Enteroendocrine System Research Articles

Type 2 diabetes mellitus remission in sleeve gastrectomy patients: Role of enteroendocrine response and serum citrulline and I-FABP levels

IntroductionThis prospective cohort study examines the relationship between post-sleeve gastrectomy (SG) weight loss and serum citrulline, I-FABP levels, and the I-FABP/citrulline ratio in obese patients, alongside the correlation with type 2 diabetes mellitus (T2DM) remission. Methods88 participants were enrolled, including 48 undergoing SG and 21 with T2DM. 40 healthy individuals served as controls. Preoperative and 1-year postoperative assessments included citrulline, I-FABP, glucose, insulin, HbA1c, and C peptide levels. ResultsSignificant weight loss and T2DM remission (11/21) were observed post-SG. Preoperatively, patients had low citrulline and high I-FABP levels, which normalized postoperatively. A positive correlation was found between the I-FABP/citrulline ratio and weight, BMI, glucose, insulin, and C peptide levels. ConclusionSG not only induces enterocyte dysfunction and mass recovery but also may facilitate T2DM remission and alleviate obesity-related effects on the enteroendocrine system. These findings highlight the potential beneficial effects of SG on enteroendocrine function in obese patients.

Evaluation of the relationship between plasma glucagon-like peptide-2 and gastrointestinal dysbiosis in canine chronic enteropathies.

Chronic enteropathies are a common cause of morbidity in dogs and are associated with disruption of the normal gastrointestinal mucosal barrier. The objective of this prospective study was to determine the association between measures of gastrointestinal dysbiosis and plasma concentrations of glucagon-like peptide-2, a hormone responsible for normal mucosal structure, in dogs with chronic enteropathies. Fecal 16S V4 rRNA gene sequencing and quantitative PCR via the dysbiosis index was performed on 16 healthy controls and 18 dogs with chronic enteropathy prior to and 1 month after initiation of individualized therapy. Fasting and post-prandial plasma GLP-2 concentrations were measured via ELISA in healthy dogs and chronic enteropathy dogs at both time points. Alpha and beta diversity indices, as well as bacterial population abundances were compared between groups and time-points. Principal component analysis combined with least squares regression was used to identify taxa contributing to glucagon-like peptide-2 variance among groups. While the dysbiosis index did not differ between healthy dogs and dogs with chronic enteropathy, 16S V4 genomic sequencing identified 47 operational taxonomic units that differed between the groups, all but 2 of which resolved following chronic enteropathy treatment. Principal component analysis identified 6 families and 19 genera that contributed to differences in glucagon-like peptide-2 concentrations between groups. Dysbiosis associated with chronic enteropathies in dogs may contribute to the observed lower plasma glucagon-like peptide-2 concentrations. Further research into mechanisms of microbiota impact on the enteroendocrine system is needed. Association between glucagon-like peptide-2 secretion and microbiome indices may help to guide research into future treatment strategies for dogs with chronic enteropathy.

The Expression of Amino Acid and Fatty Acid Receptors Show an Age-Dependent Pattern Involving Oral Cavity, Jejunum and Lower Gut Sensing in Broiler Chickens.

This work aimed to evaluate the gene expression of amino acids (AA) and fatty acids (FA) sensors in the gastrointestinal tract (GIT) of chickens at two different ages (7 and 26 days post-hatch). Sixteen broilers (Ross 308) were selected, and ten sections of the GIT, including upper (tongue base, upper palate, crop, proventriculus), middle (gizzard, duodenum, jejunum, ileum), and lower GIT section (cecum, colon) were collected for analysis. Relative gene expression of AA (T1R1, T1R3, mGluR1, mGluR4, CaSR, GPR139, GPRC6A, GPR92) and FA (FFAR2, FFAR3, FFAR4) sensors were assessed using qPCR. The statistical model included age, GIT section, and gene. In addition, the correlations between gene expressions were calculated. At day 7, a significantly (p = 0.004) higher expression of AA sensors in the oral cavity and FA sensors in the lower GIT section (i.e., cecum and colon) compared to the middle section was recorded. A higher expression of AA compared to FA sensors was detected at the upper GIT section in 7 (p < 0.001) and 26-day-old chickens (p = 0.026). Thus, at day 7, AA sensors were predominantly (p < 0.05) expressed in the upper GIT section (mainly oral cavity), while FA sensors were mainly expressed in the lower GIT section, at cecum (FFR2 and 4) or colon (FFAR3). These results may indicate that in early life, both ends of the GIT are fundamental for feed intake (oral cavity) and development of the microbiota (cecum and colon). In contrast, at 26 days of age, the results showed the emergence of both AA and FA sensors in the jejunum, presumably indicating the essential role of the jejunum in the digestion absorption of nutrients and the signaling to the brain (gut-brain axis) through the enteroendocrine system. Significant positive correlations were observed between T1R1 and T1R3 (r = 0.85, p < 0.001), CaSR and T1R1 (r = 0.78, p < 0.001), CaSR and T1R3 (r = 0.45, p < 0.050), and mGluR1 and FFAR3 (r = 0.46, p < 0.050). It is concluded that the gene expression is greater in the oral cavity for AA sensors and the lower gut for FA sensors. On day 26, the role of jejunum regarding nutrient sensing is highlighted.

