Male-specific colon motility dysfunction in the TashT mouse line

Abstract

Background

In Hirschsprung disease (HSCR), the absence of myenteric neural ganglia in the distal bowel prevents motility and thereby causes functional intestinal obstruction. Although surgical resection of the aganglionic segment allows HSCR children to survive this condition, a number of patients still suffer from impaired motility despite having myenteric ganglia in their postoperative distal bowel. Such phenomenon is also observed in patients suffering from other enteric neuropathies and, in both cases, colonic dysmotility is believed to result from abnormalities of myenteric ganglia and/or associated interstitial cells of Cajal (ICC). To better understand this, we used a recently described HSCR mouse model called TashT.

Methods

Intestinal motility parameters were assessed and correlated with extent of aganglionosis and with neuronal density in ganglionated regions. The neural composition of the myenteric plexus and the status of ICC networks was also evaluated using immunofluorescence.

Key Results

TashT^Tg/Tg mice display a strong male bias in the severity of both colonic aganglionosis and hypoganglionosis, which are associated with male-specific reduced colonic motility. TashT^Tg/Tg male mice also exhibit a specific increase in nNos⁺ neurons that is restricted to the most distal ganglionated regions. In contrast, Calretinin⁺ myenteric neurons, Sox10⁺ myenteric glial cells, and cKit⁺ ICC are not affected in TashT^Tg/Tg mice.

Conclusions and Inferences

Male-specific impairment of colonic motility in TashT^Tg/Tg mice is associated with both severe hypoganglionosis and myenteric neuronal imbalance. Considering these parameters in the clinic might be important for the management of postoperative HSCR patients.

In this study, we report that adult TashT^Tg/Tg mice that do not develop aganglionic megacolon suffer from chronic constipation in a male-specific manner. Extensive characterization of gastrointestinal (GI) motility and myenteric plexus structure/composition suggests that this is due to aganglionosis and/or hypoganglionosis combined with male-specific neuronal subtypes' imbalance in the ganglionated distal colon.

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