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Background and Aims: The group of disorders known as Disorders of Gut Brain Interaction (DGBI) were originally labeled functional GI disorders and were thought to be disorders of the gastrointestinal tract that had several psychological conditions as comorbidities. Despite mounting evidence that psychological morbidity plays an innate role in the etiology and maintenance of DGBI, none of the Rome IV criteria include any measure of psychological symptoms. This study tested the hypothesis that individuals would cluster differently if GI symptoms alone were considered versus GI symptoms combined with measures of psychological symptoms. Methods: Data were obtained from the Rome Foundation Global Epidemiology Study measuring Rome IV GI symptoms, psychological measures and demographic characteristics. Latent profile models were used to cluster individuals based on (i) GI symptoms only (GI only) and then (ii) GI and psychological measures (GI + Psych). Key Results: Individuals clustering into the same group of individuals whether formed via GI only or GI + Psych, ranged from 96% for a 2‐class solution (the most simplistic) to 76% with 6 classes (the parsimonious system) and 59% with twenty‐two classes (mimicking Rome IV). The generalisability of this finding between six geographic regions was confirmed with agreement varying between 95%–97% for 2 clusters and 71–79% for 6 classes and 51%–63% for 22 classes. These findings were also consistent between DGBI (range 94% with 2 classes to 50% with 22 classes) and non‐DGBI (range 97% with 2 clusters to 65% with 22 classes) groups. Conclusions & Inferences: Our data suggest that considering psychological as well as gastrointestinal symptoms would lead to a different clustering of individuals in more complex, and accurate, classification systems. For this reason, future work on DGBI classification should consider inclusion of psychological traits. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusions Inhibitory neuromuscular transmission in the gastrointestinal tract is mediated by intrinsic nitrergic and purinergic neurons. Purines activate G protein‐coupled receptor P2Y1 receptors, increasing intracellular Ca2+ that activates small conductance calcium‐activated potassium (SKCa) channels. Little is known about the effect of adrenergic receptor activation on intestinal smooth muscle. In vascular tissue, stimulation of α‐adrenoceptors causes smooth muscle contraction, while their effect on intestinal tissue is poorly understood. This study aimed to pharmacologically characterize the effect of α‐adrenoceptor activation in the rat colon, which shares similar inhibitory pathways to the human colon.Muscle bath experiments were performed with the rat proximal, mid, and distal colon oriented both circularly and longitudinally.The α1‐adrenoceptor agonist phenylephrine (PE) (10−8–10−5 M) evoked concentration‐dependent relaxations of the intestinal smooth muscle from all regions and orientations. However, in the mid‐circular colon at low PE concentrations, a contraction sensitive to 10−5 M phentolamine (non‐selective α‐adrenoceptor blocker), the neural blocker tetrodotoxin (TTX; 10−6 M), and atropine (10−6 M) was recorded. PE‐induced relaxations were insensitive to TTX (10−6 M) and the nonselective β‐adrenoceptor blocker propranolol (10−6 M). In contrast, PE‐induced relaxations were blocked by phentolamine (10−5 M), prazosin (10−6 M) (α1‐adrenoceptor blocker), and RS17053 (10−6 M) (α1A‐blocker), but not by yohimbine (10−6 M) (α2‐adrenoceptor blocker). Apamin (10−6 M), a SKCa channel blocker, abolished PE‐induced relaxations.Contractile responses in the circular muscle of the mid colon could be attributed to α‐adrenoceptors located on enteric cholinergic neurons. Stimulation of α1A‐adrenoreceptors activates SKCa channels to cause smooth muscle relaxation, which constitutes a signaling pathway that shares similarities with P2Y1 receptors. [ABSTRACT FROM AUTHOR]

Background: In 2018 diagnostic criteria for pediatric intestinal pseudo‐obstruction (PIPO) were established. Neuromuscular dysfunction of the gastrointestinal tract is one of these, and often examined through antroduodenal manometry (ADM). There is little data on antroduodenal manometries in children. Our objectives were to retrospectively apply these criteria to children evaluated for suspected motility disorder, to reevaluate the ADM patterns and compare children who did and did not meet the PIPO criteria and also with healthy adults. Methods: Children with a suspected gastrointestinal motility disorder previously investigated with 24‐h 8‐lead ADM were reevaluated by applying the 2018 ESPGHAN/NASPGHAN PIPO diagnostic criteria and the 2018 ANMS‐NASPGHAN guidelines. ADM findings were compared between children who retrospectively fulfilled a PIPO diagnosis, children who did not, and a control group of healthy adults. Key Results: Of 34 children (age 7.9 (±5.1) years, 18 males), 12 retrospectively fulfilled the 2018 PIPO diagnostic criteria. Twenty‐five children (10 in the PIPO group) had abnormal diagnostic findings on ADM, whereas 9 (2 in the PIPO group) had no such findings. A PIPO diagnosis implied a significantly higher degree of abnormal ADM patterns (2.33 vs. 1.23, p = 0.02). There were no major differences in quantitative ADM measurements between the groups except higher pressures in children. Conclusions and Inferences: Children who retrospectively fulfilled a PIPO diagnosis had a significantly higher abundance of abnormal ADM findings compared with symptomatic children without PIPO and healthy adults. Our data indicate a need for set criteria for evaluation of ADM in children with suspected PIPO. [ABSTRACT FROM AUTHOR]

