The TNF-\u03b1 antagonist etanercept reverses age-related decreases in colonic SERT expression and faecal output in mice

Bhavik Anil Patel,Kasonde Mandona,Leena Parmar,M Jill Saffrey,Chunfang Wang,Sara Fidalgo,Richard N Ranson,Mark S Yeoman,Melanie S Flint,Annabelle Panossian

doi:10.1038/srep42754

Bhavik Anil Patel, Kasonde Mandona + Show 8 more

Open Access

https://doi.org/10.1038/srep42754

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Abstract

Treatment for chronic constipation in older people is challenging and the condition has a major impact on quality of life. A lack of understanding about the causes of this condition has hampered the development of effective treatments. 5-HT is an important pro-kinetic agent in the colon. We examined whether alterations in colonic 5-HT signalling underlie age–related changes in faecal output in mice and whether these changes were due to an increase in TNF-α. Components of the 5-HT signalling system (5-HT, 5-HIAA, SERT) and TNF-α expression were examined in the distal colon of 3, 12, 18 and 24-month old mice and faecal output and water content monitored under control conditions and following the administration of etanercept (TNF-α inhibitor; 1 mg Kg−1). Faecal output and water content were reduced in aged animals. Age increased mucosal 5-HT availability and TNF-α expression and decreased mucosal SERT expression and 5-HIAA. Etanercept treatment of old mice reversed these changes, suggesting that age-related changes in TNFα expression are an important regulator of mucosal 5-HT signalling and pellet output and water content in old mice. These data point to “anti-TNFα” drugs as potential treatments for age-related chronic constipation.

Highlights

Treatment for chronic constipation in older people is challenging and the condition has a major impact on quality of life
The main findings of this study are 1) TNF-αexpression is elevated in the distal colon of 24 month old mice and this change is associated with a decrease in faecal pellet output and pellet water content; 2) Treatment of 24-month old mice with etanercept, a TNF-αantagonist, reversed the age-related decreases in pellet output and water content; 3) Etanercept reversed the age-related increase in mucosal 5-HT availability and decrease in serotonin transporter (SERT) expression suggesting that the age-related increase in TNF-αobserved in this tissue is responsible for the changes in SERT expression
Work in this and a previous study[6] has demonstrated that aged mice develop a phenotype that has some of the characteristics of human constipation

Summary

Introduction

Treatment for chronic constipation in older people is challenging and the condition has a major impact on quality of life. Components of the 5-HT signalling system (5-HT, 5-HIAA, SERT) and TNF-α expression were examined in the distal colon of 3, 12, 18 and 24month old mice and faecal output and water content monitored under control conditions and following the administration of etanercept (TNF-α inhibitor; 1 mg Kg−1). Etanercept treatment of old mice reversed these changes, suggesting that age-related changes in TNFα expression are an important regulator of mucosal 5-HT signalling and pellet output and water content in old mice. These data point to “anti-TNFα” drugs as potential treatments for age-related chronic constipation. Previously in old mice[6] and those observed in humans with CC14 Together these data strongly suggest that alterations in mucosal 5-HT can modulate colonic motility

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