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Bile acids (BAs) are known to be important regulators of intestinal motility and epithelial fluid and electrolyte transport. Over the past two decades, significant advances in identifying and characterizing the receptors, transporters, and ion channels targeted by BAs have led to exciting new insights into the molecular mechanisms involved in these processes. Our appreciation of BAs, their receptors, and BA-modulated ion channels as potential targets for the development of new approaches to treat intestinal motility and transport disorders is increasing. In the current review, we aim to summarize recent advances in our knowledge of the different BA receptors and BA-modulated ion channels present in the gastrointestinal system. We discuss how they regulate motility and epithelial transport, their roles in pathogenesis, and their therapeutic potential in a range of gastrointestinal diseases.

The intestinal tract is lined by a single layer of epithelium that is one of the fastest regenerating tissues in the body and which therefore requires a very active and exquisitely controlled stem cell population. Rapid renewal of the epithelium is necessary to provide a continuous physical barrier from the intestinal luminal microenvironment that contains abundant microorganisms, whilst also ensuring an efficient surface for the absorption of dietary components. Specialised epithelial cell populations are important for the maintenance of intestinal homeostasis and are derived from adult intestinal stem cells (ISCs). Actively cycling ISCs divide by a neutral drift mechanism yielding either ISCs or transit-amplifying epithelial cells, the latter of which differentiate to become either absorptive lineages or to produce secretory factors that contribute further to intestinal barrier maintenance or signal to other cellular compartments. The mechanisms controlling ISC abundance, longevity and activity are regulated by several different cell populations and signalling pathways in the intestinal lamina propria which together form the ISC niche. However, the complexity of the ISC niche and communication mechanisms between its different components are only now starting to be unravelled with the assistance of intestinal organoid/enteroid/colonoid and single-cell imaging and sequencing technologies. This review explores the interaction between well-established and emerging ISC niche components, their impact on the intestinal epithelium in health and in the context of intestinal injury and highlights future directions and implications for this rapidly developing field.

Despite the increasing prevalence and medical burden of obesity, the understanding of gastrointestinal physiology in obesity is scarce, which hampers drug development.To investigate the effect of obesity and food intake on gastrointestinal transit, pressure and pH.An exploratory cross-sectional study using a wireless motility capsule (SmartPill©) was performed in 11 participants with obesity and 11 age- and gender-matched participants with normal weight (group) in fasted and fed state (visit). During the first visit, the capsule was ingested after an overnight fast. During a second visit, the capsule was ingested after a nutritional drink to simulate fed state. Linear mixed models were constructed to compare segmental gastrointestinal transit, pressure and pH between groups (obesity or control) and within every group (fasted or fed).Food intake slowed gastric emptying in both groups (both P 0.0001), though food-induced gastric contractility was higher in participants with obesity compared to controls (P = 0.02). In the small intestine, a higher contractility (P = 0.001), shorter transit (P = 0.04) and lower median pH (P = 0.002) was observed in participants with obesity compared to controls. No differences were observed for colonic measurements.Obesity has a profound impact on gastrointestinal physiology, which should be taken into account for drug development.

Purpose of review There is a growing body of evidence implicating the role of the gut-brain axis in a multitude of inflammatory and non-inflammatory gastrointestinal disorders. The interaction between the gut and the brain is bidirectional and its therapeutic manipulation is gaining traction as the new frontier in the management of gastrointestinal disorders. This review summarizes the recent literature on this subject and serves as a reference for future research directions. Recent findings Recent studies have shown that the gut-brain axis, through its main communicator - the vagal nerve - plays a multimodal role in manipulating gastrointestinal physiology. This is evident systemically via the cholinergic anti-inflammatory pathway, through its effect on intestinal barrier function and also locally on intestinal epithelial and immune cells. Vagal nerve stimulation and faecal microbiota transplantation are two ways by which therapeutic manipulation has been attempted with success. Summary There has been exceptional progress in our understanding of the gut-brain axis in recent literature. Its role in the modulation of a multitude of gastrointestinal disorders is becoming clear. Preclinical findings are sufficient for this research to proceed to clinical trials in order to harness its clinical therapeutic potential for the care of patients.

Gastric acid secretion plays a pivotal role in the physiology of gastrointestinal tract. The functioning of the system encompasses a P2 ATPase pump (which shuttles electroneutral function at low pH) along with different voltage sensitive/neutral ion channels, cytosolic proteins, acid sensor receptors as well hormonal regulators. The increased acid secretion is a pathological marker of several diseases like peptic ulcer, gastroesophageal reflux disease (GERD), chronic gastritis, and the bug Helicobacter pylori (H. pylori) has also a critical role, which altogether affects the patient's quality of life. This review comprehensively describes about the nature of potassium ion channel and its mediators, the different clinical strategy to control acid rebound, and some basic experimental observations performed to study the interplay of ion channels, pumps, as well as mediators during acid secretion. Different aspects of regulation of gastric acid secretion have been focused either in terms of physiology of secretion or molecular interactions. The importance of H pylori infection and its treatment have also been discussed. Furthermore, the relevance of calcium signaling during acid secretion has been reviewed. The entire theme will make anyone to understand in details about the gastric secretion machinery in general.

The physiological properties of the gastrointestinal tract, such as pH, fluid volume, bile salt concentration, and gastrointestinal transit time, are highly variable in vivo. These properties can affect the dissolution and absorption of a drug, depending on its properties and formulation. The effect of gastrointestinal physiology on the bioperformance of a drug was studied in silico for a delayed-release pantoprazole tablet and an immediate-release dolutegravir tablet. Physiologically based absorption models were developed and virtual clinical trials were performed. Reasons for the variability in drug bioperformance between subjects were investigated, taking into account differences in gastrointestinal tract characteristics, pharmacokinetic parameters, and additional parameters (e.g., permeability). Default software parameters describing gastrointestinal physiology in the fasted and fed states, and variation in these parameters, were altered to match variability in these parameters reported in vivo. The altered model physiologies better described the variability of gastrointestinal conditions, and therefore the results of virtual trials using these physiologies are likely to be more relevant in vivo. With such altered gastrointestinal physiologies used to develop models, it is possible to obtain additional knowledge and improve the understanding of subject-formulation interactions.

