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

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.

Factors related to acupuncture response in patients with chronic severe functional constipation: Secondary analysis of a randomized controlled trial

“…Bhavik Anil Patel et al . showed that fecal output and water content were reduced in aged animals and that age increased the availability of mucosal 5-hydroxytryptamine and tumor necrosis factor expression and decreased mucosal serotonin transporter expression and the availability of 5-hydroxyindoleacetic acid [ 24 ]. Moreover, constipation in elderly patients is also related to other factors, such as pelvic floor aging, decreased social activity, psychological disorders, comorbidity, and the effects of multiple drug usage [ 25 ].…”

Dysbiosis contributes to chronic constipation development via regulation of serotonin transporter in the intestine

“…Most (over 95%) 5-HT in body is secreted by enterochromaffin cells and it plays a important role in gut motility which has been found in many researches. It also associated with gastrointestinal motility disorder and abnormal sensation 12 – 14 . The plasma level of 5-HT in constipation-type IBS is reduced 15 , while by contrast, the plasma 5-HT level in diarrhea-type irritable bowel syndrome (IBS) patients is increased 16 .…”

Developmental and age-dependent plasticity of GABAA receptors in the mouse colon: Implications in colonic motility and inflammation

“…Nonetheless, numerous studies (4,17,43) have suggested that changes in the neurotransmitter systems of the ENS are a contributing factor to the developmental and the ageinduced decline in GI motility. However, it is important to note that mucosal signalling through the 5-HT system has also been shown to play an important role in age-induced changes in GI motility (44).…”