Background: Evaluation of gut motility in clinical practice is currently limited. A novel medical system (MoPill™) consisting of a capsule that wirelessly transmits radiofrequency signals to assess motility via 3D location, was used to conduct this study. The objectives were to: (1) confirm the safety of the MoPill™ system; (2) compare the 3D location transmitted by the capsule to its location captured by abdominal x‐rays; 3 determine gastric emptying (GE), whole gut transit time (WGTT) and segmental transit times. Methods: The MoPill™ system consists of an electronic capsule (2 × 1.2 cm), eight color‐coded adhesive sensors (6 × 5.5 cm), a recorder (15 × 11 × 2 cm), and software on a laptop. Four sensors were applied to the abdomen and four to the back. Healthy subjects who had fasted overnight ingested a 250‐calorie protein bar, 17 oz. of water, followed by an activated capsule. No further caloric contents were permitted for the next 5 h. At 1, 5, and 24 h (if the capsule had not been expelled), upright abdominal X‐rays (AP and lateral) were obtained to assess the location of the capsule, which was compared to the gastrointestinal positioning system (GPS) location determined by the MoPill™ system. Identification of the capsule's anatomical location by the MoPill™ system was based on (1) the 3D (x, y, z) location; (2) time; (3) trajectory (e.g., going up the right side of the body signified ascending colon); (4) frequency of contractions (e.g., 3 cycles/min for the stomach); and (5) milestone relationship (e.g., pyloric passage must follow the end of gastric contractions). GE was determined first by the end of the 3 cycles/min rhythmic movement of the stomach and then again by pyloric expulsion on 3D location. Small intestine transit was taken as the duration from pyloric expulsion to arrival in the cecum. Colon transit time was determined by calculating the duration from 3D arrival in the cecum to passage of the capsule out of the body (i.e., loss of signal accompanying a bowel movement). Key Results: Ten healthy subjects (five women; mean age 34; mean BMI 24) were enrolled, and nine provided reliable data. The variation between the x‐ray and the estimated (i.e., identified by the MoPill™ system) location of the capsule was within an average of 3.5 cm (range 0.9–9.4 cm). The mean GE was 3.1 h. The small intestine's mean transit time was 4.3 h. The mean colonic transit time was 17.6 h. There were no adverse events recorded during the study. Conclusions & Inferences: MoPill™ is a novel gastrointestinal positional system that accurately identifies the location of a capsule compared to an X‐ray. MoPill™ system also recognizes GE, small bowel, colonic, and WGTT as well as segmental gut location and movement characteristics. MoPill™ offers the potential for new insights into GI motility disorders not attainable by current modalities. [ABSTRACT FROM AUTHOR]

Background: Duchenne's muscular dystrophy (DMD) is a severe type of hereditary, neuromuscular disorder caused by a mutation in the dystrophin gene resulting in the absence or production of truncated dystrophin protein. Conventionally, clinical descriptions of the disorder focus principally on striated muscle defects; however, DMD manifestations involving gastrointestinal (GI) smooth muscle have been reported, even if not rigorously studied. Purpose: The objective of the present review is to offer a comprehensive perspective on the existing knowledge concerning GI manifestations in DMD, focusing the attention on evidence in DMD patients and mdx mice. This includes an assessment of symptomatology, etiological pathways, and potential corrective approaches. This paper could provide helpful information about DMD gastrointestinal implications that could serve as a valuable orientation for prospective research endeavors in this field. This manuscript emphasizes the effectiveness of mdx mice, a DMD animal model, in unraveling mechanistic insights and exploring the pathological alterations in the GI tract. The gastrointestinal consequences evident in patients with DMD and the mdx mice models are a significant area of focus for researchers. The exploration of this area in depth could facilitate the development of more efficient therapeutic approaches and improve the well‐being of individuals impacted by the condition. [ABSTRACT FROM AUTHOR]

Background: There is compelling evidence that microbe‐host interactions in the intestinal tract underlie many human disorders, including disorders of gut‐brain interactions (previously termed functional bowel disorders), such as irritable bowel syndrome (IBS). Small intestinal bacterial overgrowth (SIBO) has been recognized for over a century in patients with predisposing conditions causing intestinal stasis, such as surgical alteration of the small bowel or chronic diseases, including scleroderma and is associated with diarrhea and signs of malabsorption. Over 20 years ago, it was hypothesized that increased numbers of small intestine bacteria might also account for symptoms in the absence of malabsorption in IBS and related disorders. This SIBO‐IBS hypothesis stimulated significant research and helped focus the profession's attention on the importance of microbe‐host interactions as a potential pathophysiological mechanism in IBS. Purpose: However, after two decades, this hypothesis remains unproven. Moreover, it has led to serious unintended consequences, namely the widespread use of unreliable and unvalidated breath tests as a diagnostic test for SIBO and a resultant injudicious use of antibiotics. In this review, we examine why the SIBO hypothesis remains unproven and, given the unintended consequences, discuss why it is time to reject this hypothesis and its reliance on breath testing. We also examine recent IBS studies of bacterial communities in the GI tract, their composition and functions, and their interactions with the host. While these studies provide important insights to guide future research, they highlight the need for further mechanistic studies of microbe‐host interactions in IBS patients before we can understand their possible role in diagnosis and treatment of patient with IBS and related disorders. [ABSTRACT FROM AUTHOR]

Dr. Gary M. Mawe, a highly respected scholar and leader in the field of Neurogastroenterology and Motility, passed away on February 17, 2024. He was known for his outstanding scholarship, as well as his charm, wit, generosity, and enthusiasm for science and life. Dr. Mawe conducted research on various aspects of gallbladder function, serotonin signaling in intestinal inflammation, and reflex circuits in the intestines. He was highly respected in his field and had a profound impact on his colleagues and students. He was also known for his kindness, warmth, and genuine interest in others, and for promoting equity, diversity, and inclusivity. His loss will be deeply felt by his colleagues, friends, and family. [Extracted from the article]

