Gastrointestinal neuroendocrine peptides/amines in inflammatory bowel disease

Inflammatory bowel disease(IBD) is a chronic recurrent condition whose etiology is unknown,and it includes ulcerative colitis,Crohn's disease,and microscopic colitis. These three diseases differ in clinical manifestations,courses,and prognoses. IBD reduces the patients' quality of life and is an economic burden to both the patients and society. Interactions between the gastrointestinal(GI) neuroendocrine peptides/amines(NEPA) and the immune system are believed to play an important role in the pathophysiology of IBD. Moreover,the interaction between GI NEPA and intestinal microbiota appears to play also a pivotal role in the pathophysiology of IBD. This review summarizes the available data on GI NEPA in IBD,and speculates on their possible role in the pathophysiology and the potential use of this information when developing treatments. GI NEPA serotonin,the neuropeptide Y family,and substance P are proinflammatory,while the chromogranin/secretogranin family,vasoactive intestinal peptide,somatostatin,and ghrelin are antiinflammatory. Several innate and adaptive immune cells express these NEPA and/or have receptors to them. The GI NEPA are affected in patients with IBD and in animal models of human IBD. The GI NEPA are potentially useful for the diagnosis and follow-up of the activity of IBD,and are candidate targets for treatments of this disease.

Mechanistic links between gut microbial community dynamics, microbial functions and metabolic health

Gut microbes comprise a high density, biologically active community that lies at the interface of an animal with its nutritional environment. Consequently their activity profoundly influences many aspects of the physiology and metabolism of the host animal. A range of microbial structural components and metabolites directly interact with host intestinal cells and tissues to influence nutrient uptake and epithelial health. Endocrine, neuronal and lymphoid cells in the gut also integrate signals from these microbial factors to influence systemic responses. Dysregulation of these host-microbe interactions is now recognised as a major risk factor in the development of metabolic dysfunction. This is a two-way process and understanding the factors that tip host-microbiome homeostasis over to dysbiosis requires greater appreciation of the host feedbacks that contribute to regulation of microbial community composition. To date, numerous studies have employed taxonomic profiling approaches to explore the links between microbial composition and host outcomes(especially obesity and its comorbidities), but inconsistent host-microbe associations have been reported. Available data indicates multiple factors have contributed to discrepancies between studies. These include the high level of functional redundancy in host-microbiome interactions combined with individual variation in microbiome composition; differences in study design, diet composition and host system between studies; and inherent limitations to the resolution of r RNA-based community profiling. Accounting for these factors allows for recognition of the common microbial and host factors driving community composition and development of dysbiosis on high fat diets. New therapeutic intervention options are now emerging.

Fecal microbiota transplantation for irritable bowel syndrome:An intervention for the 21st century

Irritable bowel syndrome(IBS)affects about 12%of the global population.Although IBS does not develop into a serious disease or increase mortality,it results in a considerable reduction in the quality of life.The etiology of IBS is not known,but the intestinal microbiota appears to play a pivotal role in its pathophysiology.There is no effective treatment for IBS,and so the applied treatments clinically focus on symptom relief.Fecal microbiota transplantation(FMT),an old Chinese treatment,has been applied to IBS patients in seven randomized controlled trials(RCTs).Positive effects on IBS symptoms in various degrees were obtained in four of these RCTs,while there was no effect in the remaining three.Across the seven RCTs there were marked differences in the selection processes for the donor and treated patients,the transplant dose,the route of administration,and the methods used to measure how the patients responded to FMT.The present frontier discusses these differences and proposes:(1)criteria for selecting an effective donor(superdonor);(2)selection criteria for patients that are suitable for FMT;(3)the optimal FMT dose;and(4)the route of transplant administration.FMT appears to be safe,with only mild,self-limiting side effects of abdominal pain,cramping,tenderness,diarrhea,and constipation.Although it is early to speculate about the mechanisms underlying the effects of FMT,the available data suggest that changes in the intestinal bacteria accompanied by changes in fermentation patterns and fermentation products(specifically short-chain fatty acids)play an important role in improving the IBS symptoms seen after FMT.FMT appears to be a promising treatment for IBS,but further studies are needed before it can be applied in everyday clinical practice.

