Intrarectal Capsazepine Administration Modulates Colonic Mucosal Health in Mice

Abstract

Antagonism of transient receptor potential vanniloid-1 (TRPV1) and desensitization of transient receptor potential ankyrin-1 (TRPA1) nociceptors alleviate inflammatory bowel diseases (IBD)-associated chronic pain. However, there is limited literature available about their role in regulating the mucosal layer, its interaction with host physiology, and luminal microbial community. The present study focuses on the effects’ intra rectal administration of capsazepine (modulator of TRPA1/TRPV1 expressing peptidergic sensory neurons) on colonic mucus production and gut health. We performed histological analysis, gut permeability alteration, gene expression changes, metabolite profiling, and gut microbial abundance in the ileum, colon, and cecum content of these animals. Intra rectal administration of capsazepine modulates TRPA1/TRPV1-positive nociceptors (behavioral pain assays) and resulted in damaged mucosal lining, increased gut permeability, and altered transcriptional profile of genes for goblet cell markers, mucus regulation, immune response, and tight junction proteins. The damage to mucosal lining prevented its role in enterosyne (short chain fatty acids) actions. These results suggest that caution must be exercised before employing TRPA1/TRPV1 modulation as a therapeutic option to alleviate pain caused due to IBD.

Capsazepine-Induced Altered Colonic Mucosal Health Limits Isomalto-oligosaccharide Action in High-Fat Diet-Fed C57BL/6J Mice

“…In the HFD + CPZ group, there was further increase in the intestinal permeability, suggesting that CPZ rectal treatment along with HFD aggravated the damage to gut barrier. This observation corroborates to our previous findings demonstrating detrimental outcomes of CPZ . Our previous studies have demonstrated that IMO supplementation improves HFD-induced alteration in intestinal permeability. , However, in the present study, no improvement in intestinal permeability was observed in the HFD + CPZ + IMO group.…”

“…Colon innervating TRPA1 and TRPV1 +ve peptidergic sensory neurons regulate intestinal pain during inflammatory conditions like IBD , and are crucial for colonic mucosal health. ,, Our group’s previous research demonstrated the functional role of TRPA1 and TRPV1 channels in the regulation of intestinal mucus homeostasis. ,, CPZ administration inhibits TRPA1- and TRPV1-mediated nociceptive response and has been proposed as a possible candidate for therapeutics for IBD . However, it also reduces gastrointestinal mucus production and alters gut barrier integrity, which contrasts to its protective effects. , HFD feeding has detrimental effects on glucose homeostasis, mucus content in the colon, and gut barrier integrity. ,, Hence, considering the clinical scenario, we studied how HFD consumption affects the colonic mucosal health of mucosal compromised patients (CPZ administered). Furthermore, the efficacy of prebiotics in these conditions was tested.…”

“…The HFD group received rectal administration of PBS as vehicle (200 μL rectally, twice a day for 7 days followed by once in 2 days for 8 weeks). The HFD + CPZ group received rectal administration of CPZ as previously described with slight modification. , In brief, 200 μL of 531 μM CPZ rectal enemas twice daily for 7 days was administered. After 7 days, TRPA1 and TRPV1-associated pain responses using the eye wipe test and tail flick test were used to study the effect of rectal CPZ on functioning of TRPA1 and TRPV1 sensory nociceptive neurons.…”

“…Transient receptor potential channel antagonism (TRPV1) and desensitization (TRPA1) alleviate IBD-associated chronic pain. − An interesting study by Kistner et al, reported that capsazepine (CPZ)-induced systemic desensitization of TRPA1/TRPV1expressing sensory neurons results in prevention of pain or inflammation . However, our recent work using the same dose and mode of administration of CPZ suggests damaged mucosal lining, increased gut permeability, and an altered transcriptional profile of genes for goblet cell markers, mucus regulation, immune response, and TJPs …”

“…14 However, our recent work using the same dose and mode of administration of CPZ suggests damaged mucosal lining, increased gut permeability, and an altered transcriptional profile of genes for goblet cell markers, mucus regulation, immune response, and TJPs. 18 In the present work, we sought to study how the effects of a combination of intrarectal CPZ administration induced altered colonic mucosal health and HFD administration in mice. Furthermore, we also studied whether this combination prevents protective actions of dietary prebiotic, isomaltooligosaccharides, on HFD-associated complications.…”