FRI009 Microbiome Affects Host Metabolic Homeostasis Via Differential Regulation Of Gene Expression In The Endocrine System

Abstract Disclosure: W. Milhouse: None. H. Ren: None. Dysbiosis has been implicated in many metabolic disorders, but the exact role of microbiota is not completely understood. To address this question, we used germ-free (GF) and conventional (CON) mouse models to examine the expression of genes critical for endocrine regulation of metabolic homeostasis. Samples of the mediobasal hypothalamus (MBH) were obtained from 18 germ-free and 18 conventional C57BL/6 mice (n=9 males, 9 females). Each gene transcript was quantified using quantitative real-time polymerase chain reaction (qRT-PCR). We also collected the serum from both cohorts and measured ad libitum insulin and leptin concentrations by enzyme-linked immunosorbent assay (ELISA). Our results showed that, in the MBH, GF mice had increased expression of neuropeptides involved in feeding regulation, i.e., Neuropeptide Y (Npy) and Proopiomelanocortin (Pomc), compared to CON mice (p &amp;lt; 0.0001). Furthermore, CON mice had increased expression of a negative regulator of leptin signaling, Suppressor of cytokine signaling 3 (Socs3), in the MBH. Consistently, serum leptin in CON male mice was higher than that of male GF mice (p &amp;lt; 0.001). In the gut samples, the GF cohort demonstrated increased expression of gut hormones that promote satiety, such as Peptide yy (Pyy) and Cholecystokinin (Cck), respectively (p &amp;lt; 0.05 and p &amp;lt; 0.0001). The absence of a microbiome had differing effects on the expression of incretin hormones and the G protein-coupled receptors (GPCRs) that stimulate their secretion. In the jejunum, ileum, and colon of CON mice, expression of Glucagon-like peptide 1 (Glp-1) was increased compared to that of GF mice (p &amp;lt; 0.001, p &amp;lt; 0.05, and p &amp;lt; 0.0001, respectively). Conversely, Glucose-dependent insulinotropic polypeptide (Gip) showed increased expression in the duodenum of male and female GF mice (p &amp;lt; 0.0001). G protein-coupled receptor 119 (Gpr119) and G protein-coupled receptor 120 (Gpr120) showed increased expression only in the colon of female GF mice (p &amp;lt; 0.0001 and p &amp;lt; 0.01, respectively). Germ-free and conventional mice demonstrated comparable ad libitum insulin concentrations. We conclude that the increased expression of Pomc, Gip, Cck, and Pyy and the increased leptin sensitivity in GF mice contribute to the lean phenotype observed in these mice. The additional increase in Npy and decrease in Glp-1 likely play a compensatory role in regulating energy consumption and expenditure. Thus, the microbiome may impinge upon diverse effectors of the neuroendocrine and enteroendocrine systems to regulate host metabolism, influencing energy consumption and expenditure in the development of obesity. Presentation: Friday, June 16, 2023

Host-diet-gut microbiome interactions influence human energy balance: a randomized clinical trial