A case report of endocrine cell carcinoma in the sigmoid colon with inferior mesenteric vein tumor embolism

We report a case of endocrine cell carcinoma in the sigmoid colon with inferior mesenteric vein （IMV） tumor embolism. A 79-year-old woman was admitted to our hospital with narrowing of the stools. We performed colonoscopy, computed tomography and positron emission tomography, which disclosed sigmoid colon cancer with IMV tumor embolism. She underwent sigmoidectomy and lymph node dissection. The tumor was diagnosed as endocrine cell carcinoma （type 4, pSS, med, INFa, v3, n1, stage Ⅲb）. Immunohistochemically, chromographin A, synaptophysin, cytokeratin 20 and mucicarmine showed partial staining, and CD56 was totally reactive. Three months after operation multiple liver metastases appeared. She was treated with chemotherapy of cisplatin （CDDP） ＋ irinotecan （CPT11）. This case highlights the aggressiveness of endocrine cell carcinoma with tumor embolism, and it is essential to establish an accurate diagnosis and effective treatment.

Development of innovative tools for investigation of nutrient-gut interaction

The gastrointestinal tract is the key interface between the ingesta and the human body.There is wide recognition that the gastrointestinal response to nutrients or bioactive compounds,particularly the secretion of numerous hormones,is critical to the regulation of appetite,body weight and blood glucose.This concept has led to an increasing focus on“gut-based”strategies for the management of metabolic disorders,including type 2 diabetes and obesity.Understanding the underlying mechanisms and downstream effects of nutrient-gut interactions is fundamental to effective translation of this knowledge to clinical practice.To this end,an array of research tools and platforms have been developed to better understand the mechanisms of gut hormone secretion from enteroendocrine cells.This review discusses the evolution of in vitro and in vivo models and the integration of innovative techniques that will ultimately enable the development of novel therapies for metabolic diseases.

Dual regulatory role for phosphatase and tensin homolog in specification of intestinal endocrine cell subtypes

AIM:To investigate the impact of phosphatase and tensin homolog(Pten) in the specification of intestinal enteroendocrine subpopulations.METHODS:Using the Cre/loxP system,a mouse with conditional intestinal epithelial Pten deficiency was generated.Pten mutant mice and controls were sacrificed and small intestines collected for immunofluorescence and quantitative real-time polymerase chain reaction.Blood was collected on 16 h fasted mice by cardiac puncture.Enzyme-linked immunosorbent assay was used to measure blood circulating ghrelin,somatostatin(SST) and glucose-dependent insulinotropic peptide(GIP) levels.RESULTS:Results show an unexpected dual regulatory role for epithelial Pten signalling in the specification/differentiation of enteroendocrine cell subpopulations in the small intestine.Our data indicate that Pten positively regulates chromogranin A(CgA) expressing subpopulations,including cells expressing secretin,ghrelin,gastrin and cholecystokinin(CCK).In contrast,Pten negatively regulates the enteroendocrine subtype specification of non-expressing CgA cells such as GIP and SST expressing cells.CONCLUSION:The present results demonstrate that Pten signalling favours the enteroendocrine progenitor to specify into cells expressing CgA including those producing CCK,gastrin and ghrelin.

Irritable bowel syndrome:Emerging paradigm in pathophysiology

Irritable bowel syndrome(IBS)is one of the most common gastrointestinal disorders,characterized by abdominal pain,bloating,and changes in bowel habits.These symptoms cannot be explained by structural abnormalities and there is no specific laboratory test or biomarker for IBS.Therefore,IBS is classified as a functional disorder with diagnosis dependent on the history taking about manifested symptoms and careful physical examination.Although a great deal of research has been carried out in this area,the pathophysiology of IBS is complex and not completely understood.Multiple factors are thought to contribute to the symptoms in IBS patients;altered gastrointestinal motility,visceral hypersensitivity,and the brain-gut interaction are important classical concepts in IBS pathophysiology.New areas of research in this arena include inflammation,postinfectious low-grade inflammation,genetic and immunologic factors,an altered microbiota,dietary factors,and enteroendocrine cells.These emerging studies have not shown consistent results,provoking controversy in the IBS field.However,certain lines of evidence suggest that these mechanisms are important at least a subset of IBS patients,confirming that IBS symptoms cannot be explained by a single etiological mechanism.Therefore,it is important to keep in mind that IBS requires a more holistic approach to determining effective treatment and understanding the underlying mechanisms.

