Auto‐Immunity Targeting the Enteric Nervous System May Cause Constipation in Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) that is primarily associated with somatic motor, sensory, and visual deficits. This disease can also cause gastrointestinal (GI) dysmotility, including constipation, but the etiology of this symptom in MS is poorly understood. Additionally, patients with MS typically have serum antibodies against CNS myelin and neuronal proteins that are also found in the enteric nervous system (ENS). Here, we test the hypothesis that constipation in MS is caused by auto‐antibodies that target the ENS. First, we investigated whether serum from MS patients contains antibodies that are immunoreactive against ENS targets of guinea pig myenteric plexus. We found that MS serum (n=20) targets ENS cells more intensely than age and gender matched healthy serum (n=20) (p<0.05), with stained structures including enteric neurons and glia. Next, we tested whether mice with experimental autoimmune encephalomyelitis (EAE) exhibit signs of constipation by assessing whole GI transit, colonic propulsive motility, and fecal consistency. EAE was induced in C57BL/6 or SJL/J mice by immunization against mouse spinal cord homogenate. Whole GI transit was slower in EAE SJL mice than controls (p<0.05) but was not different in EAE C57 mice. Both SJL and C57 mice with EAE had significantly slower colonic transit than control mice of the same background (C57 & SJL p<0.05). The percentage of fecal water content was significantly lower in SJL and C57 EAE mice compared to controls (C57 p<0.01, SJL p<0.0001). To test whether antibodies play a role in GI dysmotility in EAE, we assessed motility in B cell deficient EAE mice (muMt− mice). Colonic transit time was slower in EAE muMt− mice compared to muMt− control mice (p<0.05), but there was no difference in fecal water content. In summary, these data demonstrate that serum antibodies in MS patients target the ENS and could cause constipation. Further, the EAE mouse model of MS has disrupted GI motility, and this effect is partially ameliorated in B cell deficient EAE mice. Together, these data suggest that GI dysmotility in MS involves an autoimmune mediated disruption of enteric neuro‐glial function.Support or Funding InformationSupported by a pilot grant from the NMSS, and a predoctoral fellowship to ETS from NIDDK/NIH.