Involvement of Intestinal Enteroendocrine Cells in Neurological and Psychiatric Disorders

Abstract

Neurological and psychiatric patients have increased dramatically in number in the past few decades. However, effective treatments for these diseases and disorders are limited due to heterogeneous and unclear pathogenic mechanisms. Therefore, further exploration of the biological aspects of the disease, and the identification of novel targets to develop alternative treatment strategies, is urgently required. Systems-level investigations have indicated the potential involvement of the brain–gut axis and intestinal microbiota in the pathogenesis and regulation of neurological and psychiatric disorders. While intestinal microbiota is crucial for maintaining host physiology, some important sensory and regulatory cells in the host should not be overlooked. Intestinal epithelial enteroendocrine cells (EECs) residing in the epithelium throughout intestine are the key regulators orchestrating the communication along the brain-gut-microbiota axis. On one hand, EECs sense changes in luminal microorganisms via microbial metabolites; on the other hand, they communicate with host body systems via neuroendocrine molecules. Therefore, EECs are believed to play important roles in neurological and psychiatric disorders. This review highlights the involvement of EECs and subtype cells, via secretion of endocrine molecules, in the development and regulation of neurological and psychiatric disorders, including Parkinson’s disease (PD), schizophrenia, visceral pain, neuropathic pain, and depression. Moreover, the current paper summarizes the potential mechanism of EECs in contributing to disease pathogenesis. Examination of these mechanisms may inspire and lead to the development of new aspects of treatment strategies for neurological and psychiatric disorders in the future.

Emerging epigenetic dynamics in gut-microglia brain axis: experimental and clinical implications for accelerated brain aging in schizophrenia

“…Among these hormones are ghrelin and somatostatin, which are both critical to appetite regulation and exert a global effect on metabolism and growth ( Qi et al, 2021 ). Additionally, EECs are responsible for serotonin secretion in the gut ( Yu and Li, 2022 ). However, serotonergic dysregulation, particularly in the hippocampus, a highly plastic region linked to cognitive dysfunction and other behavioral deficits, has been consistently reported in the pathogenesis of SCZ ( Chatterjee et al, 2012 ; Ben-Azu et al, 2018b , 2023 ).…”

The Aging Enteric Nervous System

“…The most dominant subtype of intestinal enteroendocrine cells (EECs) in the colon is the enterochromaffin cell type (ECC). These cells communicate with luminal bacteria and interact with the afferent and efferent nerve terminals in the lamina propria by activated chemosensory receptors [95]. Though ECC comprises only 1% of intestinal epithelial cells, they produce and release 90% of the body's 5-HT [96,97].…”

“…The enteroendocrine L cell subtype produces and secretes glucagon-like peptide-1 (GLP1), GLP2, peptide YY (PYY), and oxyntomodulin. GLP1 and GLP2 have neuroprotective effects and trigger neurogenesis as well as anti-inflammatory effects [95], whereas PYY has an anti-secretory effect and prolongs intestinal transit [93]. Although some neuroendocrine molecules secreted by EECs have a beneficial effect, they are observed to correlate with multiple neurological and psychiatric disorders [95].…”

Mechanisms underlying the gut–brain communication: How enterochromaffin (EC) cells activate vagal afferent nerve endings in the small intestine

“…It is now appreciated that sensory nerve pathways between the gut and brain have significant roles in numerous physiological processes that underlie homeostasis, including hunger and satiety (Borgmann et al., 2021), responses to fluid and food intake (Bai et al., 2019; Shechter & Schwartz, 2018), gastric acid secretion (Mediavilla, 2020; Raybould et al., 1990), and responses to stress and mood (Guerrero‐Hreins et al., 2021). In fact, a variety of neurodegenerative diseases have also been linked to disruptions of the gut–brain axis (Yu & Li, 2022). Precisely how sensory nerves within the gut–brain axis contribute to health and disease is a major unresolved issue.…”