Background and Purpose: The pathophysiology of obesity has been the product of extensive research, revealing multiple interconnected mechanisms contributing to body weight regulation. The regulation of energy balance involves an intricate network, including the gut–neuroendocrine interplay. As a consequence, research on the gut–brain–microbiota axis in obesity has grown extensively. The physiology of the gastrointestinal tract, far from being underexplored, has significant implications for the development of specific complications in people living with obesity across the fields of gastroenterology, nutrition, and pharmacology. Clinical research indicates higher fasting bile acids serum levels, and blunted postprandial increases in bilious secretions in people living with obesity. Findings are less straightforward for the impact of obesity on gastric emptying with various studies reporting accelerated, normal, or delayed gastric emptying rates. Conversely, the effect of obesity on gastrointestinal pH, gastrointestinal transit, and gastric and pancreatic enzyme secretion is largely unknown. In this review, we explore the current evidence on the gastrointestinal physiology of obesity. [ABSTRACT FROM AUTHOR]

Background: Disrupted circadian rhythms may result from a misalignment between the environmental cycles (due to shift work, sleep restriction, feeding at an unusual time of day) and endogenous rhythms or by physiological aging. Among the numerous adverse effects, disrupted rhythms affect the brain‐gut axis, contributing to the pathogenesis of several diseases in the gastrointestinal tract, for example, abdominal pain, constipation, gastric dyspepsia, inflammatory bowel disease, irritable bowel syndrome, and others. Methods: This study evaluated the rat gastric emptying, gastrointestinal motility, a clock gene, gut hormones, and the neuron activity on the nucleus of tractus solitarius (NTS), area postrema (AP), and the dorsal motor nucleus of the vagus (DMV) in rats with restricted food access to the rest phase for 4 weeks. Key Results: Our results show that food restricted to the rest light period disturbed the expression pattern of a series of transcripts, including metabolic and circadian regulation. Also, the secretion of gastrointestinal hormones, gastric emptying, intestinal motility, and NTS, AP, and DMV activity were altered. Conclusions & Inferences: These data indicate the importance of the time of the day food is ingested on the regulation of energy balance and the endocrine activity of the stomach and small intestine, emphasizing the importance of food as a powerful circadian synchronizer and an essential factor for the triggering of gastrointestinal diseases and metabolic problems. These findings offer a novel clue regarding the obesity‐promoting effect attributed to feeding time and open the possibility of treating this and other intestinal disorders. [ABSTRACT FROM AUTHOR]

Background/Purpose: Gastrointestinal (GI) dysmotility is categorized by muscle or nerve dysfunctions in any portion of the GI tract, which leads to abnormalities in GI motor and sensory function. Symptoms may vary depending on the organ affected and can be debilitating. Treatment usually involves diet and lifestyle changes. Pharmacotherapy is limited in effectiveness with various side effects. Transcutaneous electrical stimulation (TES), a noninvasive, needleless technique that provides electrical stimulation using cutaneous non‐needle electrodes, has become increasingly popular. It has been shown to be beneficial in treating GI motility disorders. Methods: This review paper navigates through the different TES techniques, including transcutaneous peripheral nerve (vagal/sacral/tibial nerves) electrical stimulation, transcutaneous electrical acustimulation (stimulation via acupuncture point), transcutaneous interferential current therapy, and transcutaneous electrical nerve stimulation. Key Results: As we delve deeper, we explore the promising effects of TES on dysphagia, gastroesophageal reflux disease, functional dyspepsia, gastroparesis, postoperative ileus, constipation, and irritable bowel syndrome. The literature at hand speaks volumes about the therapeutic prowess of this noninvasive technique. Conclusion & Inferences: The time is ripe to evaluate further the full therapeutic potential of TES, a noninvasive, nonpharmaceutical, nonsurgical, and home‐based self‐administrative technique in managing GI motility disorders. [ABSTRACT FROM AUTHOR]

Background: Enterochromaffin (EC) cell‐derived 5‐hydroxytryptamine (5‐HT) is a mediator of toxin‐induced reflexes, initiating emesis via vagal and central 5‐HT3 receptors. The amine is also involved in gastrointestinal (GI) reflexes that are prosecretory and promotile, and recently 5‐HT's roles in chemosensation in the distal bowel have been described. We set out to establish the efficacy of 5‐HT signaling, local 5‐HT levels and pharmacology in discrete regions of the mouse small and large intestine. We also investigated the inter‐relationships between incretin hormones, glucagon‐like peptide‐1 (GLP‐1) and gastric inhibitory polypeptide (GIP) and endogenous 5‐HT in mucosal and motility assays. Methods: Adult mouse GI mucosae were mounted in Ussing chambers and area‐specific studies were performed to establish the 5‐HT3 and 5‐HT4 pharmacology, the sidedness of responses, and the inter‐relationships between incretins and endogenous 5‐HT. Natural fecal pellet transit in vitro and full‐length GI transit in vivo were also measured. Key Results: We observed the greatest level of tonic and exogenous 5‐HT‐induced ion transport and highest levels of 5‐HT in ascending colon mucosa. Here both 5‐HT3 and 5‐HT4 receptors were involved but elsewhere in the GI tract epithelial basolateral 5‐HT4 receptors mediate 5‐HT's prosecretory effect. Exendin‐4 and GIP induced 5‐HT release in the ascending colon, while L cell‐derived PYY also contributed to GIP mucosal effects in the descending colon. Both peptides slowed colonic transit. Conclusions & Inferences: We provide functional evidence for paracrine interplay between 5‐HT, GLP‐1 and GIP, particularly in the colonic mucosal region. Basolateral epithelial 5‐HT4 receptors mediated both 5‐HT and incretin mucosal responses in healthy colon. [ABSTRACT FROM AUTHOR]