Pancreatic β cell regeneration induced by clinical and preclinical agents

Diabetes,one of the most common chronic diseases in the modern world,has pancreaticβcell deficiency as a major part of its pathophysiological mechanism.Pancreatic regeneration is a potential therapeutic strategy for the recovery ofβcell loss.However,endocrine islets have limited regenerative capacity,especially in adult humans.Almost all hypoglycemic drugs can protectβcells by inhibitingβcell apoptosis and dedifferentiation via correction of hyperglycemia and amelioration of the consequent inflammation and oxidative stress.Several agents,including glucagon-like peptide-1 andγ-aminobutyric acid,have been shown to promoteβcell proliferation,which is considered the main source of the regeneratedβcells in adult rodents,but with less clarity in humans.Pancreatic progenitor cells might exist and be activated under particular circumstances.Artemisinins andγ-aminobutyric acid can induceα-to-βcell conversion,although some disputes exist.Intestinal endocrine progenitors can transdeterminate into insulin-producing cells in the gut after FoxO1 deletion,and pharmacological research into FoxO1 inhibition is ongoing.Other cells,including pancreatic acinar cells,can transdifferentiate intoβcells,and clinical and preclinical strategies are currently underway.In this review,we summarize the clinical and preclinical agents used in different approaches forβcell regeneration and make some suggestions regarding future perspectives for clinical application.

Maternal antibiotic treatment affects offspring gastric sensing for umami taste and ghrelin regulation in the pig

Background:Scarce is knowledge on the process regulating the development of acid secretion,orexigenic signaling,and chemosensing in the stomach of young pigs.Changes of early microbial encounters by suckling pigs can interact with the gut maturation,by the induction of different molecular signaling.Our goal was to assess if the age of offspring and the maternal environment,influenced by sow antibiotic treatment peripartum,could affect gastric morphology and the expression of genes involved in the control of hydrochloric secretion,feed intake,taste,and inflammation in offspring stomach.Methods:84 pigs from sows fed a diet with amoxicillin(on-d10 to+d21 from farrowing,ANT)or without(CON)were sacrificed at d14,d21,d28(weaning)or d42.Samples of oxyntic(OXY),pyloric(PY)and cardiac mucosae close to OXY were collected and parietal and enteroendocrine cells(EECs)were counted.Relative gene expression of a set of 11 key genes(ATP4A,SSTR2,GAST,GHRL,MBOAT4,PCSK1,GNAT1,TAS1R1,TAS1R3,IL8 and TNF)was assessed by qRT-PCR.In addition,40 offspring obtained from the same ANT and CON sows were offered a normal or a fatenriched diet for 4 weeks between 140 and 169 d of age,and then OXY and PY were sampled.Results:The number of parietal and EECs increased with age(P<0.001).ATP4A increased with age(within suckling,P=0.043,post-weaning vs.suckling,P<0.001),SSTR2 increased only after weaning(P<0.001).In OXY,GHRL increased during suckling(P=0.012),and post-weaning as a trend(P=0.088).MBOAT4 tended to increase during suckling(P=0.062).TAS1R1 increased from suckling to post-weaning period(P=0.001)and was lower in ANT offspring(P=0.013).GNAT1 in PY was higher in ANT offspring(P=0.041).Antibiotic treatment of sows peripartum increased expression of GHRL and MBOAT4 in OXY of growing-finishing offspring aged 5 months.Conclusions:Data show that sensing for umami taste and ghrelin regulation can be affected by maternal environment,but the development of acid secretion,orexigenic signaling and taste perception in the stomach are mostly developmentally controlled.

PFOA/PFOS Facilitated Intestinal Fatty Acid Absorption by Activating the PPARαPathway:Insights from Organoids Model

Perfluorooctanoic acid(PFOA)and perfluorooctanesulfonate(PFOS)continue to be extensively present in the natural environment and seriously threaten human health.The intestinal tract is the primary organ of PFOA/PFOS exposure due to the consumption of contaminated food and drinking water.However,it remains unclear how PFOA/PFOS affects intestinal function and overall health.The aim of this study was to investigate the influence of PFOA/PFOS on the absorption of fatty acids in the intestine and the underlying mechanisms using three-dimensional(3D)intestinal organoids.Our results showed that PFOS,but not PFOA,could significantly enhance the fatty acid uptake capacity without obvious damage to the organoids.Furthermore,PFOS markedly reduced the protein levels of ChgA in enteroendocrine cells,but with no observed impact on aldolase B+enterocytes.Mechanistically,exposure to PFOS induced the activation of the peroxisome proliferator-activated receptor(PPAR)αpathway in intestinal organoids,with enhanced expression of PPARαtarget genes associated with fatty acid metabolism,such as Fabp1 and Cd36(fatty acid transporter genes),Acox1 and Pdk4(fatty acid oxidation genes),and Plin2 and Plin3(lipid droplet synthesis genes).These data suggest that PFOS have the potential to affect the absorption function of the intestinal epithelium through the PPARαpathway,and its effect is much stronger than that of PFOA.Our findings also highlight that organoids can be used as a valuable model for conducting toxicological research on environmental chemicals.