The gut microbiome is emerging as a key modulator of human energy balance. Prior studies in humans lacked the environmental and dietary controls and precision required to quantitatively evaluate the contributions of the gut microbiome. Using a Microbiome Enhancer Diet (MBD) designed to deliver more dietary substrates to the colon and therefore modulate the gut microbiome, we quantified microbial and host contributions to human energy balance in a controlled feeding study with a randomized crossover design in young, healthy, weight stable males and females (NCT02939703). In a metabolic ward where the environment was strictly controlled, we measured energy intake, energy expenditure, and energy output (fecal and urinary). The primary endpoint was the within-participant difference in host metabolizable energy between experimental conditions [Control, Western Diet (WD) vs. MBD]. The secondary endpoints were enteroendocrine hormones, hunger/satiety, and food intake. Here we show that, compared to the WD, the MBD leads to an additional 116 ± 56 kcals (P < 0.0001) lost in feces daily and thus, lower metabolizable energy for the host (89.5 ± 0.73%; range 84.2-96.1% on the MBD vs. 95.4 ± 0.21%; range 94.1-97.0% on the WD; P < 0.0001) without changes in energy expenditure, hunger/satiety or food intake (P > 0.05). Microbial 16S rRNA gene copy number (a surrogate of biomass) increases (P < 0.0001), beta-diversity changes (whole genome shotgun sequencing; P = 0.02), and fermentation products increase (P < 0.01) on an MBD as compared to a WD along with significant changes in the host enteroendocrine system (P < 0.0001). The substantial interindividual variability in metabolizable energy on the MBD is explained in part by fecal SCFAs and biomass. Our results reveal the complex host-diet-microbiome interplay that modulates energy balance.

GSPE Pre-Treatment Exerts Long-Lasting Preventive Effects against Aging-Induced Changes in the Colonic Enterohormone Profile of Female Rats.

The impact that healthy aging can have on society has raised great interest in understanding aging mechanisms. However, the effects this biological process may have on the gastrointestinal tract (GIT) have not yet been fully described. Results in relation to changes observed in the enteroendocrine system along the GIT are controversial. Grape seed proanthocyanidin extracts (GSPE) have been shown to protect against several pathologies associated with aging. Based on previous results, we hypothesized that a GSPE pre-treatment could prevent the aging processes that affect the enteroendocrine system. To test this hypothesis, we treated 21-month-old female rats with GSPE for 10 days. Eleven weeks after the treatment, we analyzed the effects of GSPE by comparing these aged animals with young animals. Aging induced a greater endocrine response to stimulation in the upper GIT segments (cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1)), a decrease in the mRNA abundance of GLP-1, peptide YY (PYY) and chromogranin A (ChgA) in the colon, and an increase in colonic butyrate. GSPE-treated rats were protected against a decrease in enterohormone expression in the colon. This effect is not directly related to the abundance of microbiome or short-chain fatty acids (SCFA) at this location. GSPE may therefore be effective in preventing a decrease in the colonic abundance of enterohormone expression induced by aging.

The microbiome-gut-brain axis in epilepsy: pharmacotherapeutic target from bench evidence for potential bedside applications.

The gut-brain axis augments the bidirectional communication between the gut and brain and modulates gut homeostasis and the central nervous system through the hypothalamic-pituitary-adrenal axis, enteroendocrine system, neuroendocrine system, inflammatory and immune pathways. Preclinical and clinical reports showed that gut dysbiosis might play a major regulatory role in neurological diseases such as epilepsy, Parkinson's, multiple sclerosis, and Alzheimer's disease. Epilepsy is a chronic neurological disease that causes recurrent and unprovoked seizures, and numerous risk factors are implicated in developing epilepsy. Advanced consideration of the gut-microbiota-brain axis can reduce ambiguity about epilepsy pathology, antiepileptic drugs, and effective therapeutic targets. Gut microbiota sequencing analysis reported that the level of Proteobacteria, Verrucomicrobia, Fusobacteria, and Firmicutes was increased and the level of Actinobacteria and Bacteroidetes was decreased in epilepsy patients. Clinical and preclinical studies also indicated that probiotics, ketogenic diet, faecal microbiota transplantation, and antibiotics can improve gut dysbiosis and alleviate seizure by enhancing the abundance of healthy biota. This study aims to give an overview of the connection between gut microbiota, and epilepsy, how gut microbiome changes may cause epilepsy, and whether gut microbiome restoration could be used as a treatment for epilepsy.