Opioids are well known to cause adverse effects on the gastrointestinal tract including nausea, vomiting, and constipation. Data regarding how opioids affect the esophagus are more limited. Opioid‐induced esophageal dysfunction (OIED) is a clinical syndrome defined by chronic opioid use (≥3 months), esophageal symptoms (mainly dysphagia), and esophageal motility abnormalities diagnosed by manometry including achalasia type III, hypercontractile esophagus, distal esophageal spasm, and esophagogastric junction outflow obstruction. Up until now, the effect of opioids on esophageal motility assessed by the functional lumen imaging probe (FLIP) had not been described. In this issue of NGM, Patel et al. report that FLIP assessment in patients with esophageal symptoms showed that chronic opioid users have a significant increase in repetitive retrograde contractions, but no significant reduction in distensibility at the esophagogastric junction compared to non‐users. Additionally, perceptive symptoms were higher, and quality of life metrics were lower in the chronic opioid users. This review article will discuss our current understanding of OIED and provide context for this latest study in chronic opioid users. Further investigation with larger prospective studies is needed to understand the pathophysiology, diagnosis, and management of OIED. [ABSTRACT FROM AUTHOR]

Background: Hyoscine butylbromide (HBB) has been available for use as an antispasmodic since 1951 and is indicated for the treatment of abdominal pain associated with cramps. A previous review in 2007 summarized the evidence on the mode of action of HBB in vitro and in vivo in both animal and human studies. However, since then, novel publications have appeared within the literature and also our knowledge of what represents normal motility in humans has evolved. Purpose: This review is the result of the collaboration between a basic scientist and clinicians with the aim of providing an updated overview of the mechanisms of action of HBB and its clinical efficacy to guide not only use in clinical practice, but also future research. [ABSTRACT FROM AUTHOR]

Background: Impaired bidirectional communication between the gastrointestinal tract and the central nervous system (CNS) is closely related to the development of irritable bowel syndrome (IBS). Studies in patients with IBS have also shown significant activation of the hypothalamus and amygdala. However, how neural circuits of the CNS participate in and process the emotional and intestinal disorders of IBS remains unclear. Methods: The GABAergic neural pathway projecting from the central amygdala (CeA) to the lateral hypothalamus (LHA) in mice was investigated by retrograde tracking combined with fluorescence immunohistochemistry. Anxiety, depression‐like behavior, and intestinal motility were observed in the water‐immersion restraint stress group and the control group. Furthermore, the effects of the chemogenetic activation of the GABAergic neural pathway of CeA‐LHA on behavior and intestinal motility, as well as the co‐expression of orexin‐A and c‐Fos in the LHA, were explored. Key Results: In our study, Fluoro‐Gold retrograde tracking combined with fluorescence immunohistochemistry showed that GABAergic neurons in the CeA were projected to the LHA. The microinjection of the gamma‐aminobutyric acid (GABA) receptor antagonist into the LHA relieved anxiety, depression‐like behavior, and intestinal motility disorder in the IBS mice. The chemogenetic activation of GABAergic neurons in the CeA‐LHA pathway led to anxiety, depression‐like behavior, and intestinal motility disorder. In addition, GABAergic neurons in the CeA‐LHA pathway inhibited the expression of orexin‐A in the LHA, and orexin‐A was co‐expressed with GABAA receptors. Conclusions & Inferences: The CeA‐LHA GABAergic pathway might participate in the occurrence and development of IBS by regulating orexin‐A neurons. [ABSTRACT FROM AUTHOR]

Background: Despite numerous studies on the enteric nervous system (ENS), we lack fundamental knowledge on neuronal densities or total neuron numbers in different species. There are more anecdotal than actual figures on nerve counts. Methods: We used standardized preparation techniques and immunohistochemistry with validated panneuronal markers (human or mouse anti‐HuD/C) to determine neuronal densities in specimen from the entire gastrointestinal tract of mice, guinea pig, and humans. In parallel, we measured the dimensions of the gastrointestinal regions in mouse and guinea pig. For humans, we had to rely on literature data. Key Results: The average neuronal densities along the gastrointestinal tract were 35,011 ± 25,017 1/cm2 for the myenteric and 16,685 ± 9098 1/cm2 for the submucous plexus in mice, 24,315 ± 16,627 and 11,850 ± 6122 1/cm2 for guinea pig myenteric and submucous plexus, respectively, and 21,698 ± 9492 and 16,367 ± 5655 1/cm2 for human myenteric and submucous plexus, respectively. The total number of neurons in the ENS was 2.6 million for mice, 14.6 million for guinea pig, and 168 million for human. Conclusions & Inferences: This study reports the first comprehensive nerve cell count in mice, guinea pig, and human ENS. Neuronal densities were comparable between the three species and the differences in the total numbers of enteric neurons are likely due to body size and intestinal length. The number of enteric neurons is comparable to the number of neurons in the spinal cord for all three species. [ABSTRACT FROM AUTHOR]

Background: Serotonin (5‐HT) is an important mediator in the gastrointestinal tract, acting on different neuronal 5‐HT receptors. The ionotropic 5‐HT3 receptor mediates immediate but transient spike discharge in human enteric neurons. We studied the role of the metabotropic 5‐HT1P, 5‐HT4, and 5‐HT7 receptors to activate human submucous neurons. Methods: Neuroimaging using the voltage sensitive dye Di‐8‐ANEPPS was performed in submucous plexus preparations from human surgical specimens of the small and large intestine. We synthesized a new, stable 5‐HT1P agonist, 5‐benzyloxyhydrazonoindalpine (5‐BOHIP). Key Results: 5‐HT evoked a fast and late‐onset spike discharge in enteric neurons. The fast component was blocked by the 5‐HT3 receptor antagonist cilansetron, while the remaining sustained response was significantly reduced by the 5‐HT1P receptor antagonist 5‐hydroxytryptophanyl‐5‐hydroxytryptophan amide (5‐HTP‐DP). The newly synthesized 5‐HT1P agonist 5‐BOHIP induced a slowly developing, long‐lasting activation of submucous neurons, which was blocked by 5‐HTP‐DP. We could not demonstrate any 5‐HT7 receptor‐induced spike discharge based on the lack of response to 5‐carboxamidotryptamine. Similarly, the 5‐HT4 agonists 5‐methoxytryptamine and prucalopride evoked no immediate or late‐onset spike discharge. Conclusions & Inferences: Our work demonstrated for the first time the presence of functional 5‐HT1P receptors on human submucous neurons. Furthermore, we found no evidence for a role of 5‐HT4 or 5‐HT7 receptors in the postsynaptic activation of human submucous neurons by 5‐HT. [ABSTRACT FROM AUTHOR]

