You Talking to Me? Says the Enteric Nervous System (ENS) to the Microbe. How Intestinal Microbes Interact with the ENS.

Mammalian organisms form intimate interfaces with commensal and pathogenic gut microorganisms. Increasing evidence suggests a close interaction between gut microorganisms and the enteric nervous system (ENS), as the first interface to the central nervous system. Each microorganism can exert a different effect on the ENS, including phenotypical neuronal changes or the induction of chemical transmitters that interact with ENS neurons. Some pathogenic bacteria take advantage of the ENS to create a more suitable environment for their growth or to promote the effects of their toxins. In addition, some commensal bacteria can affect the central nervous system (CNS) by locally interacting with the ENS. From the current knowledge emerges an interesting field that may shape future concepts on the pathogen-host synergic interaction. The aim of this narrative review is to report the current findings regarding the inter-relationships between bacteria, viruses, and parasites and the ENS.

5-HT3A serotonin receptor in the gastrointestinal tract: the link between immune system and enteric nervous system in the digestive form of Chagas disease.

Chagas disease is caused by Trypanosoma cruzi and remains one of the most neglected diseases in Latin America. One of its clinical forms is Chagas megacolon. Despite being known for more than half a century, detailed causes are still obscure. Recent evidence indicates a close relationship between the immune system and the enteric nervous system in the etiology of chagasic megacolon pathology. It is believed that low expression of the 5-HT3A serotonin receptor on lymphocytes could be linked to megacolon development. To test this hypothesis, this work investigated the distribution of CD4, CD8, and CD20 lymphocytes and their 5-HT3A receptor expression. The results demonstrated that Chagas patients without megacolon present a higher expression of the 5-HT3A receptor in all analyzed lymphocytes compared with Chagas patients with megacolon. These data suggest that the high expression of this receptor may lead to immunomodulation and prevent the development of Chagas megacolon.

Concomitant helminth infection downmodulates the Vaccinia virus-specific immune response and potentiates virus-associated pathology.

The aim of this work was to elucidate the immunopathological mechanisms of how helminths may influence the course of a viral infection, using a murine model. Severe virulence, a relevant increase in the virus titres in the lung and a higher mortality rate were observed in Ascaris and Vaccinia virus (VACV) co-infected mice, compared with VACV mono-infected mice. Immunopathological analysis suggested that the ablation of CD8+ T cells, the marked reduction of circulating CD4+ T cells producing IFN-γ, and the robust pulmonary inflammation were associated with the increase of morbidity/mortality in co-infection and subsequently with the negative impact of concomitant pulmonary ascariasis and respiratory VACV infection for the host. On the other hand, when evaluating the impact of the co-infection on the parasitic burden, co-infected mice presented a marked decrease in the total number of migrating Ascaris lung-stage larvae in comparison with Ascaris mono-infection. Taken together, our major findings suggest that Ascaris and VACV co-infection may potentiate the virus-associated pathology by the downmodulation of the VACV-specific immune response. Moreover, this study provides new evidence of how helminth parasites may influence the course of a coincident viral infection.

An imbalance between substance P and vasoactive intestinal polypeptide might contribute to the immunopathology of megaesophagus after Trypanosoma cruzi infection.

Megaesophagus is one of the major causes of morbidity in chronic Chagas disease, and extensive denervation, associated with an inflammatory process, is recognized as the key factor for alterations in motility and disease development. Here, we analyzed esophagus samples from necropsied, infected individuals--6 cases with megaesophagus and 6 cases without megaesophagus--for the relative areas of expression of 2 neuromediators, substance P and vasoactive intestinal peptide, which are known to activate or inhibit, respectively, local immune cells. Samples from 6 noninfected individuals were used as controls. Esophageal sections were immunohistochemically stained for protein gene product 9.5, vasoactive intestinal peptide, and substance P, and the relative areas of expression of the latter 2 were calculated. Morphometric analyses revealed increased substance P and decreased vasoactive intestinal peptide relative areas in esophageal sections from patients with megaesophagus. Furthermore, in the group of patients without megaesophagus, the loss of vasoactive intestinal peptide positively correlated with the denervation process. We suggest that an imbalance between vasoactive intestinal peptide and substance P production results in the reestablishment and maintenance of the inflammatory process, leading to denervation and, consequently, promoting the development of megaesophagus.

Regenerative process evaluation of neuronal subclasses in chagasic patients with megacolon.

Chagas' disease is one of the most serious parasitic diseases of Latin America, with a social and economic impact far outweighing the combined effects of other parasitic diseases such as malaria, leishmaniasis and schistosomiasis. In the chronic phase of this disease, the destruction of enteric nervous system (ENS) components leads to megacolon development. Previous data presented that the regeneration tax in the ENS neurons is augmented in chagasic patients. Although, there are several neuronal types with different functions in the intestine a detailed study about the regeneration of every neuronal type was never performed before. Therefore, the aim of this study was to evaluate the regeneration tax of every neuronal cell type in the ENS from chagasic patients with megacolon and non-infected individuals. A neuronal regeneration marker (GAP-43) was used in combination with a pan-neuronal marker (Peripherin) and several neuropeptides markers (cChat, Substance P, NPY, VIP and NOS), and it was considered as positive just with the combination of these markers. Our results demonstrated that the regeneration levels of cChat, Substance P, and NPY were similar in chagasic patients and non-infected individuals. However, levels of VIP and NOS neuropeptides were increased in chagasic patients when compared with non-infected individuals. We believe that the augment in the regeneration occur due to an increased destruction of selective neuronal types. These results corroborates with previous studies that pointed out to selective destruction of VIP and NOS neurons in chagasic patients.