Enteroendocrine cells (EECs) in both invertebrates and vertebrates derive from intestinal stem cells (ISCs) and are scattered along the digestive tract, where they function in sensing various environmental stimuli and subsequently secrete neurotransmitters or neuropeptides to regulate diverse biological and physiological processes. To fulfill these functions, EECs are specified into multiple subtypes that occupy specific gut regions. With advances in single-cell technology, organoid culture experimental systems, and CRISPR/Cas9 mediated genomic editing, rapid progress has been made towards characterization of EEC subtypes in mammals. Additionally, studies of genetic model organisms-especially Drosophila melanogaster-have also provided insights about the molecular processes underlying EEC specification from ISCs and about the establishment of diverse EEC subtypes. In this review we compare the regulation of EEC specification and function in mammals and Drosophila, with a focus on EEC subtype characterization, on how internal and external regulators mediate EEC subtype specification, and on how EEC-mediated intra- and inter-organ communications affect gastrointestinal physiology and pathology.

The sodium–hydrogen exchanger isoform 3 (NHE3, SLC9A3) is abundantly expressed in the gastrointestinal tract and is proposed to play essential roles in Na+ and fluid absorption as well as acid–base homeostasis. Mutations in the SLC9A3 gene can cause congenital sodium diarrhea (CSD). However, understanding the precise role of intestinal NHE3 has been severely hampered due to the lack of a suitable animal model. To navigate this problem and better understand the role of intestinal NHE3, we generated a tamoxifen-inducible intestinal epithelial cell-specific NHE3 knockout mouse model (NHE3IEC-KO). Before tamoxifen administration, the phenotype and blood parameters of NHE3IEC-KO were unremarkable compared with control mice. After tamoxifen administration, NHE3IEC-KO mice have undetectable levels of NHE3 in the intestine. NHE3IEC-KO mice develop watery, alkaline diarrhea in combination with a swollen small intestine, cecum and colon. The persistent diarrhea results in higher fluid intake. After 3 weeks, NHE3IEC-KO mice show a ∼25% mortality rate. The contribution of intestinal NHE3 to acid–base and Na+ homeostasis under normal conditions becomes evident in NHE3IEC-KO mice that have metabolic acidosis, lower blood bicarbonate levels, hyponatremia and hyperkalemia associated with drastically elevated plasma aldosterone levels. These results demonstrate that intestinal NHE3 has a significant contribution to acid–base, Na+ and volume homeostasis, and lack of intestinal NHE3 has consequences on intestinal structural integrity. This mouse model mimics and explains the phenotype of individuals with CSD carrying SLC9A3 mutations.

Circadian rhythms ensure that physiological processes occur at the most biologically meaningful time. The circadian timing in the gastrointestinal tract involves interlocking transcriptional and translational feedback loops that culminate in the rhythmic expression and activity of a set of clock genes and related hormones. The suprachiasmatic nucleus and peripheral core molecular clocks oscillate every 24 hours and are responsible for the periodic activity of various segments and transit along the gastrointestinal tract. Environmental cues may alter or reset these rhythms to align them with new circumstances. Colonic motility also follows a circadian rhythm with reduced nocturnal activity. Healthy humans have normal bowel motility during the day, frequently following awakening or following a meal, with minimal activity during the night. Maladjusted circadian rhythms in the bowel have been linked to digestive pathologies, including constipation and irritable bowel syndrome. Our advanced knowledge of the link between the circadian clock and gastrointestinal physiology provides potential therapeutic approaches for the treatment of gastrointestinal diseases. This review seeks to establish evidence for the correlation between circadian rhythm, bowel movements and digestive health, and examine the implications of disrupted circadian rhythms on gut physiology.

The enteroendocrine cells in gastrointestinal (GI) tract synthesize more than thirty hormones in mammals. Among these cells, the enterochromaffin (EC) cells are probably the most important one due to the fact that they produce melatonin. The rate-limiting enzymes for melatonin synthesis including arylalkylamine-N-acetyltransferase (AANAT, currently the SNAT) and hydroxyindole-O-methyltransferase (HIOMT, currently the ASMT) have been identified in EC cells and this has confirmed the local melatonin production in GI tract by these cells. EC cells play a critical role in regulation of gastrointestinal physiology, particularly, in protection of the GI tract from free radical attack and inflammatory reaction. GI tract is the major site exposed to the oxidative stress and inflammation because of the food residue metabolism and the presence of trillions of microbes including the pathological bacteria. Thus, it requires strong protection. Melatonin synthesized by the EC cells provides the onsite protection in GI tract since this molecule is the potent free radical scavenger and effective ant-inflammatory agent. In this review we summarize the available information regarding the structural and functional variability of the EC cells as well as their pathophysiological roles in the GI tract. The focus is given to the protective effects of melatonin produced by the EC cells on the oxidative stress, inflammation and microbiota balance in GI tract.

Despite structural similarity, the five subtypes comprising the cholinergic muscarinic family of G protein-coupled receptors regulate remarkably diverse biological functions. This mini review focuses on the closely related and commonly co-expressed M1R and M3R muscarinic acetylcholine receptor subtypes encoded respectively by CHRM1 and CHRM3. Activated M1R and M3R signal via Gq and downstream initiate phospholipid turnover, changes in cell calcium levels, and activation of protein kinases that alter gene transcription and ultimately cell function. The unexpectedly divergent effects of M1R and M3R activation, despite similar receptor structure, distribution, and signaling, are puzzling. To explore this conundrum, we focus on the gastrointestinal (GI) tract and liver because abundant data identify opposing effects of M1R and M3R activation on the progression of gastric, pancreatic, and colon cancer, and liver injury and fibrosis. Whereas M3R activation promotes GI neoplasia, M1R activation appears protective. In contrast, in murine liver injury models, M3R activation promotes and M1R activation mitigates liver fibrosis. We analyze these findings critically, consider their therapeutic implications, and review the pharmacology and availability for research and therapeutics of M1R and M3R-selective agonists and antagonists. We conclude by considering gaps in knowledge and other factors that hinder the application of these drugs and the development of new agents to treat GI and liver diseases.

