EECs are located in the epithelium throughout the GI tract. They dynamically produce and store various peptide hormones and bioactive components, depending on the intestinal segments and epithelial homeostasis status. The regulation of EECs’ content profile, as well as their functions in energy metabolism and roles as incretins, has been reviewed elsewhere [20,21]. EECs can be further categorized into multiple subtypes, depending on their endocrine molecules production and secretion. For example, G cells can be identified by the secretion of gastrin; K cells uniquely secrete gastric inhibitory peptides; L cells produce and secrete GLP1, GLP2, PYY, and oxyntomodulin; I cells produce cholecystokinin (CCK); N cells secrete neurotensin; S cells secrete secretin; enterochromaffin cells (ECs) secrete serotonin; and enterochromaffin-like cells secrete histamine [20,21]. Here, we only focus on the subtypes of EECs that are potentially involved in neurological and psychiatric disorders.

L cells mostly secrete GLP1, GLP2, PYY, and oxyntomodulin, although PYY might also be co-expressed with gastrin, which is mostly secreted by G cells [22]. GLP1, GLP2, and PYY, which are secreted by L cells, and serotonin, secreted predominantly by ECs (Figure 2), are discussed in this paper. GLP1 and GLP2 have been shown to correlate with multiple neurological disorders. Serotonin also showed a correlation with depression and visceral pain, although this is still under debate. Besides incretin functions, GLP1 has been shown to exert anti-inflammatory effects in both the GI tract and central nervous system (CNS) [23,24,25]. Moreover, GLP1 possesses neuroprotective effects and triggers neurogenesis [26,27,28,29,30,31]. New evidence suggested that GLP1 and glucagon-like peptide 1 receptor (GLP1R), a receptor of GLP1, have protective effects on hypothalamic inflammation and leptin sensitivity in mice [25,32]. Despite the well-known source and their effects within the CNS, the GLP1 derived from intestinal EECs has also been suggested to play a role in neurological pathology, due to the feature wherein GLP1 is able to pass through the brain–blood barrier [33,34,35]. Similar to GLP1, L-cell-secreted GLP2 also possesses anti-inflammation effects [36,37,38]. In cows, GLP2 administration increased the intestinal villi height, mucosal surface, and proliferating cells, and decreased inflammation [39]. Further, GLP2 has a neuroprotective effect and can trigger neurogenesis in a similar manner as GLP1 [29,37,40,41,42]. Interestingly, the anti-inflammatory effects of other components of EEC content have recently been revealed, including PYY [43,44] and serotonin [45,46], which are likely associated with neuroinflammation. Therefore, accumulating evidence suggests that EECs and ECs could play important pathogenic and regulatory roles in neurological and psychiatric disorders.

PD is a common movement disorder that was originally characterized as a neurodegenerative disorder due to the loss of dopaminergic neurons and accumulated aggregation of α-synuclein fibrils (called Lewy bodies) (reviewed elsewhere previously [47]). However, studies have shown a new pathogenic aspect of PD, which could be linked to intestinal disorders, as well as to changes in intestinal microbiota and metabolites [15,48,49]. For instance, inflammatory bowel disease (IBD) has increased by 22 to 35% regarding the incidence of PD [50]. In addition, Sampson et al. reported that the GI microbiota was required for motor deficits, microglia activation, and α-synuclein pathology (PD symptoms), in a germ-free mice model overexpressing α-synuclein. Further, their results indicated that the microbial metabolites produced in PD patients enhanced the pathophysiology of PD [15]. Although with a negative correlation, others also found an association among the GI microbiota, the total faecal SCFAs, and PD incidence [48]. Researchers hypothesized that the origin of PD might lie in the enteric nervous system (ENS) [51,52]. Accordingly, α-synuclein was detected in GI mucosa in early PD patients [53,54].

Given the important luminal chemo-sensing and neuroendocrine functions of EECs, these recent results point to a hypothesis that EECs contribute to and regulate the pathogenesis of PD. Interestingly, in human intestinal tissue, the α-synuclein that triggers PD was colocalized with EECs, such as L cells and K cells [55,56]. Although the authors have not confirmed the original secretion location of the α-synuclein, the data in these studies strengthen the possibility of EECs’ involvement in PD progression.

Two potential mechanisms of EECs’ contribution in PD pathogenesis have been proposed. On one hand, the EECs are likely to be a source of α-synuclein, which is generated in response to specific microbial activation. Thereafter, the α-synuclein is transported into the brain via nerves, leading to the accumulation of α-synuclein [57] (Figure 3a). In line with this hypothesis, a very recent research work revealed the potential mechanisms. The authors identified an increased population of microorganism Akkermansia muciniphila in the guts of PD patients. The metabolites of this microorganism initiated α-synuclein aggregation in EECs, via activation of ryanodine receptor (RyR), calcium ion (Ca²⁺) release, and increased mitochondrial reactive oxygen species (ROS) generation [58] (Figure 3b). Moreover, a newly published paper indicated that another microbial metabolite, sodium butyrate, increased the α-synuclein mRNA expression in EECs through the autophagy-related 5 (Atg5) dependent autophagy pathway [59]. Holmqvist et al. provided evidence that α-synuclein was able to move from the intestine to the brain in rats [60]. Further, the transportation of α-synuclein from EECs to neurons requires GTPase called Ras-related protein Rab-35 (Rab35) and cell-to-cell contact, which is in line with the EECs’ characteristics [61].

On the other hand, the EECs’ secretion could also be suppressed by alterations in luminal SCFA concentrations and profiles. This could be the consequence of changes in specific microbes, which then increase the systemic inflammation, and this eventually enhances the progression of PD [62,63,64]. It was suggested that sodium butyrate increased the pro-inflammatory cytokines and α-synuclein mRNA expression in an EECs cell line and neuroblast cell line treated with EECs conditional medium [59]. Further, the EECs facilitate α-synuclein transport, which could trigger inflammation responses in microglia [65,66]. In contrast, a study in a PD mouse model suggested that the oral administration of butyrate could have protective effects on the neurobehavioral impairment via increased EEC activities, such as increased colonic GLP1 expression and brain GLP1R gene expression [67]. A recent animal study also indicated the neuroprotective effect of GLP1, triggered by chlorogenic acid [31]. These conflicting characteristics of EECs might be due to the variations in EECs’ homeostasis status or the hormone composition of EECs. In other words, the EECs that secrete GLP1 could be beneficial in terms of inflammation reduction, while the EECs that cannot secrete GLP1 but produce α-synuclein could be harmful. However, the detailed mechanism for either hypothesis is still unclear, especially regarding the extent to which EECs contribute to inflammation in PD patients. Future study will be needed to investigate the detailed mechanisms of EECs in PD progression.