Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) in young adults that has serious negative socioeconomic effects. In addition to symptoms caused by CNS pathology, the majority of MS patients frequently exhibit gastrointestinal dysfunction, which was previously either explained by the presence of spinal cord lesions or not directly linked to the autoimmune etiology of the disease. Here, we studied the enteric nervous system (ENS) in a B cell- and antibody-dependent mouse model of MS by immunohistochemistry and electron microscopy at different stages of the disease. ENS degeneration was evident prior to the development of CNS lesions and the onset of neurological deficits in mice. The pathology was antibody mediated and caused a significant decrease in gastrointestinal motility, which was associated with ENS gliosis and neuronal loss. We identified autoantibodies against four potential target antigens derived from enteric glia and/or neurons by immunoprecipitation and mass spectrometry. Antibodies against three of the target antigens were also present in the plasma of MS patients as confirmed by ELISA. The analysis of human colon resectates provided evidence of gliosis and ENS degeneration in MS patients compared to non-MS controls. For the first time, this study establishes a pathomechanistic link between the well-established autoimmune attack on the CNS and ENS pathology in MS, which might provide a paradigm shift in our current understanding of the immunopathogenesis of the disease with broad diagnostic and therapeutic implications.

In the gastrointestinal (GI) tract, nitric oxide (NO) has been shown over the last 25 years to exert a prominent function as inhibitory neurotransmitter. Apart from the regulation of secretion and resorption, NO from nitrergic neurons has been demonstrated to be crucial for GI smooth muscle relaxation and motility. In fact, several human diseases such as achalasia, gastroparesis, slow transit constipation or Hirschsprung's disease may involve dysfunctional nitrergic signaling. Most of NO's effects as neurotransmitter are mediated by NO-sensitive guanylyl cyclase (NO-GC) and further transduced by cGMP-dependent mechanisms. In contrast to the vascular system where NO from the endothelium induces relaxation by acting on NO-GC solely in smooth muscle cells, GI tissues contain several different NO-GCexpressing cell types that include smooth muscle cells, interstitial cells of Cajal and fibroblast-like cells. Based on this diverse localization of the NO receptor, the exact pathway(s) leading to NO-induced relaxation are still unknown. Global and cell-specific knockout mouse strains have been generated that lack enzymes participating in nitrergic signaling. These animals have been helpful in examining the role of NO in smooth muscle of the GI tract. Here, we discuss the current knowledge on NO-mediated mechanisms in the relaxation of GI smooth muscle in stomach, small and large intestine including sphincters. Special focus is placed on the integration of nitrergic signals by specialized cell types within the gut smooth muscle layers.

We conclude that short rings of murine colon can be effectively used to record spontaneous contractions. Although NO-GC in SMC determines smooth muscle tone, concerted action of NO-GC in both SMC and ICC modulates slow phasic contractions and large contractions.

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Background Nitric oxide (NO) mediates inhibitory neurotransmission and is a critical component of neuronal programs that generate propulsive contractions. NO acts via its receptor NO‐sensitive guanylyl cyclase (NO‐GC) which is expressed in smooth muscle cells (SMC) and interstitial cells of Cajal (ICC). Organ bath studies with colonic rings from NO‐GC knockout mice (GCKO) have indicated NO‐GC to modulate spontaneous contractions. The cell‐specific effects of NO‐GC on the dominant pan‐colonic propulsive contraction, the long distance contractions (LDCs), of whole colon preparations have not yet been described. Methods Contractions of whole colon preparations from wild type (WT), global, and cell‐specific GCKO were recorded. After transformation into spatiotemporal maps, motility patterns were analyzed. Simultaneous perfusion of the colon enabled the correlation of outflow with LDCs to analyze contraction efficiency. Key Results Deletion of NO‐GC in both ICC and SMC (ie, in GCKO and SMC/ICC‐GCKO) caused loss of typical LDC activity and instead generated high‐frequency LDC‐like contractions with inefficient propulsive activity. Frequency was also increased in WT, SMC‐GCKO, and ICC‐GCKO colon in the presence of L‐NAME to block neuronal NO synthase. LDC efficiency was dependent on NO‐GC in SMC as it was reduced in GCKO, SMC‐GCKO, and ICC/SMC‐GCKO colon; LDC efficiency was decreased in all genotypes in the presence of L‐NAME. Conclusions and Inferences NO/cGMP signaling is critical for normal peristaltic movements; as NO‐GC in both SMC and ICC is essential, both cell types appear to work in synchrony. The efficiency of contractions to expel fluid is particularly influenced by NO‐GC in SMC.