BackgroundMost people with cystic fibrosis (pwCF) suffer from gastrointestinal symptoms and are at risk of gut complications. Gut microbiota dysbiosis is apparent within the CF population across all age groups, with evidence linking dysbiosis to intestinal inflammation and other markers of health. This pilot study aimed to investigate the potential relationships between the gut microbiota and gastrointestinal physiology, transit, and health.Study DesignFaecal samples from 10 pwCF and matched controls were subject to 16S rRNA sequencing. Results were combined with clinical metadata and MRI metrics of gut function to investigate relationships.ResultspwCF had significantly reduced microbiota diversity compared to controls. Microbiota compositions were significantly different, suggesting remodelling of core and rarer satellite taxa in CF. Dissimilarity between groups was driven by a variety of taxa, including Escherichia coli, Bacteroides spp., Clostridium spp., and Faecalibacterium prausnitzii. The core taxa were explained primarily by CF disease, whilst the satellite taxa were associated with pulmonary antibiotic usage, CF disease, and gut function metrics. Species-specific ordination biplots revealed relationships between taxa and the clinical or MRI-based variables observed.ConclusionsAlterations in gut function and transit resultant of CF disease are associated with the gut microbiota composition, notably the satellite taxa. Delayed transit in the small intestine might allow for the expansion of satellite taxa resulting in potential downstream consequences for core community function in the colon.HighlightsFaecal microbiota significantly differs between pwCF and healthy controlsKey SCFA producers contributed to microbiota dissimilarity between groupsPulmonary antibiotic treatment heavily impacted gut microbiotaIntestinal physiology and transit impacted satellite microbiota composition

The microbiome plays an important role in maintaining human health. Despite multiple factors being attributed to the shaping of the human microbiome, extrinsic factors such diet and use of medications including antibiotics appear to dominate. Mucosal surfaces, particularly in the gut, are highly adapted to be able to tolerate a large population of microorganisms whilst still being able to produce a rapid and effective immune response against infection. The intestinal microbiome is not functionally independent from the host mucosa and can, through presentation of microbe-associated molecular patterns (MAMPs) and generation of microbe-derived metabolites, fundamentally influence mucosal barrier integrity and modulate host immunity. In a healthy gut there is an abundance of beneficial bacteria that help to preserve intestinal homoeostasis, promote protective immune responses, and limit excessive inflammation. The importance of the microbiome is further highlighted during dysbiosis where a loss of this finely balanced microbial population can lead to mucosal barrier dysfunction, aberrant immune responses, and chronic inflammation that increases the risk of disease development. Improvements in our understanding of the microbiome are providing opportunities to harness members of a healthy microbiota to help reverse dysbiosis, reduce inflammation, and ultimately prevent disease progression.

Background Of the various drug therapies that influence gastrointestinal (GI) physiology, one of the most important are the acid-reducing agents (ARAs). Because changes in GI physiology often influence the pharmacokinetics of drugs given orally, there is a need to identify in vitro methods with which such effects can be elucidated. Objective Literature concerning the effects of ARAs (antacids, H2-receptor antagonists, and proton pump inhibitors [PPIs]) on GI physiology are reviewed with the aim of identifying conditions under which drugs are released after oral administration in the fasted state. In vitro dissolution tests to mimic the effects in the stomach were designed for H2-receptor antagonists and PPIs. Conclusions The impact of ARAs on GI physiology depends on the type, duration, and amount of ARA administered as well as the location in the GI tract, with greatest impact on gastric physiology. While ARAs have a high impact on the gastric fluid pH and composition, changes in volume, viscosity, surface tension, and gastric emptying appear to be less profound. The proposed dissolution tests enable a ready comparison between dosage form performance in healthy adults and those receiving PPIs or H2-receptor antagonists.

Obesity is a prevalent disease with significant morbidity and mortality. It is a state of chronic low-grade inflammation due to excess body fat. Weight homeostasis is maintained through changes in various gastrointestinal hormones caused by dietary intake. However, being overweight or obese breaks the balance of these appetite-related gastrointestinal hormones and creates resistance to the actions of these hormones. The sensitivity of vagal afferent neurons to peripheral signals becomes blunted. Cytokines produced by excessive fat tissue damage our normal immune system, making us vulnerable to infection. In addition, various changes in gastrointestinal motility occur. Therefore, this review focuses on the various changes in gastrointestinal hormones, the immune state, the vagus nerve, and gastrointestinal movement in obese patients. (Korean J Med 2019;94:403-409)

ATP is both an important mediator of physiological gut functions such as motility and epithelial function, and a key danger signal that mediates cell death and tissue damage. The actions of extracellular ATP are regulated through the catalytic functions extracellular nucleoside triphosphate diphosphohydrolase-1 (NTPDase1), -2, -3, and -8, which ultimately generate nucleosides. Ectonucleotidases have distinct cellular associations, but the specific locations and functional roles of individual NTPDases in the intestine are still poorly understood. Here, we tested the hypothesis that differential and cell-selective regulation of purine hydrolysis by NTPDase1 and -2 plays important roles in gut physiology and disease. We studied Entpd1 and Entpd2 null mice in health and following colitis driven by 2% dextran sulfate sodium (DSS) administration using functional readouts of gut motility, epithelial barrier function, and neuromuscular communication. NTPDase1 is expressed by immune cells, and the ablation of Entpd1 altered glial numbers in the myenteric plexus. NTPDase2 is expressed by enteric glia, and the ablation of Entpd2 altered myenteric neuron numbers. Mice lacking either NTPDase1 or -2 exhibited decreased inhibitory neuromuscular transmission and altered components of inhibitory junction potentials. Ablation of Entpd2 increased gut permeability following inflammation. In conclusion, the location- and context-dependent extracellular nucleotide phosphohydrolysis by NTPDase1 and -2 substantially impacts gut function in health and disease. NEW & NOTEWORTHY Purines are important mediators of gastrointestinal physiology and pathophysiology. Nucleoside triphosphate diphosphohydrolases (NTPDases) regulate extracellular purines, but the roles of specific NTPDases in gut functions are poorly understood. Here, we used Entpd1- and Entpd2-deficient mice to show that the differential and cell-selective regulation of purine hydrolysis by NTPDase1 and -2 plays important roles in barrier function, gut motility, and neuromuscular communication in health and disease.

Gastrointestinal symptoms are common in both inflammatory and non-inflammatory connective tissue disorders and can involve any part of the gastrointestinal tract from the mouth to the anus. Dysphagia, gastrooesophageal reflux, nausea, vomiting, abdominal pain and change in bowel habit are common symptoms and usually arise from gastrointestinal dysmotility and altered visceral sensitivity. In scleroderma, sensorimotor dysfunction is pronounced and can result in complications such as Barrett's oesophagus, gastroparesis, small intestinal bacterial overgrowth, malabsorption and malnutrition, with an associated reduction in survival. Treatment is aimed at symptom control and prevention of complications. In hypermobile Ehlers–Danlos syndrome, symptoms are often caused by functional gastrointestinal disorders such as functional dyspepsia or irritable bowel syndrome, or are secondary to associated co-morbidities (e.g. chronic pain, anxiety, postural tachycardia syndrome, opioid use). Dysmotility in the oesophagus, stomach and colon is common, so gastrointestinal physiology testing can be informative and prokinetics can be useful therapeutically. A holistic approach to management must be taken to address all contributing factors, especially anxiety and diet.

