Background & Aims Enteric neurons have been reported to be increased in inflamed regions of the bowel in patients with inflammatory bowel disease (IBD) or intestinal neurogangliomatosis. It is impossible to determine whether this hyperinnervation predates intestinal inflammation, results from it, or contributes to its severity in humans, so we studied this process in mice. Methods To determine whether the density of enteric neurons determines the severity of inflammation, we studied transgenic mice that have greater-than-normal (Hand2+/− mice) or fewer-than-normal (NSE-noggin mice, which overexpress noggin under the control of the neuron-specific enolase promoter) numbers of neurons in the enteric nervous system (ENS). Colitis was induced with trinitrobenzene sulfonic acid or dextran sulfate sodium and the intensity of the resulting inflammation in Hand2+/− and NSE-noggin mice was compared with that of wild-type littermates. Results Severity of each form of colitis (based on survival, symptom, and histologic scores; intestinal expression of genes that encode proinflammatory molecules; and levels of neutrophil elastase and p50 NF- Hand2+/− mice and significantly increased in NSE-noggin animals. Neither mouse differed from wild-type in the severity of delayed-type hypersensitivity (edema, T-cell and neutrophil infiltration, or expression of interleukin- - - -dinitro-1-fluorobenzene. Transgene effects on inflammation were therefore restricted to the gastrointestinal tract. Conclusion The severity of intestinal inflammation is associated with the density of the enteric innervation in mice. Abnormalities in ENS development might therefore contribute to the pathogenesis of IBD.

Background & Aims Hand2 is a basic helix-loop-helix transcription factor required for terminal differentiation of enteric neurons. We studied Hand2 haploinsufficient mice, to determine whether reduced expression of Hand2 allows sufficient enteric neurogenesis for survival but not for development of a normal enteric nervous system (ENS). Methods Enteric transcripts that encode Hand2 and the neuron-specific embryonic lethal abnormal vision proteins HuB, HuC, and HuD were quantified. Immunocytochemistry was used to identify and quantify neurons. Apoptosis was analyzed with the TUNEL procedure. Intracellular microelectrodes were used to record inhibitory junction potentials. Gastrointestinal transit and colonic motility were measured in vivo. Results Levels of of enteric Hand2 transcripts were associated with genotypes of mice, in the following order: Hand2+/+ > Hand2LoxP/+ > Hand2+/− > Hand2LoxP/−. Parallel reductions were found in expression of HuD and, in regional and phenotypic manners, numbers of neurons; numbers of nNOS+ and calretinin+, but not substance P+ or vasoactive intestinal peptide+ neurons, decreased. No effects were observed in stomach or cecum. Apoptosis was not detected, consistent with the concept that Hand2 inhibits neuronal differentiation, rather than regulates survival. The amplitude of inhibitory junction potentials in colonic circular muscle was similar in Hand2 wild-type and haploinsufficient mice, although in haploinsufficient mice, the purinergic component was reduced and a nitrergic component appeared. The abnormal ENS of haploinsufficient mice slowed gastrointestinal motility but protected mice against colitis. Conclusion Reduced expression of factors required for development of the ENS can cause defects in the ENS that are subtle enough to escape detection yet cause significant abnormalities in bowel function.

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A 77 year old African American woman with atrial fibrillation treated with amiodarone 200 mg daily for 67 months presented with new onset ascites, watery diarrhea, and peripancreatic lymphadenopathy. She had a mild elevation of her transaminases and alkaline phosphatase, though initial workup centered on ruling out malignancy. Ultimately, her liver biopsy demonstrated evidence of amiodarone induced hepatotoxicity. She had persistent liver damage requiring frequent paracenteses. This case highlights the importance of reassessing the need for amiodarone and performing routine recommended screening of liver chemistries during treatment.