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

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-alpha. Components of the 5-HT signalling system (5-HT, 5-HIAA, SERT) and TNF-alpha 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-alpha inhibitor; 1 mg Kg(-1)). Faecal output and water content were reduced in aged animals. Age increased mucosal 5-HT availability and TNF-alpha expression and decreased mucosal SERT expression and 5-HIAA. Etanercept treatment of old mice reversed these changes, suggesting that age-related changes in TNF alpha expression are an important regulator of mucosal 5-HT signalling and pellet output and water content in old mice. These data point to anti-TNF alpha drugs as potential treatments for age-related chronic constipation.