The absorption of iron is influenced by numerous dietary and physiological factors. We have previously demonstrated that zinc treatment of intestinal cells increases iron absorption via induction of the apical membrane iron transporter divalent metal ion transporter-1 (DMT1). To better understand the mechanisms of zinc-induced iron absorption, we have studied the effect of zinc on iron uptake, iron transporter and iron regulatory protein (IRP 1 and 2) expression and the impact of the PI3K pathway in differentiated Caco-2 cells, an intestinal cell culture model. We found that zinc induces DMT1 protein and mRNA expression. Zinc-induced DMT1 expression and iron absorption were inhibited by siRNA silencing of DMT1. Furthermore, zinc treatment led to increased abundance of IRP2 protein in cell lysates and in polysomal fractions, implying its binding to target mRNAs. Zinc treatment induced Akt phosphorylation, indicating the activation of the PI3K pathway. LY294002, a specific inhibitor of PI3K inhibited zinc-induced Akt phosphorylation, iron uptake, DMT1 and IRP2 expression. Furthermore, LY294002 also decreased the basal level of DMT1 mRNA but not protein expression. siRNA silencing of IRP2 led to down-regulation of both basal and zinc-induced DMT1 protein expression, implying possible involvement of post-transcriptional regulatory mechanisms. In agreement with these findings, zinc treatment stabilized DMT1 mRNA levels in actinomycin D-treated cells. Based on these findings, we conclude that zinc-induced iron absorption involves elevation of DMT1 expression by stabilization of its mRNA, by a PI3K/IRP2-dependent mechanism.

The gut is the site of digestion and absorption as well as serving as an endocrine and immune organ. All of these functions may be affected by critical illness. This review will discuss secondary effects of critical illness on the gut in terms of gastrointestinal function that is clinically observable and discuss consequences of gut dysfunction with critical illness to patient outcome. Because there is little evidence-based medicine in the veterinary field, much of our understanding of gut dysfunction with critical illness comes from animal models or from the human medical field. We can extrapolate some of these conclusions and recommendations to companion animals, particularly in dogs, who have similar gastrointestinal physiology to people. Additionally, the evidence regarding gut dysfunction in veterinary patients will be explored. By recognizing signs of dysfunction early and taking preventative measures, we may be able to increase success with treatment of critical illnesses.

International audience; L’étude des maladies digestives est parfois limitée par l’accès aux tissus de patients et les modèles précliniques ne sont pas toujours fidèles aux pathologies observées chez l’homme. Dans ce contexte, le développement d’organoïdes intestinaux à partir de cellules souches pluripotentes humaines représente une avancée importante dans l’étude des processus physiologiques et des pathologies digestives. Dans cette revue, nous rappelons les étapes majeures du développement du tractus digestif chez l’homme et décrivons le rationnel de la différenciation dirigée des cellules souches pluripotentes humaines. Nous faisons également un état des lieux sur les différents types d’organoïdes intestinaux existants et leurs applications en recherche fondamentale et préclinique. Enfin, nous discutons des opportunités offertes par les organoïdes intestinaux humains dans un contexte de médecine de précision et de médecine réparatrice.

Background and Aim: Non-Alcoholic Fatty Liver Disease (NAFLD) is the major cause of chronic liver disease in developed countries. In this study, we identified the most important transcription factors and biological mechanisms affecting the incidence of fatty liver disease using the promoter region data mining. Materials and Methods In this study, at first, the marker genes associated with this disease were detected and the pattern of transcription factors was examined by the Genomatix software. In the whole of genome, genes with a similar binding pattern for transcription factors in the promoter region were identified as potentially effective genes on the fatty liver. By using the Cytoscape software (3.6.0), the network of transcription factors and target genes was mapped. Finally, the most important biological pathways associated with genes derived from fatty liver were studied using the DAVID database. Results: The protein network fitting showed Creb1, Jun and Max transcription factors and Sfpi1, Ddit3 and Gsk3b genes play an important role in the development of this disease. Gene ontology analysis revealed that biological pathways including apoptosis, intracellular signals, and biosynthesis of aromatic compounds and signaling pathways of circadian rhythm, non-alcoholic fatty liver, and chemokine signals contributed to the occurrence of fatty liver disease. Conclusion: Increasing the expression of transcription factors and genes produced can be one of the most factors affecting the onset of the disease, also, biological pathways including apoptosis, intracellular signals, and biosynthesis of aromatic compounds and signaling pathways of circadian rhythm, non-alcoholic fatty liver, and chemokine signals are important in fatty liver phenomenon.

Circadian rhythms regulate much of gastrointestinal physiology including cell proliferation, motility, digestion, absorption, and electrolyte balance. Disruption of circadian rhythms can have adverse consequences including the promotion of and/or exacerbation of a wide variety of gastrointestinal disorders and diseases. Areas covered: In this review, we evaluate some of the many gastrointestinal functions that are regulated by circadian rhythms and how dysregulation of these functions may contribute to disease. This review also discusses some common gastrointestinal disorders that are known to be influenced by circadian rhythms as well as speculation about the mechanisms by which circadian rhythm disruption promotes dysfunction and disease pathogenesis. We discuss how knowledge of circadian rhythms and the advent of chrono-nutrition, chrono-pharmacology, and chrono-therapeutics might influence clinical practice. Expert opinion: As our knowledge of circadian biology increases, it may be possible to incorporate strategies that take advantage of circadian rhythms and chronotherapy to prevent and/or treat disease.

The first year of life is a crucial period during which the composition and functionality of the gut microbiota develop to stabilize and resemble that of adults. Throughout this process, the gut microbiota has been found to contribute to the maturation of the immune system, in gastrointestinal physiology, in cognitive advancement and in metabolic regulation. Breastfeeding, the “golden standard of infant nutrition,” is a cornerstone during this period, not only for its direct effect but also due to its indirect effect through the modulation of gut microbiota. Human milk is known to contain indigestible carbohydrates, termed human milk oligosaccharides (HMOs), that are utilized by intestinal microorganisms. Bacteria that degrade HMOs likeBifidobacterium longumsubsp.infantis,Bifidobacterium bifidum, andBifidobacterium brevedominate the infant gut microbiota during breastfeeding. A number of carbohydrate active enzymes have been found and identified in the infant gut, thus supporting the hypothesis that these bacteria are able to degrade HMOs. It is suggested that via resource-sharing and cross-feeding, the initial utilization of HMOs drives the interplay within the intestinal microbial communities. This is of pronounced importance since these communities promote healthy development and some of their species also persist in the adult microbiome. The emerging production and accessibility to metagenomic data make it increasingly possible to unravel the metabolic capacity of entire ecosystems. Such insights can increase understanding of how the gut microbiota in infants is assembled and makes it a possible target to support healthy growth. In this manuscript, we discuss the co-occurrence and function of carbohydrate active enzymes relevant to HMO utilization in the first year of life, based on publicly available metagenomic data. We compare the enzyme profiles of breastfed children throughout the first year of life to those of formula-fed infants.