The Gut Microbiome Influences the Gene Expression Profile of Neuroendocrine and Enteroendocrine Systems

Objective/Hypothesis: The gut microbiome influences metabolism, but the underlying mechanisms are not completely understood. We hypothesized that the gut microbiome modulates metabolism by regulating the expression of key neuroendocrine and enteroendocrine genes such as neuropeptide Y (Npy) which is a potent brain orexigenic peptide and G-protein-coupled receptor-17 (Gpr17) which decreases incretin secretion in the gut.&#x0D; Approach: The gene expression profiles in mouse hypothalamus and gastrointestinal tract segments (duodenum, jejunum, ileum, and colon) were compared from germ-free (GF) mice (n=9 females, n=9 males) and conventional mice (n=9 females, n=9 males). Gene transcription was determined through total RNA yield extracted from the various tissues using qRT-qPCR. The data was analyzed using two-way ANOVA and unpaired t-test.&#x0D; Results: We found that RNA yield in brain and gut tissues differed in a sex and microbiome dependent manner. The medial basal hypothalamus of the female germ-free mice had lower RNA yield compared with conventional female mice (p=0.0082). In the intestine, the RNA concentrations of the germ-free mice showed a decrease from the proximal to distal gut, however, an opposite trend was observed in the conventional mice with an overall increase of concentration from the proximal to distal gut. This trend may reflect the high concentration of the microbiota in the distal gut. Regarding gene expression of the neuroendocrine and enteroendocrine systems, Npy had lower expression in the medial basal hypothalamus (MBH) of conventional males (p=0.004), Gpr17 showed moderate duodenal expression in conventional mice (p=0.029), and Gpr17 showed increased duodenal expression in germ-free females (p=0.044).&#x0D; Summary/Conclusions: With enriched microbiota in the ileum and colon, our results indicate that gut microbiota increase host gene transcription in the distal gut segments. Future studies will aim at investigating the mechanistic link between the microbiome and regulation of gene expression in neuroendocrine and enteroendocrine tissues.

Inhibitory Effects of Dansam and &lt;italic&gt;Dansam-eum&lt;/italic&gt; on Reflux Esophagitis and Migration of Cancer Cells

Purpose: We examined the effects of Dansam (Salvia miltiorrhiza Bunge, SM) and Dansam-eum (DSE) on gastroesophageal reflux disease (GERD) and reflux esophagitis by comparing the inhibitory effects of SM and DSE with the representative treatment of PPI Omeprazole to determine if the effects of the prescription DSE based on Korean medicine are better than those of a single-use of SM.Methods: We performed experiments using both animal models and cancer cells.Results: Comparison of SM and DSE with PPI in the animal model tests revealed that the effects were superior for SM and DSE than for PPI in all categories (8-OHdG, p-IκB, PAR2, COX-1, cathelicidin, p-JNK, Caspase 3, ATP6V1B1, GRPR, serotonin, and NPY). In three categories (COX-1, serotonin, and NPY), SM and DSE showed superior results over the Controls. In the animal model tests, DSE was superior to SM in all categories except for serotonin. The anti-cancer effects observed in cancer cell tests revealed that SM and DSE had meaningful results in terms of cytotoxicity and cell movement rate, as well as in cancer cell apoptosis.Conclusions: We confirmed that SM and DSE can have effects on reflux esophagitis through the regulation of oxidative stress, inflammation, mucosal protection, apoptosis, proton pumping, and the enteroendocrine system in the stomach and esophagus. We also confirmed that SM and DSE have superior effects to those of PPI on all aspects, especially gastric mucosa protection and enteroendocrine system control. We also confirmed that SM and DSE have anti-cancer effects. Above all, we confirmed that DSE has superior effects on almost all aspects compared to using SM alone.

Neuroendocrinology of the lung revealed by single-cell RNA sequencing.

