Enteric nervous system as a target and source of SARS-CoV-2 and other viral infections.

Coronavirus disease 2019 (COVID-19) has been demonstrated to affect several systems of the human body, including the gastrointestinal and nervous systems. The enteric nervous system (ENS) is a division of the autonomic nervous system that extends throughout the gut, regulates gastrointestinal function, and is therefore involved in most gut dysfunctions, including those resulting from many viral infections. Growing evidence highlights enteric neural cells and microbiota as important players in gut inflammation and dysfunction. Furthermore, the ENS and gastrointestinal immune system work together establishing relevant neuroimmune interactions during both health and disease. In recent years, gut-driven processes have also been implicated as players in systemic inflammation and in the initiation and propagation of several central nervous system pathologies, which seem to be hallmarks of COVID-19. In this review, we aim to describe evidence of the gastrointestinal and ENS infection with a focus on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We discuss here viral-induced mechanisms, neuroplasticity, and neuroinflammation to call attention to the enteric neuroglial network as a nervous system with a sensitive and crucial position to be not only a target of the new coronavirus but also a way in and trigger of COVID-19-related symptoms.

Neuroimmune Connectomes in the Gut and Their Implications in Parkinson's Disease.

The gastrointestinal tract is the largest immune organ and it receives dense innervation from intrinsic (enteric) and extrinsic (sympathetic, parasympathetic, and somatosensory) neurons. The immune and neural systems of the gut communicate with each other and their interactions shape gut defensive mechanisms and neural-controlled gut functions such as motility and secretion. Changes in neuroimmune interactions play central roles in the pathogenesis of diseases such as Parkinson's disease (PD), which is a multicentric disorder that is heterogeneous in its manifestation and pathogenesis. Non-motor and premotor symptoms of PD are common in the gastrointestinal tract and the gut is considered a potential initiation site for PD in some cases. How the enteric nervous system and neuroimmune signaling contribute to PD disease progression is an emerging area of interest. This review focuses on intestinal neuroimmune loops such as the neuroepithelial unit, enteric glial cells and their immunomodulatory effects, anti-inflammatory cholinergic signaling and the relationship between myenteric neurons and muscularis macrophages, and the role of α-synuclein in gut immunity. Special consideration is given to the discussion of intestinal neuroimmune connectomes during PD and their possible implications for various aspects of the disease.

Enteric glia as a player of gut-brain interactions during Parkinson's disease.

The enteric glia has been shown as a potential component of neuroimmune interactions that signal in the gut-brain axis during Parkinson's disease (PD). Enteric glia are a peripheral glial type found in the enteric nervous system (ENS) that, associated with enteric neurons, command various gastrointestinal (GI) functions. They are a unique cell type, with distinct phenotypes and distribution in the gut layers, which establish relevant neuroimmune modulation and regulate neuronal function. Comprehension of enteric glial roles during prodromal and symptomatic phases of PD should be a priority in neurogastroenterology research, as the reactive enteric glial profile, gastrointestinal dysfunction, and colonic inflammation have been verified during the prodromal phase of PD-a moment that may be interesting for interventions. In this review, we explore the mechanisms that should govern enteric glial signaling through the gut-brain axis to understand pathological events and verify the possible windows and pathways for therapeutic intervention. Enteric glia directly modulate several functional aspects of the intestine, such as motility, visceral sensory signaling, and immune polarization, key GI processes found deregulated in patients with PD. The search for glial biomarkers, the investigation of temporal-spatial events involving glial reactivity/signaling, and the proposal of enteric glia-based therapies are clearly demanded for innovative and intestine-related management of PD.

High-fat diets on the enteric nervous system: Possible interactions and mechanisms underlying dysmotility.

Obesity is a chronic disease that affects various physiological systems. Among them, the gastrointestinal tract appears to be a main target of this disease. High-fat diet (HFD) animal models can help recapitulate the classic signs of obesity and present a series of gastrointestinal alterations, mainly dysmotility. Because intestinal motility is governed by the enteric nervous system (ENS), enteric neurons, and glial cells have been studied in HFD models. Given the importance of the ENS in general gut physiology, this review aims to discuss the relationship between HFD-induced neuroplasticity and gut dysmotility observed in experimental models. Furthermore, we highlight components of the gut environment that might influence enteric neuroplasticity, including gut microbiota, enteric glio-epithelial unit, serotonin release, immune cells, and disturbances such as inflammation and oxidative stress.

Brazil Nut (Bertholletia excelsa H.B.K) Retards Gastric Emptying and Modulates Enteric Glial Cells in a Dose-Dependent Manner.

BACKGROUND: The role of food and nutrients in the regulation of enteric glial cell functions is unclear. Some foods influence enteric neurophysiology and can affect glial cell functions that include regulation of the intestinal barrier, gastric emptying, and colonic transit. Brazil nuts are the most abundant natural source of selenium, unsaturated fatty acids, fibers, and polyphenols. OBJECTIVE: The study investigated the effects of a Brazil nut-enriched diet on enteric glial cells and gastrointestinal transit. METHODS: Two-month-old male Wistar rats were randomized to a standard diet (control group, CG), standard diet containing 5% (wt/wt) Brazil nut (BN5), and standard diet containing 10% (wt/wt) Brazil nut (BN10) (n = 9 per group). After eight weeks, the animals underwent constipation and gastric emptying tests to assess motility. Evaluations of colonic immunofluorescence staining for glial fibrillary acidic protein (GFAP) and myenteric ganglia area were performed. RESULTS: The BN5 group showed increased weight gain while the BN10 group did not (p < 0.0001). The BN10 group showed higher gastric residue amounts compared to the other groups (p = 0.0008). The colon exhibited an increase in GFAP immunoreactivity in the BN5 group compared to that in the other groups (p = 0.0016), and the BN10 group presented minor immunoreactivity compared to the CG (p = 0.04). The BN10 group presented a minor ganglia area compared to the CG (p = 0.0155). CONCLUSION: The Brazil nut-enriched diet modified the gastric residual, colonic GFAP immunoreactivity, and myenteric ganglia area after eight weeks in healthy male Wistar rats.

Enteric glial cell reactivity in colonic layers and mucosal modulation in a mouse model of Parkinson's disease induced by 6-hydroxydopamine.

Enteric glial cells (EGCs) constitute the majority of the neural population of the enteric nervous system and are found in all layers of the gastrointestinal tract. It is active in enteric functions such as immunomodulation, participating in inflammation and intestinal epithelial barrier (IEB) regulation. Both EGCs and IEB have been described as altered in Parkinson's disease (PD). Using an animal model of PD induced by 6-hydroxydopamine (6-OHDA), we investigated the effect of ongoing neurodegeneration on EGCs and inflammatory response during short periods after model induction. C57Bl/6 male mice were unilaterally injected with 6-OHDA in the striatum. Compared to the control group, 6-OHDA animals showed decreased relative water content in their feces from 1 w after model induction. Moreover, at 1 and 2 w post-induction, groups showed histopathological changes indicative of intestinal inflammation. We identified an increase in IBA1 and GFAP levels in the intestinal mucosa. At an earlier survival of 48 h, we detected an increase in GFAP in the neuromuscular layer, suggesting that it was a primary event for the upregulation of GDNF, TNF-α, and occludin in the intestinal mucosa observed after 1 w. Within 2 w, we identified a decrease in the expression of occludin barrier proteins. Thus, EGCs modulation may be an early enteric signal induced by parkinsonian neurodegeneration, followed by inflammatory and dysmotility signs besides IEB modification.