Purpose Bariatric surgery alters gastrointestinal anatomy. In this exploratory study, the SmartPill® wireless motility capsule (WMC) was used to study changes in gastrointestinal physiology following biliopancreatic diversion with duodenal switch (BPD/DS). Material and Methods Twenty-eight BPD/DS patients (35 ± 11 years, 50% females, body mass index [BMI] 56 ± 5) were to be examined preoperatively and postoperatively. In addition to transit time, appetite control and gastrointestinal symptoms were studied by patient-scored questionnaires (visual analogue scale and Gastrointestinal Symptom Rating Scale (GSRS)). Data was compared to 41 lean unoperated controls. Results About 1.8 years postoperatively, 18 patients (BMI 35.8 ± 8.3) returned for a second WMC test. As expected, small bowel transit time was reduced, from 3.9 ± 1.6 h to 2.8 ± 2.0, p = 0.02, and at both these time points, it was shorter than in lean controls (5.4 ± 1.9 h, p = 0.001). Postoperatively, a trend towards reduced colon and whole gut transit times was seen in BPD/DS-patients, thus approaching those of lean controls. Surprisingly, BPD/DS patients scored higher satiety than controls preoperatively as well as increased hunger and desire to eat postoperatively. Compared to lean, BPD/DS patients reported a higher total GSRS score at both time points (1.2 ± 0.2 vs 1.7 ± 0.6 and 2.3 ± 0.5, p < 0.001). Postoperatively, the scores for diarrhea and indigestion increased. Conclusions The novel use of the SmartPill system in BPD/DS patients gave the expected readouts. Although small bowel transit time was further shortened after BPD/DS, whole gut transit time did not differ from controls. Typical gastrointestinal symptoms were reported postoperatively. Graphical abstract

Intestinal macrophages play a key role in the gut immune system and the regulation of gastrointestinal physiology, including gut motility and secretion. Their ability to keep the gut from chronic inflammation despite constantly facing foreign antigens has been an important focus in gastrointestinal research. However, the heterogeneity of intestinal macrophages has impeded our understanding of their specific roles. It is now becoming clear that subsets of intestinal macrophages play diverse roles in various gastrointestinal diseases. This occurs through a complex interplay between cytokine production and enteric nervous system activation that differs for each pathologic condition. Key diseases and disorders in which intestinal macrophages play a role include postoperative ileus, inflammatory bowel disease, necrotizing enterocolitis, as well as gastrointestinal disorders associated with human immunodeficiency virus and Parkinson’s disease. Here, we review the identification of intestinal macrophage subsets based on their origins and functions, how specific subsets regulate gut physiology, and the potential for these heterogeneous subpopulations to contribute to disease states. Furthermore, we outline the potential for these subpopulations to provide unique targets for the development of novel therapies for these disorders.

Function diagrams put the focus on physiology and physiological concepts rather than the associated anatomy. Function diagrams could potentially serve as an elaboration tool and memory aid (mnemonic) to improve learning and recall. The function diagram prototype of the gastrointestinal system can aid in the instruction of difficult gastrointestinal physiology topics using a sequential focus on fundamental gastrointestinal functions.

The gastrointestinal (GI) tract is essential for the absorption of nutrients, induction of mucosal and systemic immune responses, and maintenance of a healthy gut microbiota. Key aspects of gastrointestinal physiology are controlled by the enteric nervous system (ENS), which is composed of neurons and glial cells. The ENS is exposed to and interacts with the outer (microbiota, metabolites, and nutrients) and inner (immune cells and stromal cells) microenvironment of the gut. Although the cellular blueprint of the ENS is mostly in place by birth, the functional maturation of intestinal neural networks is completed within the microenvironment of the postnatal gut, under the influence of gut microbiota and the mucosal immune system. Recent studies have shown the importance of molecular interactions among microbiota, enteric neurons, and immune cells for GI homeostasis. In addition to its role in GI physiology, the ENS has been associated with the pathogenesis of neurodegenerative disorders, such as Parkinson's disease, raising the possibility that microbiota-ENS interactions could offer a viable strategy for influencing the course of brain diseases. Here, we discuss recent advances on the role of microbiota and the immune system on the development and homeostasis of the ENS, a key relay station along the gut-brain axis.

Inflammatory bowel disorder, an inflammatory condition of the gastrointestinal tract, particularly affects the ileum and colon section. Treatment strategies for this inflammatory disorder needs special attention for the inhibition of pathogenetic stages of the underlying inflammatory cascade. Conventional therapies of the available treatments are providing limited activity towards controlling this disease, concurrently accompanied with dependence, adverse effects, and unfavorable pharmacokinetic profile of the drug, which ultimately affects the quality of life of the patients. Novel drug delivery systems under the umbrella of nanotechnology have brought several options to improve the treatment through targeting approach to the intestinal inflammatory cells, reduction in systemic exposure, and prevention of unnecessary flushing of therapeutics from the inflamed cells. This chapter focused on gastrointestinal physiology that need to be considered while delivering drugs using the nanotechnological platforms to improve the efficacy and safety of the medicaments in inflammatory bowel disorder.

1. Physiology of excitable cells -- 2. Physiology of the nervous system -- 3. Respiratory physiology -- 4. Cardiovascular physiology -- 5. Gastrointestinal physiology -- 6. Liver physiology -- 7. Renal physiology -- 8. Acid-base physiology -- 9. Physiology of blood -- 10. Physiology of the immune system -- 11. Endocrine physiology -- 12. Metabolism, nutrition, exercise and temperature regulation -- 13. Physiology of pain -- 14. Maternal and neonatal physiology -- 15. Physiology of ageing -- 16. Special environments.

Food intake is tightly regulated by complex and coordinated gut-brain interactions. Nutrients rapidly modulate activity in key populations of hypothalamic neurons that regulate food intake, including hunger-sensitive agouti-related protein (AgRP)-expressing neurons. Because individual macronutrients engage specific receptors in the gut to communicate with the brain, we reasoned that macronutrients may utilize different pathways to reduce activity in AgRP neurons. Here, we revealed that AgRP neuron activity in hungry mice is inhibited by site-specific intestinal detection of different macronutrients. We showed that vagal gut-brain signaling is required for AgRP neuron inhibition by fat. In contrast, spinal gut-brain signaling relays the presence of intestinal glucose. Further, we identified glucose sensors in the intestine and hepatic portal vein that mediate glucose-dependent AgRP neuron inhibition. Therefore, distinct pathways are activated by individual macronutrients to inhibit AgRP neuron activity.