Mounting evidence highlights the pivotal role of enteric microbes as a dynamic interface with the host. Indeed, the gut microbiota, located in the lumen of the gastrointestinal (GI) tract, influence many essential physiological processes that are evident in both healthy and pathological states. A key signaling molecule throughout the body is serotonin (5‐hydroxytryptamine; 5‐HT), which acts in the GI tract to regulate numerous gut functions including intestinal motility and secretion. The gut microbiota can modulate host 5‐HT systems both directly and indirectly. Direct actions of gut microbes, evidenced by studies using germ‐free animals or antibiotic administration, alter the expression of key 5‐HT‐related genes to promote 5‐HT biosynthesis. Indirectly, the gut microbiota produce numerous microbial metabolites, whose actions can influence host serotonergic systems in a variety of ways. This review summarizes the current knowledge regarding mechanisms by which gut bacteria act to regulate host 5‐HT and 5‐HT‐mediated gut functions, as well as implications for 5‐HT in the microbiota–gut–brain axis. [ABSTRACT FROM AUTHOR]

Systemic sclerosis (SSc) is a chronic and generalized disease affecting the connective tissue of the skin and many internal organs, in particular the gastrointestinal tract. The esophagus is involved in up to 80% of the cases and represents a major cause of serious morbidities that deeply impact on the quality of life and survival of patients. Indeed, the presence of esophageal dysfunction is a good prognostic indicator in SSc, primarily due to its impact on pulmonary disease. Thus, the detection of esophageal motility alterations plays a critical role to prevent the development of both esophageal and pulmonary complications and to improve the survival of these patients. Currently, this diagnostic work‐up has been limited to the use of esophageal manometry, which is considered the gold standard for the evaluation of motor physiology and pathophysiology of this organ in different clinical situations. However, in recent years, new equipments such as high‐resolution (−impedance) manometry and functional luminal imaging probe have been developed and used in many esophageal clinical settings, including SSc. In this mini‐review, we summarize current evidence regarding esophageal dysmotility, in the light of new data on secondary peristalsis published in this issue of the journal. [ABSTRACT FROM AUTHOR]

Background: Aging is a complex biological process and associated with a progressive decline in functions of most organs including the gastrointestinal (GI) tract. Age‐related GI motor disorders/dysfunctions include esophageal reflux, dysphagia, constipation, fecal incontinence, reduced compliance, and accommodation. Although the incidence and severity of these diseases and conditions increase with age, they are often underestimated due in part to nonspecific and variable symptoms and lack of sufficient medical attention. They negatively affect quality of life and predispose the elderly to other diseases, sarcopenia, and frailty. The mechanisms underlying aging‐associated GI dysfunctions remain unclear, and there is limited data examining the effect of aging on GI motor functions. Many studies on aging‐associated changes to cells within the tunica muscularis including enteric neurons, smooth muscles, and interstitial cells have proposed that cell loss and/or molecular changes may be involved in the pathogenesis of age‐related GI motor disorders/dysfunctions. There is also evidence that the aging contributes to phenotypic changes in innate immune cells, which are physically and functionally linked to other cells in the tunica muscularis and can alter GI (patho) physiology. However, various patterns of changes have been reported, some of which are contradictory, indicating a need for additional work in this area. Purpose: Although GI infection due to intestinal bacterial overgrowth, bleeding, and cancers are also important and common problems in the elderly patients, this mini‐review focuses on data obtained from enteric neuromuscular aging research with the goal of better understanding the cellular and molecular mechanisms of enteric neuromuscular aging to enhance future therapy. [ABSTRACT FROM AUTHOR]

Background: Ingestible wireless capsules, including the 3D‐transit magnetic capsule and the wireless motility capsule (WMC), describe gastrointestinal (GI) motility from changes in position or pressure. This study aimed to combine information on contractile events in terms of position (assessed with the 3D‐transit) and change in pressure (assessed with the WMC) throughout the entire GI tract. Methods: The 3D‐transit capsule and WMC were combined into a single‐wireless unit system. Three‐dimensional space‐time coordinates, pressure, and pH data from a pilot case were analyzed as the combined unit passed the GI tract. Two single and three continuous contraction patterns were defined according to pressure changes and quantified through the GI tract. Key results: The combined unit was well tolerated and provided information on contractions throughout the gut. Single contraction patterns with no significant progressive movement of the unit were most prevalent in the stomach and the rectosigmoid colon. During the continuous contraction patterns, the unit moved in an antegrade or retrograde direction. Longer distance and higher velocity were seen during antegrade than during retrograde movements. The motility indices (as measured with WMC) in combined ascending, transverse and descending colon showed a positive linear association (r = 0.7) to the capsule movements (as measured with 3D‐transit). Conclusions & inferences: The combined system provides synchronous information about movements and gut contractions. These measurements can be used to extract more information from existing recordings and may enhance our understanding of GI motility in health and disease. [ABSTRACT FROM AUTHOR]

