Sexually Dimorphic Effects of Histamine Degradation by Enteric Glial Histamine N-Methyltransferase (HNMT) on Visceral Hypersensitivity

Abstract

Histamine is a neuromodulator that affects gut motility and visceral sensitivity through intrinsic and extrinsic neural pathways, yet the mechanisms regulating histamine availability in these pathways remain poorly understood. Here, we show that enteric glia contribute to histamine clearance in the enteric nervous system (ENS) through their expression of the enzyme histamine N-methyltransferase (HNMT). Glial HNMT expression was initially assessed using immunolabeling and gene expression, and functionally tested using CRISPR-Cas9 to create a Cre-dependent conditional Hnmt ablation model targeting glia. Immunolabeling, calcium imaging, and visceromotor reflex recordings were used to assess the effects on ENS structure and visceral hypersensitivity. Immunolabeling and gene expression data show that enteric neurons and glia express HNMT. Deleting Hnmt in Sox10+ enteric glia increased glial histamine levels and altered visceromotor responses to colorectal distension in male mice, with no effect in females. Interestingly, deleting glial Hnmt protected males from histamine-driven visceral hypersensitivity. These data uncover a significant role for glial HNMT in histamine degradation in the gut, which impacts histamine-driven visceral hypersensitivity in a sex-dependent manner. Changes in the capacity of glia to clear histamines could play a role in the susceptibility to developing visceral pain in disorders of the gut–brain interaction.

Sex Differences in Visceral Pain and Comorbidities: Clinical Outcomes, Preclinical Models, and Cellular and Molecular Mechanisms

“…Similarly, dextran sodium sulfate (DSS) treatment to induce colonic inflammation affects male mice stronger than female mice showing less inflammatory infiltrates, less crypt damage, and lower TNFα production in the colon of female mice than male mice [52], with sex-differential changes in the immune responses in the colon [53]. Histamine enema increases visceral hypersensitivity in male mice but not female mice and deletion of histamine N-methyltransferase (HNMT) from enteric glia protects males from histamine-driven visceral hypersensitivity, with no effects on female mice [54]. Isovalerate, a bacterially derived shortchain fatty acid, into gut also increases visceral hypersensitivity in male mice but not female mice [26].…”

Sex Differences in Visceral Pain and Comorbidities: Clinical Outcomes, Preclinical Models, and Cellular and Molecular Mechanisms

“…Similarly, dextran sodium sulfate (DSS) treatment to induce colonic inflammation affects male mice more strongly than female mice showing less inflammatory infiltrates, less crypt damage, and lower TNFα production in the colon of female mice than male mice [56], with sex-differential changes in the immune responses in the colon [57]. Histamine enema increases visceral hypersensitivity in male mice but not female mice and deletion of histamine N-methyltransferase (HNMT) from enteric glia protects males from histamine-driven visceral hypersensitivity, with no effects on female mice [58]. The male-preferred colonic inflammatory pain (nociceptive pain) in experimental mice is similar to that observed in clinics showing IBS-D to be more prevalent in men than women [35].…”