Although oral drugs account for 80% of the world drug market, many difficulties arise in their development. The drug absorption profile after oral administration may be influenced by multiple factors, including dosing conditions and physiological state of the gastrointestinal (GI) tract. Variability in GI fluid volume may influence the absorption characteristics. Indeed, the contributions of passive diffusion, transporters, and metabolic enzymes depend on GI drug concentration, which is influenced by changes in GI fluid volume. However, this important variable has been neglected in many prediction methods for oral drug absorption and drug interactions, and for convenience it is often assumed that the GI water volume is fixed at a constant value. Major global regulatory agencies such as the U.S. Food and Drug Administration (FDA), European Medicines Agency (EMA), and Japanese Pharmaceuticals and Medical Devices Agency (PMDA) recommend using a constant fluid volume of 250 mL (the fluid volume of a glass of water) to estimate the theoretical GI concentration of drugs after oral administration. However, the actual volume of water in the GI tract is both time- and site-dependent as a result of water intake, absorption, secretion, and GI transit. This review article summarizes our data showing that luminal water volume is influenced by the osmolality of the applied solution, and illustrates how this effect may contribute to changes in GI drug concentration, resulting in altered drug absorption.

Purpose of review The current review outlines the existing research on the impact of circadian rhythm on gastrointestinal toxicity associated with cancer treatment and explores clinical evidence for utilizing circadian-based approaches in addressing gastrointestinal symptoms such as nausea, vomiting, diarrhea, mucositis, and hepatotoxicity. Recent findings Recent evidence highlights circadian control of gastrointestinal physiology of appetite, digestion, nutrient absorption, and cellular proliferation in the digestive system. In addition, animal models support the mechanistic rationale of using chronotherapy (a type of anticancer therapy delivered at specific times with the goal of producing less toxicity and greater treatment response) to minimize gastrointestinal-impact of systemic cancer treatments. In addition, earlier research demonstrates that many chemotherapeutic agents are responsive to circadian timing in animals. On the contrary, clinical trials focused on minimizing gastrointestinal toxicity using chronotherapy have been limited in recent years and have not yielded the efficacy initially hoped for. Instead, researchers focused on understanding circadian rhythm's influence on the gastrointestinal system at a mechanistic level as well as measuring circadian rhythm at an individual level. Summary Although using circadian timing is a promising target for reducing gastrointestinal toxicity, recent evidence suggests that more research is needed to understand circadian rhythm before circadian-based interventions can be developed that will result in lessening of gastrointestinal toxicity.

It is recommended that patients with acute upper gastrointestinal bleeding undergo endoscopy within 24 hours after gastroenterologic consultation. The role of endoscopy performed within time frames shorter than 24 hours has not been adequately defined.To evaluate whether urgent endoscopy improves outcomes in patients predicted to be at high risk for further bleeding or death, we randomly assigned patients with overt signs of acute upper gastrointestinal bleeding and a Glasgow-Blatchford score of 12 or higher (scores range from 0 to 23, with higher scores indicating a higher risk of further bleeding or death) to undergo endoscopy within 6 hours (urgent-endoscopy group) or between 6 and 24 hours (early-endoscopy group) after gastroenterologic consultation. The primary end point was death from any cause within 30 days after randomization.A total of 516 patients were enrolled. The 30-day mortality was 8.9% (23 of 258 patients) in the urgent-endoscopy group and 6.6% (17 of 258) in the early-endoscopy group (difference, 2.3 percentage points; 95% confidence interval [CI], -2.3 to 6.9). Further bleeding within 30 days occurred in 28 patients (10.9%) in the urgent-endoscopy group and in 20 (7.8%) in the early-endoscopy group (difference, 3.1 percentage points; 95% CI, -1.9 to 8.1). Ulcers with active bleeding or visible vessels were found on initial endoscopy in 105 of the 158 patients (66.4%) with peptic ulcers in the urgent-endoscopy group and in 76 of 159 (47.8%) in the early-endoscopy group. Endoscopic hemostatic treatment was administered at initial endoscopy for 155 patients (60.1%) in the urgent-endoscopy group and for 125 (48.4%) in the early-endoscopy group.In patients with acute upper gastrointestinal bleeding who were at high risk for further bleeding or death, endoscopy performed within 6 hours after gastroenterologic consultation was not associated with lower 30-day mortality than endoscopy performed between 6 and 24 hours after consultation. (Funded by the Health and Medical Fund of the Food and Health Bureau, Government of Hong Kong Special Administrative Region; ClinicalTrials.gov number, NCT01675856.).

Bariatric surgery is currently the most effective weight loss treatment of severe obesity and its associated comorbidities and is being increasingly used to treat children and adolescents with severe obesity, including those with Type 2 Diabetes (T2D). This review focuses on the conventional management of T2D in children and adolescents, comparison of various types of bariatric surgeries, effect of bariatric surgery on gastrointestinal physiology and metabolism, current literature on the use of bariatric surgery to treat youth with severe obesity and T2D, and the potential complications of bariatric surgery in this population.

Linked to the growing obesity epidemic, demand for bariatric and metabolic surgery has increased, the most common procedures being sleeve gastrectomy and Roux-en-Y gastric bypass. Originally, bariatric procedures were described as purely restrictive, malabsorptive, or combined restrictive–malabsorptive procedures limiting food intake, nutrient absorption, or both. Nowadays, anatomical alterations are known to affect gastrointestinal physiology, which in turn affects the digestion and absorption of nutrients and drugs. Therefore, understanding gastrointestinal physiology is crucial to preventing postoperative nutritional deficiencies and optimising postoperative drug therapy. Preclinical and clinical research indicates that sleeve gastrectomy accelerates liquid and solid gastric emptying and small intestinal transit, and increases bile acid serum levels, whereas its effect on gastrointestinal acidity, gastric and pancreatic secretions, surface area, and colonic transit remains largely unknown. Roux-en-Y gastric bypass diminishes gastric acid secretion, accelerates liquid gastric emptying, and increases bile acid serum levels, but its effects on intestinal pH, solid gastric emptying, intestinal transit time, gastric enzyme secretions, and surface area remain largely unknown. In this Review, we summarise current knowledge of the effects of these two procedures on gastrointestinal physiology and assess the knowledge gaps. ispartof: The Lancet Gastroenterology and Hepatology vol:6 issue:3 pages:225-237 ispartof: location:Netherlands status: published

Food is the largest expense in fish farms. On the other hand, the fish health and wellbeing are determining factors in aquaculture production where nutrition is a vital process for growing animals. In fact, it is important to remember that digestion and nutrition are crucial for animals' physiology. However, digestion is a very complex process in which food is processed to obtain necessary nutrients and central mechanisms of this process require both endocrine and neuronal regulation. In this context, intestinal motility is essential for the absorption of the nutrients (digestive process determining nutrition). An imbalance in the intestinal motility due to an inadequate diet or an infectious process could result in a lower use of the food and inefficiency in obtaining nutrients from food. Very frequently, farmed fish are infected with different pathogenic microorganism and this situation could alter gastrointestinal physiology and, indirectly reduce fish growth. For these reasons, the present review focuses on analysing how different inflammatory molecules or infections can alter conventional modulators of fish intestinal motility.