Background: Data on the neuromodulatory effects of brain‐derived neurotrophic factor (BDNF) in the gastrointestinal tract were recently reported, but there are still no data on the presence, distribution, and release of BDNF in the gastrointestinal tract, including the internal anal sphincter (IAS). Methods: We examined the presence and distribution of BDNF and its receptor TrkB in the different IAS structures (neuronal and non‐neuronal) via immunohistochemical and immunocytochemical analyses. We also monitored the release of BDNF in an IAS muscle bath (consisting of smooth muscle cells [SMCs], myenteric plexus, and submucosal plexus) before and after different agonists, and electrical field stimulation in the absence and presence of neurotoxin tetrodotoxin. Key Results: BDNF/TrkB was found to be present in all layers of the IAS, especially the smooth muscle, mucosa, myenteric plexus, and submucosal plexus. Detailed analyses revealed a significant colocalization between BDNF and TrkB in different structures, especially in the smooth muscle, the SMCs, and both plexuses. Data further showed higher levels of BDNF in the cytosol and that of TrkB toward the periphery of the SMCs. Conclusions & Inferences: These studies showed that BDNF/TrkB was present not only in the enteric nervous system (ENS), but also in the SMCs. For the neuromodulatory effects, BDNF is released locally from the ENS ((myenteric (10.01 ± 0.23 pg/ml) and submucosal plexus (9.05 ± 0.51 pg/ml)) and the SMCs (18.63 ± 1.63 pg/ml). Collectively, these findings have pathophysiological and therapeutic implications regarding the role of BDNF/TrkB in the IAS‐associated rectoanal motility disorders. [ABSTRACT FROM AUTHOR]

Background: The enteric nervous system (ENS) is an extensive neural network embedded in the wall of the gastrointestinal tract that regulates digestive function and gastrointestinal homeostasis. The ENS consists of two main cell types; enteric neurons and enteric glial cells. In vitro techniques allow simplified investigation of ENS function, and different culture methods have been developed over the years helping to understand the role of ENS cells in health and disease. Purpose: This review focuses on summarizing and comparing available culture protocols for the generation of primary ENS cells from adult mice, including dissection of intestinal segments, enzymatic digestions, surface coatings, and culture media. In addition, the potential of human ENS cultures is also discussed. [ABSTRACT FROM AUTHOR]

Background: In mice, Schwann cell (SC) progenitors give rise to autonomic ganglion cells and migrate into the gut to become enteric neurons. It is unknown whether SC progenitors have a similar fate in humans. In search of evidence for human SC‐derived neurogenesis in the gastrointestinal (GI) tract, we studied the rectums from cadaveric controls and children with anorectal malformations (ARM). Methods: We analyzed distal rectal tissue taken at autopsy from 10 children with normal GI tracts and resected rectal specimens in 48 cases of ARM. Of these specimens, 6 had neurons within the extrinsic rectal innervation. These were further investigated with immunohistochemistry for neuronal and SC/glial markers. Key Results: Perirectal tissue from control and ARM contained GLUT1‐positive extrinsic nerves, many containing neurons. SC/glial markers (SOX10, CDH19, and PLP1) were expressed by glia in the enteric nervous system and perirectal nerves, while MPZ predominated only in glia of perirectal nerves, in both control and ARM. Neurons in perirectal nerves were 61% larger in ARM samples and co‐expressed SOX10 (81%), PLP1 (73%), and CDH19 (56%). In ARM, cytoplasmic SOX10 was co‐expressed with neuronal antigens in ~57% of submucosal and myenteric neurons, vs. ~3% in control. Furthermore, intrinsic gut neurons in ARM specimens co‐expressed PLP1 (18%) and CDH19 (18%); however, neuronal co‐expression of PLP1 and CDH19 was rarely (<2%) observed in controls. Conclusions & Inferences: Dual expression of glial and neuronal markers in rectal and perirectal neurons support a model of Schwann cell‐derived neurogenesis in the innervation of the human GI tract. [ABSTRACT FROM AUTHOR]

5‐HT4 receptors are G protein‐coupled receptors that link to the stimulatory protein Gs which activates adenylate cyclase to increase intracellular cyclic AMP which then activates protein kinase A (PKA). 5‐HT4 receptors are expressed by neurons in the central and peripheral nervous systems especially the enteric nervous system (ENS). In general, 5‐HT4 receptors are stimulatory and their activation in the ENS enhances neurotransmitter release and propulsive motility patterns. 5‐HT4 receptors are expressed by enterochromaffin (EC) cells, Goblet cells, and most enteric neurons. The study by Konen and colleagues in this issue of Neurogastroenterology and Motility features two novel 5‐HT4 receptor agonists (5‐HT4‐LA1 and 5‐HT4‐LA‐2) that are not absorbed from the gastrointestinal tract of mice and act locally in the colonic mucosa to stimulate propulsive motility. The authors show that 5‐HT4‐LA1 and 5‐HT4‐LA2 were not absorbed from the colon and that both drugs stimulated colonic transit when administered by gavage. Both agonists stimulated colonic glass bead expulsion, and 5‐HT4LA1 activation stimulated fecal output and increased fecal water content. These effects were detected in young and aged mice. 5‐HT4 receptors were also localized to the epithelium of the human duodenum, ileum, and colon. These studies highlight novel 5‐HT4 receptor agonists that have prokinetic actions on the GI tract. These drugs are not absorbed and act locally in the gut mucosa to stimulate propulsive motility while minimizing access to systemic 5‐HT4 receptors and avoiding potential unwanted side effects. [ABSTRACT FROM AUTHOR]

