The development of chagasic megacolon requires severe denervation and the reduction in interstitial cells of Cajal number might be a contributing factor

Abstract

Bassotti and Villanacci [1], we would like to emphasize that in our study [2] we identified a reduced number of interstitial cells of Cajal (ICC) in chagasic megacolon (CM), as had been previously reported in studies by Hagger et al. [3] and Geraldino et al. [4]. Hypotheses were raised trying to explain the discrepancy with the results published by Iantorno et al. [5]. Bassotti and Villanacci [1] claim that the hypotheses we proposed (inclusion of mast cells and heterogeneous distribution of ICC in different regions of the colon) are unfounded. We have no other explanations for the discrepancies between our study, which identified increasing numbers of intramuscular ICC only, and other studies [2-4], which found a reduction of ICC in all layers evaluated.Bassotti and Villanacci [1] state that we did not distinguish between well-established colonic populations of ICC. However, we did describe in our paper [2] that we counted ICC at the level of the myenteric plexus (intermuscular space between circular and longitudinal muscle layers) and from ICC in circular muscle layer separately. We did not count ICC in the submucosa nor in longitudinal muscle layers.However, we fully agree with Bassotti and Villanacci [1] that it is necessary to evaluate ICC and glial cells in conjunction with the study of enteric neurons, as our findings support the hypothesis that the development of CM requires severe denervation and the reduction in ICC number is, in part, a consequence of denervation and that this might contribute to the pathophysiology of CM.

Neuronal Parasitism, Early Myenteric Neurons Depopulation and Continuous Axonal Networking Damage as Underlying Mechanisms of the Experimental Intestinal Chagas' Disease

“…We also noticed that well-preserved integral ganglia occur side by side with lesioned ones. Our findings challenge previous proposals that ganglionic neuronal depopulation is per se the cause of dysmotility and megacolon (González Cappa et al, 1987;Adad et al, 2001Adad et al, , 2013Jabari et al, 2012). We found that these alterations take place early in the acute phase, even though the symptoms and pathological findings manifest decades later, probably resulting from cumulative damage to neurons and other elements of the intestinal wall as well as progressive functional impairment, thus explaining some contradictory findings (Ribeiro et al, 1998;Meneghelli, 1999Meneghelli, , 2004Adad et al, 2001;Da Silveira et al, 2008;Jabari et al, 2012Jabari et al, , 2013.…”

“…One of the most challenging questions of CD is how T. cruzi leads to the manifestation of chronic intestinal lesions decades after infection and thus, when parasites are rare (Zhang and Tarleton, 1999 ; Tarleton, 2001 ; Benvenuti et al, 2008 ). The damage of myenteric neurons characterizes the chronic phase of the intestinal CD (Adad et al, 2013 ; Jabari et al, 2014 ). However, as the parasitism is very low in the lesions of digestive Chagas disease (da Silveira et al, 2005 ; Wesley et al, 2019 ), it has been suggested that chronic neuronal destruction might be due to the immune response that follows the infection, as proposed for heart lesions (Teixeira et al, 2011 ).…”

“…Based on human and murine experimental data, it has been hypothesized that 50–80% of ganglionic denervation could be associated with the development of intestine's motility symptoms in humans (Koberle, 1968 ; Adad et al, 1991 , 2001 , 2013 ; Maifrino et al, 1999 ; Jabari et al, 2012 ). Here we detected ~40% of myenteric neuron loss very early in the course of the disease during the acute phase (11 d.p.i.).…”

“…The acute death of enteric neurons (ganglionic denervation), both in vivo and in vitro (Arantes et al, 2004 ; Almeida-Leite et al, 2007 ), results from the interaction of the parasite and neuronal host cells that contribute to the development of the chronic digestive disease. Although neuronal cell death was reported in human megavisceras previously (Koberle and de Alcantara, 1960 ; González Cappa et al, 1987 ; DeFaria et al, 1988 ; Adad et al, 2001 , 2013 ; da Silveira et al, 2005 ; Nascimento et al, 2010 ), studies of the mechanisms of neuronal death in vivo and in vitro are scarce (Tanowitz et al, 1992 ; Almeida-Leite et al, 2007 ).…”