Normal gastrointestinal physiology is fundamental for all the living beings. Gastrointestinal diseases mainly include gastrointestinal motility disorders, infectious inflammation (such as Helicobacter pylori infection, cholera, and intestinal parasites), non-infectious inflammation (such as chronic gastritis and Crohn's disease), and gastrointestinal cancers. In addition, intestinal microbial disorder is also an important cause of intestinal diseases, so intestinal microecological treatment (fecal microbiota transplantation) is an important mean of treating gastrointestinal diseases. In recent years, the role of autophagy in gastrointestinal diseases has been studied extensively. Autophagy is observed under various pathological processes of the gastrointestinal tract. For example, it has been demonstrated that autophagy plays an important role in maintaining the homeostasis and integrity of intestinal epithelium. Additionally, autophagy regulates host response to H. pylori infection and development of gastrointestinal cancers. Therefore, we will discuss pivotal roles of autophagy in various gastrointestinal diseases and analyze the underlying molecular mechanisms, which may provide new therapeutic targets applicable for the treatment of gastrointestinal diseases.

Summary Gastrointestinal physiology involves an intricate network of mechanical, hormonal, and motility functions, including enzymatic secretions, and acid production that work in concert to ensure the breakdown of ingested food for utilization by the body. In critical illness, this delicate interplay is disrupted with marked alterations in absorptive physiology and energy metabolism. This combination of changes necessitates a careful and nuanced approach to nutritional therapy for critically ill patients. The preillness nutrition status of the patient determines their ability to withstand and survive the critical illness state. Nutrition assessment is essential to characterize and define the nutrition status of the patient, determine appropriate nutrient intake goals, and identify the best mode for nutrient delivery. This chapter describes the current state of knowledge and evidence for the provision of nutritional therapy in the ICU patient and explains the nutritional relevance of selected diseases common to adult and pediatric ICU patients.

Background Currently, there is no therapy for obesity and related comorbidities that meets all three criteria of high clinical efficacy, wide availability, and wide acceptability. Dieting is widely available and acceptable but has poorly sustained clinical efficacy. By contrast, Roux-en-Y Gastric Bypass (GB) is highly effective but cost and safety concerns limit widespread use. Hypotheses We hypothesize that bolus jejunal feeding (BJ) via an enteral feeding tube simulates key features of GB with the potential for similar clinical benefits. We further hypothesize that a practical manner of providing BJ therapeutically is via an externally-inapparent orojejunal feeding tube. Rationale The first hypothesis is underpinned by the outcomes of research in three fields: 1. Investigations into the mechanisms underlying the benefit of GB, 2. Studies investigating gastrointestinal physiology and pathophysiology using enteral feeding tubes and, 3. Investigations into the mechanism underlying involuntary anorexia and weight loss in clinical situations that entail rapid nutrient delivery to the jejunum. There is compelling evidence that a supraphysiological rate of delivery of nutrient to the jejunum suppresses appetite and energy intake, and improves glucose homeostasis, and that these effects can be achieved non-surgically using an enteral feeding tube. The second hypothesis is supported by clinical demonstration of the feasibility of administering intermittent cycles of bolus feeds via an intraorally anchored feeding tube in ambulatory obese adults. Conclusion The hypotheses are testable in clinical studies. If validated, BJ could be used to induce the clinical benefits of GB, but without its costs or safety concerns.

Various physiological factors in the gastrointestinal (GI) tract affect the in vivo performance of orally administered dosage forms. In this review article, we summarize the formulation-related interspecies differences (particularly under the fasted state) between humans and laboratory animals. In particular, we discuss the differences in fluid characteristics in the stomach and small intestine, transit of dosage forms in the gut, and drug permeation through the intestinal epithelium after release from dosage forms. Further, we provide several case examples of oral drug formulations that were affected by species-specific differences in GI physiology between laboratory animals and humans that have been discussed at the consortium of Academy of Pharmaceutical Science and Technology, Japan. In these examples, species-specific differences in gut physiological parameters between humans and animals greatly affected the in vivo performance of dosage forms.

Zinc is one of the most studied minerals of the twenty-first century as it is practically involved in every function of the body. The importance of zinc has earned it the epithet “calcium of twenty-first century.” However, the bioavailability of zinc depends on the source of zinc and the subsequent processes of digestion, absorption and metabolism. Zinc from organic sources tends to be more available to animals than from inorganic sources. The complex gastrointestinal physiology of ruminants makes these processes even more intricate. Zinc in the rumen interacts with other substances altering its fate. Absorption of zinc from the gastrointestinal tract (GIT) was a mystery until the discovery of zinc transporter proteins. These discoveries opened new gates of wisdom and understanding about the tumultuous journey of zinc molecules through the complex GIT of ruminants. The decade-old concepts of zinc homeostasis largely based on the zinc complexes are jostling through the new theories with the focus on the free zinc ions. The present review briefly elucidates the processes of metabolism and homeostasis of zinc in ruminants.

Some traditional bariatric surgery procedures may lead to functional gut shortening, which may unsettle the fine-tuned gastrointestinal physiology and affect gut microbiota balance. Evaluate the gut microbiota behavior in rat models facing gut shortening due to intestinal bypass. Wistar rats (n = 17) were randomly distributed in three groups: (1) sham group (n = 5); (2) blind loop group (n = 6); and (3) resection group (n = 6). Intestinal samples and feces were analyzed to measure bacterial concentrations (small intestinal bacterial overgrowth—SIBO) 12 weeks after the experimental procedures. Bacterial translocation (BT) was investigated in the mesenteric lymph node (MLN), liver, spleen, and lung of the animals. In addition, inflammatory aspects were investigated in their liver and small bowel through histological analysis. Regardless of blind loop, gut shortening groups recorded similar high level of bacterial concentrations in intestine compartments, greater than that of the sham group (p ≤ 0.05). BT was only observed in the MLN of gut shortening models, with higher percentage in the blind loop group (p ≤ 0.05). The gut and liver histopathological analysis showed similar low-grade chronic inflammation in both gut shortening groups, likely associated with SIBO/BT events. Sustained SIBO/BT was associated with proximal gut shortening in half regardless of blind loop, whereas the GI tract’s ability to restore gut microbiota balance after a surgical challenge on the small bowel appears to be linked to the functional remaining gut.