Background: 5‐HT4 receptor (5‐HT4R) agonists exert prokinetic actions in the GI tract, but non‐selective actions and potential for stimulation of non‐target 5‐HT4Rs have limited their use. Since 5‐HT4Rs are expressed in the colonic epithelium and their stimulation accelerates colonic propulsion in vitro, we tested whether luminally acting 5‐HT4R agonists promote intestinal motility. Methods: Non‐absorbed 5‐HT4R agonists, based on prucalopride and naronapride, were assessed for potency at the 5‐HT4R in vitro, and for tissue and serum distribution in vivo in mice. In vivo assessment of prokinetic potential included whole gut transit, colonic motility, fecal output, and fecal water content. Colonic motility was also studied ex vivo in mice treated in vivo. Immunofluorescence was used to evaluate receptor distribution in human intestinal mucosa. Key Results: Pharmacological screening demonstrated selectivity and potency of test agonists for 5‐HT4R. Bioavailability studies showed negligible serum detection. Gavage of agonists caused faster whole gut transit and colonic motility, increased fecal output, and elevated fecal water content. Prokinetic actions were blocked by a 5‐HT4R antagonist and were not detected in 5‐HT4R knockout mice. Agonist administration promoted motility in models of constipation. Evaluation of motility patterns ex vivo revealed enhanced contractility in the middle and distal colon. Immunoreactivity for 5‐HT4R is present in the epithelial layer of the human small and large intestines. Conclusions and Inferences: These findings demonstrated that stimulation of epithelial 5‐HT4Rs can potentiate propulsive motility and support the concept that mucosal 5‐HT4Rs could represent a safe and effective therapeutic target for the treatment of constipation. [ABSTRACT FROM AUTHOR]

Background: Electrogastrography (EGG) is the method of cutaneous recording of the myoelectrical activity of the stomach. A multi‐channel signal is recorded non‐invasively by means of electrodes placed outside the epigastric area. The normal electrical rhythm of the stomach (slow wave) may become significantly disturbed due to disorders of gastrointestinal tract. Abnormally fast electrical rhythms are termed tachygastria, while abnormally slow rhythms are known as bradygastria. Because some features of biological signals may go undetected using the classical methods of signal spectral analysis, we propose a new method for EGG rhythm identification. Methods: In this study, the calculation of the basic rhythms of multi‐channel EGG signals is performed by means of the noise‐assisted multivariate empirical mode decomposition (NA‐MEMD) and Hilbert–Huang transform (HHT), using EGG data from eight healthy subjects. The results were compared with those obtained using classical spectral analysis. Key Results: The mean values of the normogastric index for preprandial and two postprandial stages were found to be 64.78 ± 11.37%, 61.29 ± 15.86%, and 63.80 ± 13.24%, respectively. The obtained values of normogastric index are consistent with the normal human physiological value, which is approximately 70% for healthy subjects. Conclusions: This method is able to capture features of the signal which are mostly undetectable by standard EGG processing methods. The EGG dominant rhythm identification using the instantaneous normogastric, bradygastric, and tachygastric indices provides new insights into biological EGG patterns. [ABSTRACT FROM AUTHOR]

Background and Aim: Muscularis macrophages (MMs) not only mediate the innate immunity, but also functionally interact with cells important for gastrointestinal motility. The aim of this study was to determine the spatial relationship and types of contacts between the MMs and neighboring cells in the muscularis propria of human and mouse stomach, small intestine, and large intestine. Methods: The distribution and morphology of MMs and their contacts with other cells were investigated by immunohistochemistry and transmission electron microscopy. Key Results: Immunohistochemistry showed variable shape and number of MMs according to their location in different portions of the muscle coat. By double labeling, a close association between MMs and neighboring cells, that is, neurons, smooth muscle cells, interstitial cells of Cajal (ICCs), telocytes (TCs)/PDGFRα‐positive cells, was seen. Electron microscopy demonstrated that in the muscle layers of both animal species, MMs have similar ultrastructural features and have specialized cell‐to‐cell contacts with smooth muscle cells and TCs/PDGFRα‐positive cells but not with ICCs and enteric neurons. Conclusion & Inferences: This study describes varying patterns of distribution of MMs between different regions of the gut, and reports the presence of distinct and extended cell‐to‐cell contacts between MMs and smooth muscle cells and between MMs and TCs/PDGFRα‐positive cells. In contrast, MMs, although close to ICCs and nerve elements, did not make contact with them. These findings indicate specialized and variable roles for MMs in the modulation of gastrointestinal motility whose significance should be more closely investigated in normal and pathological conditions. [ABSTRACT FROM AUTHOR]

Background: Gastrointestinal (GI) symptoms are common in patients with diabetes mellitus (DM). The electromagnetic 3D‐Transit system allows assessment of regional transit times and motility patterns throughout the GI tract. We aimed to compare GI transit times and detailed motility patterns of the colon in patients with DM and GI symptoms to those of healthy controls (HC). We further aimed to determine whether any abnormalities in motility were reversible by cholinergic stimulation. Methods: We compared 18 patients with DM with 20 HC by means of the 3D‐Transit system. Patients were studied before and during oral administration of 60 mg pyridostigmine. Key results: Compared to HC, patients had prolonged gastric emptying (DM: 3.3 hours (interquartile range (IQR) 2.6‐4.6); HC: 2.3 hours (IQR 1.7‐2.7) (P <.01)), colonic transit time (DM: 52.6 hours (IQR 23.3‐83.0); HC: 22.4 hours (IQR 18.9‐43.6) (P =.02)), and whole gut transit time (DM: 69.4 hours (IQR 32.9‐103.6); HC: 30.3 hours (IQR 25.2‐49.9) (P <.01)). In addition, compared to HC, patients had prolonged transit time in the ascending colon (DM: 20.5 hours (IQR 11.0‐44.0); HC: 8.0 hours (IQR 3.8‐21.0) (P <.05)) and more slow retrograde movements in the colon (DM: 2 movements (IQR 1‐4); HC: 1 movement (IQR 0‐1) (P =.01)). In patients, pyridostigmine increased the number of bowel movements (P <.01) and reduced small intestine transit times (P <.05). Conclusions: Patients with DM and GI symptoms have longer than normal GI transit times. This is only partly reversible by pyridostigmine. The increased number of retrograde colonic movements in patients could potentially explain the abnormally long transit time in proximal colon. [ABSTRACT FROM AUTHOR]