Pulmonary neuroendocrine cells (PNECs) are sensory epithelial cells that transmit airway status to the brain via sensory neurons and locally via calcitonin gene-related peptide (CGRP) and γ- aminobutyric acid (GABA). Several other neuropeptides and neurotransmitters have been detected in various species, but the number, targets, functions, and conservation of PNEC signals are largely unknown. We used scRNAseq to profile hundreds of the rare mouse and human PNECs. This revealed over 40 PNEC neuropeptide and peptide hormone genes, most cells expressing unique combinations of 5-18 genes. Peptides are packaged in separate vesicles, their release presumably regulated by the distinct, multimodal combinations of sensors we show are expressed by each PNEC. Expression of the peptide receptors predicts an array of local cell targets, and we show the new PNEC signal angiotensin directly activates one subtype of innervating sensory neuron. Many signals lack lung targets so may have endocrine activity like those of PNEC-derived carcinoid tumors. PNECs are an extraordinarily rich and diverse signaling hub rivaling the enteroendocrine system.

Enteroendocrine peptides, growth, and the microbiome during the porcine weaning transition

BackgroundGrowth rate in pigs can be affected by numerous factors that also affect feeding behavior and the microbiome. Recent studies report some communication between the microbiome and the enteroendocrine system. The present study examined if changes in the piglet microbiome between birth and during the weaning transition can be correlated either positively or negatively with growth rate and plasma concentrations of enteroendocrine peptides.ResultsDuring the post-weaning transition, a 49% reduction in average daily gain was observed at day 24 (P < 0.05) relative to day 21. Pigs recovered by day 28 with body weight and average daily gain increases of 17% and 175%, respectively relative to day 24 and the highest rate of gain was measured at day 35 (462 g/day). The time interval between day 21–24 had the highest number of correlations (n = 25) between the relative abundance differences in taxa over time and corresponding percent weight gain. Amplicon sequence variants with the greatest correlation with percent weight gain between day 21–24 belonged to families Prevotellaceae NK3B31 (ρ = 0.65, P < 0.001), Veillonellaceae (ρ = 0.63, P < 0.001) and Rikenellaceae RC9 (ρ = 0.62, P < 0.001). Seven taxa were positively correlated with percent weight gain between day 24–28. Eight taxa were positively correlated with percent weight gain between day 28–35, of which four were Clostridia. Only Lactobacillus reuteri was positively correlated across both day 24–28 and day 28–35 analyses. Insulin-like growth factor 1 (IGF-1; R2 = 0.61, P < 0.001), glucose-dependent insulinotropic polypeptide (GIP; R2 = 0.20, P < 0.001), glucagon-like peptide 1 (GLP-1; R2 = 0.51, P < 0.001), and glucagon-like peptide 2 (GLP-2; R2 = 0.21, P < 0.001) were significantly associated with the piglet fecal community NMDS, while serotonin showed no significant association (R2 = 0.03, P = 0.15). Higher concentrations of GLP-1 and GLP-2 characterized day 1 fecal communities, while GIP levels had the strongest relationship primarily with samples ordinated with the day 21 cluster.ConclusionsDemonstration of an association of certain taxa with individual gut peptides at specific ages suggests the potential for the microbiome to elicit changes in the gut enteroendocrine system during early postnatal development in the pig.

OR08-4 Endocrine Mechanisms of an Orphan G Protein-Coupled Receptor Regulating Metabolic Homeostasis