The effect of non-viable lactic acid bacteria on gastrointestinal physiology and dysfunction remains still unclear. Previous clinical trials have reported that Lactobacillus gasseri CP2305 (CP2305) exerts stress-relieving and anti-flatulent effects regardless of cell viability. In this study, we investigated the effect of viable and non-viable CP2305 cells on electrical field stimulation (EFS)-evoked increases in short-circuit current (Isc) using the Ussing chamber technique. In mucosal-submucosal preparations of rats, both viable and non-viable CP2305 cells significantly and acutely inhibited the EFS-evoked increases in Isc in the middle and distal colon and rectum but not in proximal colon. The inhibition of EFS-evoked Isc differed from strain to strain. Peripheral injection of corticotropin releasing factor (CRF) is known to mimic diarrhea symptoms in rats. Therefore, we examined the chronic effects of CP2305 cells on CRF-induced diarrhea in the rat model. Treatment with viable and non-viable CP2305 cells significantly improved CRF-induced diarrhea in the rat model. However, the treatment did not affect the fecal pellet output. These findings suggest that CP2305 has an important role in gastrointestinal physiology and dysfunction.

The well-regulated mechanisms of intestinal transit favor aboral movement of intestinal contents during the formation of normal stool. Electrical pacemakers initiate mechanical smooth muscular propulsion under regulation by the enteric nervous system-a function of the "brain-gut axis." Several unique intestinal motor patterns function in concert to enhance the activities of intestinal transit. Development of pharmacologic targets of intestinal transit mechanisms afford clinicians control in the management of functional gastrointestinal disorders. This review highlights the important physiologic events of intestinal transit, discusses selected pharmacologic and neuromodulators involved in these processes, and provides relevant clinical correlates to physiologic events.

ObjectivesDrug product performance in patients with gastrointestinal (GI) diseases can be altered compared to healthy subjects due to pathophysiological changes. In this review, relevant differences in patients with inflammatory bowel diseases, coeliac disease, irritable bowel syndrome and short bowel syndrome are discussed and possible in vitro and in silico tools to predict drug product performance in this patient population are assessed.Key findingsDrug product performance was altered in patients with GI diseases compared to healthy subjects, as assessed in a limited number of studies for some drugs. Underlying causes can be observed pathophysiological alterations such as the differences in GI transit time, the composition of the GI fluids and GI permeability. Additionally, alterations in the abundance of metabolising enzymes and transporter systems were observed. The effect of the GI diseases on each parameter is not always evident as it may depend on the location and the state of the disease. The impact of the pathophysiological change on drug bioavailability depends on the physicochemical characteristics of the drug, the pharmaceutical formulation and drug metabolism. In vitro and in silico methods to predict drug product performance in patients with GI diseases are currently limited but could be a useful tool to improve drug therapy.SummaryDevelopment of suitable in vitro dissolution and in silico models for patients with GI diseases can improve their drug therapy. The likeliness of the models to provide accurate predictions depends on the knowledge of pathophysiological alterations, and thus, further assessment of physiological differences is essential.

Cecal and ileal cannulations have previously been used to determine equine digestibility and define gastrointestinal physiology. However, research has been limited to specific portions of the equine digestive tract lacking utilization of dual cannulations. The purpose of this study was to develop and implement surgical and preoperative and postoperative procedures for cannulation of dual sections, ileum and cecum, of the equine digestive tract including development of recommendations for addressing postsurgery complications. A total of 8 ponies went through surgical procedures for the placement of a cannula at the ileum and cecum. All ponies awoke from the surgery and stood, but during postsurgical care, complications arisen including increased temperature, dehydration, lameness, herniation, and peritonitis. The survival rate of dual cannulation of the ileum and cecum was 63% of the animals with euthanization attributed to intestinal herniation. This research provides information for the academic community to better plan and implement dual cannulation of equids.

Radiotherapy-induced damage to non-cancerous gastrointestinal mucosa has effects on secretory and absorptive functions and can interfere with normal gastrointestinal physiology. Nutrient absorption and digestion may be compromised. Dietary manipulation is an attractive option with sound rationale for intervention. The aim of this review was to synthesise published evidence for the use of elemental formulae, low or modified fat diets, fibre, lactose restriction and probiotics, prebiotics and synbiotics to protect the bowel from gastrointestinal side effects during long-course, radical pelvic radiotherapy. Thirty original studies (recruitingn3197 patients) were identified comprising twenty-four randomised controlled trials, four cohort studies and two comparator trials. Endpoints varied and included symptom scales (Inflammatory Bowel Disease Questionnaire, Common Technology Criteria for Adverse Events, Radiation Therapy Oncology Group) and Bristol Stool Scale. Dietary and supplement interventions were employed with many studies using a combination of interventions. Evidence from RCT was weak for elemental, low or modified fat and low-lactose interventions and modestly positive for the manipulation of fibre during radiotherapy. Evidence for probiotics as prophylactic interventional agents was more promising with a number of trials reporting positive results but strength and strains of interventions vary, as do methodologies and endpoints making it difficult to arrive at firm conclusions with several studies lacking statistical power. This consolidated review concludes that there is insufficient high-grade evidence to recommend nutritional intervention during pelvic radiotherapy. Total replacement of diet with elemental formula could be effective in severe toxicity but this is unproven. Probiotics offer promise but cannot be introduced into clinical practice without rigorous safety analysis, not least in immunocompromised patients.

Inflammatory bowel diseases, including Crohn’s disease and ulcerative colitis, are chronic inflammatory conditions involving primarily the gastrointestinal tract. However, they may be also associated with systemic manifestations and comorbidities. The relationship between chronic inflammation and endothelial dysfunction has been extensively demonstrated. Mucosal immunity and gastrointestinal physiology are modified in inflammatory bowel diseases, and these modifications are mainly sustained by alterations of endothelial function. The key elements involved in this process are cytokines, inflammatory cells, growth factors, nitric oxide, endothelial adhesion molecules, and coagulation cascade factors. In this review, we discuss available data in literature concerning endothelial dysfunction in patients affected by inflammatory bowel disease and we focus our attention on both pharmacological and nonpharmacological therapeutic targets.