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EXPLORING THE ANTINOCICEPTIVE EFFECT OF INDOLES AND THE ARYL HYDROCARBON RECEPTOR IN AN EXPERIMENTAL MODEL OF IBD IN REMISSION
Date
May 18, 2024
Introduction: Chronic abdominal pain is a common and severely debilitating symptom of inflammatory bowel disease (IBD), that frequently occurs in patients in endoscopic remission. The mechanisms of chronic pain are not well understood, but recent data has shown that the gut microbiota plays an important role in modulating visceral sensitivity. The microbial components that mediate this effect are not fully established. Published data from our group demonstrates that elevated fecal butyrate is pro-nociceptive. Here we investigated the potential role of indoles, ligands of the aryl hydrocarbon receptor (AhR), as anti-nociceptive mediators.
Aim: To investigate the role of AhR receptors in visceral sensitivity in an experimental model of IBD in remission.
Methods: To model colitis in remission, male C57BL/6 mice were treated with 2.5% DSS in their drinking water for 5 days (n=9) or drinking water alone (n=9) and then allowed to recover for 5 weeks. Additional cohorts of animals (n=10 DSS, n=10 controls) received 3-indole propionic acid (IPA) from day 20 in their drinking water until the experimental endpoint. At week 5, visceral pain was evaluated by measuring the visceral motor reflex (VMR) to colorectal distention. The expression and activation of AhR in the dorsal root ganglia (DRG) was examined using RT-PCR. Fecal microbial composition was assessed using 16S rRNA gene V4 region amplicon sequencing.
Results: DSS-treated mice displayed increased visceral hypersensitivity compared to control mice [VMR at 60mmHg, DSS 0.045±0.007; Control 0.026± 0.006; p=0.034]. DSS-IPA mice demonstrated significantly reduced visceral hypersensitivity compared to DSS mice [VMR at 60mmHg. DSS-IPA 0.021±0.004; DSS 0.045±0.007; p=0.0036]. Ahr gene expression in the DRG was similar in all groups. IPA treatment of DSS mice resulted in comparable AhR activation in DRGs relative to control mice, demonstrated by Ahrr gene expression, which was significantly reduced in DSS-treated mice (p=0.0026). DSS-IPA mice showed reduced alpha diversity (Shannon) when compared to control (p=0.0413) or control-IPA mice (p=0.0234) which were not significantly different from each other. There was a significantly reduced differential abundance of butyrate-producing bacteria Lachnospiracea and Oscillospiraceae present in the DSS-IPA mice compared to DSS-treated mice.
Conclusions: Here we show that supplementation of an indole derivative in the post-inflammatory state reduces visceral hypersensitivity, increases the activation of AhR in DRGs and reduces the abundance of butyrate-producing microbes. These findings may lead to the design of innovative approaches for the treatment of chronic pain in IBD.
This research is funded by the Canadian Institutes for Health Research.
Aim: To investigate the role of AhR receptors in visceral sensitivity in an experimental model of IBD in remission.
Methods: To model colitis in remission, male C57BL/6 mice were treated with 2.5% DSS in their drinking water for 5 days (n=9) or drinking water alone (n=9) and then allowed to recover for 5 weeks. Additional cohorts of animals (n=10 DSS, n=10 controls) received 3-indole propionic acid (IPA) from day 20 in their drinking water until the experimental endpoint. At week 5, visceral pain was evaluated by measuring the visceral motor reflex (VMR) to colorectal distention. The expression and activation of AhR in the dorsal root ganglia (DRG) was examined using RT-PCR. Fecal microbial composition was assessed using 16S rRNA gene V4 region amplicon sequencing.
Results: DSS-treated mice displayed increased visceral hypersensitivity compared to control mice [VMR at 60mmHg, DSS 0.045±0.007; Control 0.026± 0.006; p=0.034]. DSS-IPA mice demonstrated significantly reduced visceral hypersensitivity compared to DSS mice [VMR at 60mmHg. DSS-IPA 0.021±0.004; DSS 0.045±0.007; p=0.0036]. Ahr gene expression in the DRG was similar in all groups. IPA treatment of DSS mice resulted in comparable AhR activation in DRGs relative to control mice, demonstrated by Ahrr gene expression, which was significantly reduced in DSS-treated mice (p=0.0026). DSS-IPA mice showed reduced alpha diversity (Shannon) when compared to control (p=0.0413) or control-IPA mice (p=0.0234) which were not significantly different from each other. There was a significantly reduced differential abundance of butyrate-producing bacteria Lachnospiracea and Oscillospiraceae present in the DSS-IPA mice compared to DSS-treated mice.
Conclusions: Here we show that supplementation of an indole derivative in the post-inflammatory state reduces visceral hypersensitivity, increases the activation of AhR in DRGs and reduces the abundance of butyrate-producing microbes. These findings may lead to the design of innovative approaches for the treatment of chronic pain in IBD.
This research is funded by the Canadian Institutes for Health Research.
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