Abstract G protein-coupled receptors (GPCRs) are the largest protein family and amenable for pharmacological manipulation. GPCRs in the neuroendocrine and enteroendocrine systems respond to various biological cues and in turn exert crucial roles in maintaining whole body metabolic homeostasis. For example, GPCRs in the gastrointestinal tract are involved in maintaining glucose and energy homeostasis by regulating the release of gut hormones in response to luminal dietary nutrients as well as microbial metabolites. We recently identified that an orphan GPCR, Gpr17, was co-expressed in glucagon-like peptide-1 (GLP-1)-expressing EECs in human and rodent intestinal epithelium. We reported that acute genetic ablation of Gpr17 in intestinal epithelium (iKO) improved oral glucose tolerance and glucose-stimulated insulin secretion (GSIS) in female and male mice through increased secretion of incretin hormone in response to nutrient ingestion (Cell Reports, 2022). In the neuroendocrine system, we previously identified Gpr17 as the transcription target of Forkhead box protein O1 (FoxO1) in the hypothalamus and generated hypothalamic neuron specific Gpr17 knockout animals (Cell, 2012). Our results demonstrated that agouti-related peptide (AgRP) neuron Gpr17 knockout mice had increased satiety during fasting-refeeding challenge (Diabetes, 2015) and that proopiomelanocortin (POMC) neuron Gpr17 knockout mice had increased alpha-melanocyte stimulating hormone (aMSH) processing and increased firing of POMC neurons (Nutrition &amp; Diabetes, 2019). However, how Gpr17 may regulate energy balance especially regarding leptin hormone signaling is unclear. To address this question, we used genetic knockout approach to generate Gpr17 conditional knockout in leptin receptor expressing neurons in the brain. We found Gpr17 deficiency in leptin receptor expressing neurons increased leptin sensitivity in animals and resulted in reduced food intake, which corresponded with reduced inflammatory response in the hypothalamus. Moreover, male Gpr17 whole body knockout mice have improved intraperitoneal glucose tolerance, and increased insulin sensitivity in hyperinsulinemic-euglycemic clamp studies. In conclusion, our collective body of work showed that ablation of Gpr17 signaling in the neuroendocrine and enteroendocrine systems led to improved neurohormonal regulation to maintain metabolic homeostasis, indicating functionally targeting this GPCR may lead to better therapeutic outcome of diabetes and obesity. Presentation: Saturday, June 11, 2022 12:15 p.m. - 12:30 p.m.

S149 Patient-Derived Enteroids and Colonoids for Measuring Enteroendocrine Function in Response to Luminal Contents: A Proof-of-Concept Study in Parkinson’s Disease

Introduction: In vitro studies of the gut-brain axis will require precise models of enteroendocrine function that replicate both patient-specific phenotype and intestinal milieu. Here we establish one such model for measuring the effects of stool and short-chain fatty acids (SCFA) on L-cell activity in Parkinson’s disease (PD). We have adapted a patient-derived organoid system which replicates intestinal epithelial function, immune responsiveness, and barrier integrity to respond directly to luminal contents including stool. Given the emerging importance of the enteroendocrine system in mediating microbiota-derived gut-brain signals in PD and other neurologic diseases, our system provides a needed platform for querying L-cells from a single stem-cell niche. Methods: Ileal and sigmoid colon biopsies were taken from PD patients and matched healthy volunteers between the ages of 40 and 80 years. 3D spherical organoids were generated from crypts isolated by EDTA, embedded in an extracellular matrix protein scaffold, and treated with growth factors to expand Lgr5+ stem cells through serial passages. Organoid polarity was inverted such that the apical surface faced outward. Enteroids and colonoids were then cocultured with stool supernatant or SCFA mixtures that resembled PD or control intestinal milieu. Glucagon-like peptide 1 (GLP-1) secreted by L-cells into the spheres was measured by ELISA after lysis and normalized to DNA content. Results: 3D epithelial organoids were successfully generated from ileal and colonic crypts from 7 PD and 7 control patients. L-cell presence was verified by immunohistochemistry for GLP-1 and chromogranin A. Spherical organoids were successfully inverted before coculture. GLP-1 secretion by control organoids was diminished in the presence of PD stool or SCFA relative to control milieu, and secretion by PD organoids was further diminished in either coculture condition. Conclusion: This proof-of-concept study establishes patient-derived organoids as a platform technology for measuring enteroendocrine responses to luminal contents, including stool and SCFA. Here, we use this technique to demonstrate that PD and healthy L-cells respond differently to SCFA in the stool. However, our novel system may be adapted to study a vast array of patient-specific enteroendocrine responses to stool microbiota, metabolites, and drugs.

In vivo drug discovery for increasing incretin-expressing cells identifies DYRK inhibitors that reinforce the enteroendocrine system

Analogs of the incretin hormones Gip and Glp-1 are used to treat type 2 diabetes and obesity. Findings in experimental models suggest that manipulating several hormones simultaneously may be more effective. To identify small molecules that increase the number of incretin-expressing cells, we established a high-throughput invivo chemical screen by using the gip promoter to drive the expression of luciferase in zebrafish. All hits increased the numbers of neurogenin 3-expressing enteroendocrine progenitors, Gip-expressing K-cells, and Glp-1-expressing L-cells. One of the hits, a dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) inhibitor, additionally decreased glucose levels in both larval and juvenile fish. Knock-down experiments indicated that nfatc4, a downstream mediator of DYRKs, regulates incretin+ cell number in zebrafish, and that Dyrk1b regulates Glp-1 expression in an enteroendocrine cell line. DYRK inhibition also increased the number of incretin-expressing cells in diabetic mice, suggesting a conserved reinforcement of the enteroendocrine system, with possible implications for diabetes.