Enteroglial cells act as antigen-presenting cells in chagasic megacolon.

Chagas disease is one of the most serious parasitic diseases of Latin America, with a social and economic impact far outweighing the combined effects of other parasitic diseases such as malaria, leishmaniasis, and schistosomiasis. In the chronic phase of this disease, the destruction of enteric nervous system components leads to megacolon development. Besides neurons, the enteric nervous system is constituted by enteric glial cells, representing an extensive but relatively poorly described population within the gastrointestinal tract. Several lines of evidence suggest that enteric glial cells represent an equivalent of central nervous system astrocytes. Previous data suggest that enteric glia and neurons are active in the enteric nervous system during intestinal inflammatory and immune responses. To evaluate whether these cells act as antigen-presenting cells, we investigated the expression of molecules responsible for activation of T cells, such as HLA-DR complex class II and costimulatory molecules (CD80 and CD86), by neurons and enteric glial cells. Our results indicate that only enteric glial cells of chagasic patients with megacolon express HLA-DR complex class II and costimulatory molecules, and hence they present the attributes necessary to act as antigen-presenting cells.

Characterization of enteroglial cells and denervation process in chagasic patients with and without megaesophagus.

Chagas disease is caused by infestation with the parasite Trypanosoma cruzi, and some patients who are serologically positive develop chronic megaesophagus, whereas others are symptom-free. Gastrointestinal form of Chagas disease involves an inflammatory invasion of the enteric plexuses and degeneration of enteric neurons and previous works related that enteroglial cells would be involved in enteric inflammatory responses. Because of this, the aims of this study were to determine the relation of enteroglial cells with the denervation process in chagasic patients with and without megaesophagus and seronegative individuals. Our results indicated that the innervation of the esophageal muscle was substantially reduced in patients with megaesophagus, but asymptomatic seropositive subjects were not different to seronegative controls. Besides, patients with megaesophagus had significant decreased of enteroglial cells labeled with S-100 and glial fibrillary acidic protein, whereas patients without megaesophagus presented an increased of both labels. We believe that enteroglial cells would operate a mechanism of defense in the enteric nervous system against the Trypanosoma cruzi infection, which could prevent the organ denervation and preserve the esophagus function.

Cellular and genetic mechanisms involved in the generation of protective and pathogenic immune responses in human Chagas disease.

Perhaps one of the most intriguing aspects of human Chagas disease is the complex network of events that underlie the generation of protective versus pathogenic immune responses during the chronic phase of the disease. While most individuals do not develop patent disease, a large percentage may develop severe forms that eventually lead to death. Although many efforts have been devoted to deciphering these mechanisms, there is still much to be learned before we can fully understand the pathogenesis of Chagas disease. It is clear that the host's immune response is decisive in this process. While characteristics of the parasite influence the immune response, it is becoming evident that the host genetic background plays a fundamental role in the establishment of pathogenic versus protective responses. The involvement of three complex organisms, host, parasite and vector, is certainly one of the key aspects that calls for multidisciplinary approaches towards the understanding of Chagas disease. We believe that now, one hundred years after the discovery of Chagas disease, it is imperative to continue with highly interactive research in order to elucidate the immune response associated with disease evolution, which will be essential in designing prophylactic or therapeutic interventions.

Megacolon in Chagas disease: a study of inflammatory cells, enteric nerves, and glial cells.

After acute infestation with the Chagas disease parasite, Trypanosoma cruzi, some patients who are serologically positive develop chronic megacolon and megaesophagus, whereas others are symptom-free. Chagas disease with gastrointestinal involvement involves an inflammatory invasion of the enteric plexuses and degeneration of enteric neurons. It is known that glial cells can be involved in enteric inflammatory responses. The aims were to determine the nature of any difference in lymphocytic invasion, enteric neurons, and enteric glial cells in seropositive individuals with and without megacolon. We have compared colonic tissue from serologically positive individuals with and without symptoms and from seronegative controls. Subjects with megacolon had significantly more CD-57 natural killer cells and TIA-1 cytotoxic lymphocytes within enteric ganglia, but numbers of CD-3 and CD-20 immunoreactive cells were not significantly elevated. The innervation of the muscle was substantially reduced to about 20% in megacolon, but asymptomatic seropositive subjects were not different to seronegative controls. Glial cell loss occurred equally in symptomatic and unaffected seropositive subjects, although the proportion with glial fibrillary acidic protein was greater in seropositive, nonsymptomatic subjects. Development of megacolon after acute infection with T cruzi is associated with maintained invasion of enteric ganglia with cytotoxic T cells and loss of muscle innervation, but changes in glial cell numbers are not associated with progression of enteric neuropathy.