitochondrial function in THP-1 cells. In SAMP8, enteric AD-related proteins deposition, inflammation and impaired colonic excitatory neurotransmission, occurring before the full brain pathology development, could contribute to bowel dysmotility and represent prodromal events in AD.

The management of visceral pain is a major clinical problem in patients affected by gastrointestinal disorders. The poor knowledge about pain chronicization mechanisms prompted us to study the functional and morphological alterations of the gut and nervous system in the animal model of persistent visceral pain caused by 2,4-dinitrobenzenesulfonic acid (DNBS). This agent, injected intrarectally, induced a colonic inflammation peaking on day 3 and remitting progressively from day 7. In concomitance with bowel inflammation, the animals developed visceral hypersensitivity, which persisted after colitis remission for up to three months. On day 14, the administration of pain-relieving drugs (injected intraperitoneally and intrathecally) revealed a mixed nociceptive, inflammatory and neuropathic pain originating from both the peripheral and central nervous system. At this time point, the colonic histological analysis highlighted a partial restitution of the tunica mucosa, transmural collagen deposition, infiltration of mast cells and eosinophils, and upregulation of substance P (SP)-positive nerve fibers, which were surrounded by eosinophils and MHC-II-positive macrophages. A significant activation of microglia and astrocytes was observed in the dorsal and ventral horns of spinal cord. These results suggest that the persistence of visceral pain induced by colitis results from maladaptive plasticity of the enteric, peripheral and central nervous systems.

(1) Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by abdominal pain and altered bowel habits, linked to dysbiosis and inflammation. Currently available treatments, focused on symptom management, displayed limited efficacy. Recent research highlights microbiota modulation as a potential therapeutic strategy to restore intestinal barrier integrity; (2) A dextran sulfate sodium (DSS)-induced mouse model of post-colitis IBS-like symptoms was performed to evaluate the effect of a novel mixture of Enterococcus lactis SF68^®, butyrate, and folate. Disease activity index and spleen weight were assessed. Markers of gut inflammation, intestinal barrier alterations, and gut butyrate bioavailability were measured. The activity of colonic mitochondria was also analyzed; (3) Supplementation with the novel mixture significantly reduced spleen weight and cytokine levels. The intestinal epithelial barrier was restored through an increase in claudin-1, occludin, and defensin 1–3 and a reduction in LBP plasma level. Treatment with the mixture enhanced the expression of butyrate transporters in mice. Mitochondrial activity markers, including citrate synthase and Cytochrome c oxidase, were improved by treatment; (4) The novel mixture containing Enterococcus lactis, butyrate, and folate exerted a protective effect against post-inflammatory IBS by reducing local inflammation, restoring intestinal barrier integrity, and enhancing butyrate bioavailability, suggesting its potential for managing post-inflammatory IBS symptoms effectively.