Role of gut microbiota-derived signals in the regulation of gastrointestinal motility.

The gastrointestinal (GI) tract harbors trillions of commensal microbes, called the gut microbiota, which plays a significant role in the regulation of GI physiology, particularly GI motility. The GI tract expresses an array of receptors, such as toll-like receptors (TLRs), G-protein coupled receptors, aryl hydrocarbon receptor (AhR), and ligand-gated ion channels, that sense different gut microbiota-derived bioactive substances. Specifically, microbial cell wall components and metabolites, including lipopeptides, peptidoglycan, lipopolysaccharides (LPS), bile acids (BAs), short-chain fatty acids (SCFAs), and tryptophan metabolites, mediate the effect of gut microbiota on GI motility through their close interactions with the enteroendocrine system, enteric nervous system, intestinal smooth muscle, and immune system. In turn, GI motility affects the colonization within the gut microbiota. However, the mechanisms by which gut microbiota interacts with GI motility remain to be elucidated. Deciphering the underlying mechanisms is greatly important for the prevention or treatment of GI dysmotility, which is a complication associated with many GI diseases, such as irritable bowel syndrome (IBS) and constipation. In this perspective, we overview the current knowledge on the role of gut microbiota and its metabolites in the regulation of GI motility, highlighting the potential mechanisms, in an attempt to provide valuable clues for the development of gut microbiota-dependent therapy to improve GI motility.

Mitchell-Riley Syndrome: Improving Clinical Outcomes and Searching for Functional Impact of RFX-6 Mutations.

Aims/HypothesisCaused by biallelic mutations of the gene encoding the transcription factor RFX6, the rare Mitchell–Riley syndrome (MRS) comprises neonatal diabetes, pancreatic hypoplasia, gallbladder agenesis or hypoplasia, duodenal atresia, and severe chronic diarrhea. So far, sixteen cases have been reported, all with a poor prognosis. This study discusses the multidisciplinary intensive clinical management of 4 new cases of MRS that survived over the first 2 years of life. Moreover, it demonstrates how the mutations impair the RFX6 function.MethodsClinical records were analyzed and described in detail. The functional impact of two RFX6R181W and RFX6V506G variants was assessed by measuring their ability to transactivate insulin transcription and genes that encode the L-type calcium channels required for normal pancreatic beta-cell function.ResultsAll four patients were small for gestational age (SGA) and prenatally diagnosed with duodenal atresia. They presented with neonatal diabetes early in life and were treated with intravenous insulin therapy before switching to subcutaneous insulin pump therapy. All patients faced recurrent hypoglycemic episodes, exacerbated when parenteral nutrition (PN) was disconnected. A sensor-augmented insulin pump therapy with a predictive low-glucose suspension system was installed with good results. One patient had a homozygous c.1517T>G (p.Val506Gly) mutation, two patients had a homozygous p.Arg181Trp mutation, and one patient presented with new compound heterozygosity. The RFX6V506G and RFX6R181W mutations failed to transactivate the expression of insulin and genes that encode L-type calcium channel subunits required for normal pancreatic beta-cell function.Conclusions/InterpretationMultidisciplinary and intensive disease management improved the clinical outcomes in four patients with MRS, including adjustment of parenteral/oral nutrition progression and advanced diabetes technologies. A better understanding of RFX6 function, in both intestine and pancreas cells, may break ground in new therapies, particularly regarding the use of drugs that modulate the enteroendocrine system.

Gut-Brain Communication in Parkinson's Disease: Enteroendocrine Regulation by GLP-1.

