Effect of a neural relay on liver regeneration in mice: activation of serotonin release from the gastrointestinal tract

Abstract

The development of therapeutic options to promote hepatic regeneration following severe liver injury is essential. While humoral factors have been reported as mechanisms of liver regeneration, the contributions of interorgan communication to liver regeneration have not been reported. In this study, we examined the effect of a neural relay on liver regeneration via activation of serotonin release from the gastrointestinal (GI) tract. Our results demonstrated that the afferent visceral nerve from the liver activates the efferent vagus nerve from the brain, leading to activation of serotonin release from the GI tract and contributing to liver regeneration. While it is difficult to apply these results directly to human health, we believe that this study may represent a step toward developing essential therapeutics to promote liver regeneration.

Ghrelin‐insulin‐like growth factor‐1 axis is activated via autonomic neural circuits in the non‐alcoholic fatty liver disease

“…Briefly, for PH, a midline skin incision was performed under general anesthesia, followed by removal of two‐thirds of normal liver tissue as previously described . For the selective afferent visceral nerve blockade, direct topical application of capsaicin (Wako Pure Chemical Industries, Osaka, Japan) dissolved in olive oil (50 mg/mL) was utilized to deafferentate the visceral nerve, which contains afferent sympathetic fibers from the hepatobiliary system . This method did not show effects on the other nerves, including the vagus nerves .…”

“…For the selective afferent visceral nerve blockade, direct topical application of capsaicin (Wako Pure Chemical Industries, Osaka, Japan) dissolved in olive oil (50 mg/mL) was utilized to deafferentate the visceral nerve, which contains afferent sympathetic fibers from the hepatobiliary system . This method did not show effects on the other nerves, including the vagus nerves . For selective afferent vagus nerve blockade, transection of the hepatic branch of the vagus nerve (including >90% of the afferent vagus nerve from the liver) was performed .…”

“…This method did not show effects on the other nerves, including the vagus nerves . For selective afferent vagus nerve blockade, transection of the hepatic branch of the vagus nerve (including >90% of the afferent vagus nerve from the liver) was performed . All procedures were performed under general anesthesia using intraperitoneal injection of medetomidine hydrochloride (Nippon Zenyaku Kogyo, Fukushima, Japan) 0.3 mg/kg + midazolam (Astellas Pharma, Tokyo, Japan) 4 mg/kg + butorphanol tartrate (Meiji Seika Pharma Corporation, Tokyo, Japan) 5 mg/kg.…”

“…Tissue samples for immunohistochemical staining were collected from each group at appropriate time points after the procedures. For the PH and neural blockade groups, tissues were collected 3 days after the procedure, as previously reported . Animals were deeply anesthetized with isoflurane, followed by perfusion of 4% paraformaldehyde in a transcardial manner.…”

“…Recently, it has been revealed that the autonomic nervous system is the key neural substrate that controls organ functions and mediates inter‐organ signals not only in physiological but also in pathological conditions. Indeed, it regulates the status of various diseases, the progression of cancer, and liver regeneration after partial hepatectomy . It promotes the release of serotonin from enterochromaffin cells in the small intestine via sympathetic nerve‐mediated signal transduction from the liver to the brain …”