Defective gut-brain communication has recently been proposed as a promoter of neurodegeneration, but mechanisms mediating communication remain elusive. In particular, the Parkinson's disease (PD) phenotype has been associated with both dysbiosis of intestinal microbiota and neuroinflammation. Here, we review recent advances in the PD field that connect these two concepts, providing an explanation based on enteroendocrine signaling from the gut to the brain. There have been several recent accounts highlighting the importance of the microbiota-gut-brain axis in PD. The objective of this review is to discuss the role of the neuroendocrine system in gut-brain communication as it relates to PD pathogenesis, as this system has not been comprehensively considered in prior reviews. The incretin hormone glucagon-like peptide 1 (GLP-1) is secreted by enteroendocrine cells of the intestinal epithelium, and there is evidence that it is neuroprotective in animal models and human subjects with PD. Agonists of GLP-1 receptors used in diabetes appear to be useful for preventing neurodegeneration. New tools and models have enabled us to study regulation of GLP-1 secretion by intestinal microbiota, to understand how this process may be defective in PD, and to develop methods for therapeutically modifying disease development or progression using the enteroendocrine system. GLP-1 secretion by enteroendocrine cells may be a key mediator of neuroprotection in PD, and new findings in this field may offer unique insights into PD pathogenesis and therapeutic strategies.

The Sensory Mechanisms of Nutrient-Induced GLP-1 Secretion.

The enteroendocrine system of the gut regulates energy homeostasis through the release of hormones. Of the gut-derived hormones, GLP-1 is particularly interesting, as analogs of the hormone have proven to be highly effective for the treatment of type 2 diabetes mellitus and obesity. Observations on increased levels of GLP-1 following gastric bypass surgery have enhanced the interest in endogenous hormone secretion and highlighted the potential of endogenous secretion in therapy. The macronutrients and their digestive products stimulate the secretion of GLP-1 through various mechanisms that we have only begun to understand. From findings obtained from different experimental models, we now have strong indications for a role for both Sodium-Glucose Transporter 1 (SGLT1) and the K+ATP channel in carbohydrate-induced GLP-1 secretion. For fat, the free fatty acid receptor FFA1 and the G-protein-coupled receptor GPR119 have been linked to GLP-1 secretion. For proteins, Peptide Transporter 1 (Pept1) and the Calcium-Sensing Receptor (CaSR) are thought to mediate the secretion. However, attempts at clinical application of these mechanisms have been unsuccessful, and more work is needed before we fully understand the mechanisms of nutrient-induced GLP-1 secretion.

Digital Spatial Profiling Reveals Functional Shift of Enterochromaffin Cell in Patients With Ulcerative Colitis.

As a major component of the enteroendocrine system, enterochromaffin (EC) cells play a key role in ulcerative colitis (UC). However, the scarcity of EC cells has limited the investigation of their function. In this study, we applied digital spatial profiling to acquire transcriptomic data for EC cells and other epithelial cells from colonoscopic biopsy samples from eight patients with UC and seven healthy controls. Differential expression analysis, gene set enrichment analysis, and weighted gene coexpression network analysis were performed to identify differentially expressed genes and pathways and coexpression networks. Results were validated using an online dataset obtained by single-cell RNA sequencing, along with immunofluorescence staining and quantitative real-time PCR. In healthy participants, 10 genes were significantly enriched in EC cells, functionally concentrated in protein and bioamine synthesis. A coexpression network containing 17 hub genes, including TPH1, CHGA, and GCLC, was identified in EC cells. In patients with UC, EC cells gained increased capacity for protein synthesis, along with novel immunological functions such as antigen processing and presentation, whereas chemical sensation was downregulated. The specific expression of CHGB and RGS2 in EC cells was confirmed by immunofluorescence staining. Our results illuminate the transcriptional signatures of EC cells in the human colon. EC cells’ newly observed functional shift from sensation to secretion and immunity indicates their pivotal role in UC.

Enteroendocrine System and Gut Barrier in Metabolic Disorders.

With the continuous rise in the worldwide prevalence of obesity and type 2 diabetes, developing therapies regulating body weight and glycemia has become a matter of great concern. Among the current treatments, evidence now shows that the use of intestinal hormone analogs (e.g., GLP1 analogs and others) helps to control glycemia and reduces body weight. Indeed, intestinal endocrine cells produce a large variety of hormones regulating metabolism, including appetite, digestion, and glucose homeostasis. Herein, we discuss how the enteroendocrine system is affected by local environmental and metabolic signals. These signals include those arising from unbalanced diet, gut microbiota, and the host metabolic organs and their complex cross-talk with the intestinal barrier integrity.