Background: Understanding the mechanisms underpinning the response to acute stress is critical for determining how this can be modulated in both health and disease and across sexes. Stress can markedly alter the microbiome and gut‐brain axis signaling with the serotonergic system being particularly sensitive to acute stress. As the impact of acute stress on regional serotonergic dynamics in the gut‐brain axis and the contribution of the microbiome to this are poorly appreciated, we used microbiota‐deficient mice to assess whether the serotonergic response to acute stress exposure is microbiome dependent. Methods: Adult male and female conventional, germ‐free, and colonized germ‐free mice underwent a single acute stressor and samples were harvested immediately or 45 minutes following stress. Serotonin and related metabolites and serotonergic gene expression were determined. Key Results: Our data clearly show the microbiota influenced gastrointestinal serotonergic response to acute stress in a sex‐ and region‐dependent manner. Male‐specific poststress increases in colonic serotonin were absent in germ‐free mice but normalized following colonization. mRNA serotonergic gene expression was differentially expressed in colon and ileum of germ‐free mice on a sex‐dependent basis. Within the frontal cortex, absence of the microbiome altered basal serotonin, its main metabolite 5‐hydroxyindoleacetic acid, and prevented stress‐induced increases in serotonin turnover. Conclusions and Inferences: The gut microbiome influences the set points of the brain and gastrointestinal serotonergic systems and affected their response to acute stress in a sex‐ and region‐dependent manner. [ABSTRACT FROM AUTHOR]

Background and purpose: The EndoFLIP® system is a method of delineating impedance and was first designed to investigate the characteristics of the esophago‐gastric junction. In the last decade, its use was widened to investigate other sphincteric and non‐sphincteric systems of the gastrointestinal tract. The objective of the present systematic review was to summarize the available data in literature on the use of the EndoFLIP® system in the gastrointestinal tract, including sphincteric and non‐sphincteric regions. We performed a systematic review in accordance with recommendations for systematic review using PRISMA guidelines without date restriction, until June 2020, using MEDLINE‐PubMed, Cochrane Library, and Google Scholar databases. Only articles written in English were included in the present review. Five hundred and six unique citations were identified from all database combined. Of those, 95 met the inclusion criteria. There was a lack of standardization among studies in terms of anesthetic drugs use, probe placement, and inflation protocol. In most cases, only small cohorts of patients were included. Most studies investigated the EGJ, with a potential use of the EndoFLIP® to identify a subgroup of patients with achalasia and for intraoperative assessment of treatment efficacy in achalasia. However, the use of EndoFLIP® in the esophageal body (esophageal panometry), other esophageal diseases (gastro‐esophageal reflux disease, eosinophilic esophagitis), and other sphincter regions (anal canal, pylorus) will need further confirmatory studies. The EndoFLIP® system provides detailed geometric data of the gastrointestinal lumen but further works are needed to determine its use in clinical practice. [ABSTRACT FROM AUTHOR]

Background: Intestinal resident macrophages play a crucial role in homeostasis and have been implicated in numerous gastrointestinal diseases. While historically believed to be largely of hematopoietic origin, recent advances in fate‐mapping technology have unveiled the existence of long‐lived, self‐maintaining populations located in specific niches throughout the gut wall. Furthermore, the advent of single‐cell technology has enabled an unprecedented characterization of the functional specialization of tissue‐resident macrophages throughout the gastrointestinal tract. Purpose: The purpose of this review was to provide a panorama on intestinal resident macrophages, with particular focus to the recent advances in the field. Here, we discuss the functions and phenotype of intestinal resident macrophages and, where possible, the functional specialization of these cells in response to the niche they occupy. Furthermore, we will discuss their role in gastrointestinal diseases. [ABSTRACT FROM AUTHOR]

Background: Gastrointestinal (GI) dysfunction is observed clinically after spinal cord injury (SCI) and contributes to the diminished long‐term quality of life. Our study examined the acute and chronic GI vascular changes that occur following SCI. We demonstrated that the GI vascular tract in SCI mice becomes compromised during the acute phase of injury and persists into the chronic phase of injury. Methods: Gastrointestinal vasculature permeability was measured using dynamic contrast‐enhanced magnetic resonance imaging (DCE MRI) at 48 hours, and 2 and 4 weeks following contusion spinal cord injury. Angiopoietin‐1, a vascular stabilizing protein, was administered intravenously following injury. Intestinal contractile activity assessments were performed following the last imaging session. Key results: Our results indicated that a single administration of Ang‐1 reduced vascular permeability at 48 hours but the effect was only transient. However, when the treatment paradigm was changed from a single administration to multiple administrations of Ang‐1 following contusion injury, our DCE MRI data indicated a significant decrease in GI vascular permeability 4 weeks after injury compared with vehicle control treated animals. This improved GI vascular permeability was associated with improved sustained intestinal contractile activity. We also demonstrated that Ang‐1 reduced the expression of sICAM‐1 in the ileum compared with the saline‐treated group. Conclusions and inferences: We show that the GI vasculature is compromised in the acute and chronic phase of injury following spinal contusion. Our results also indicate that multiple administrations of Ang‐1 can attenuate GI vascular permeability, possibly reduce inflammation, and improve sustained agonist‐induced contraction compared with saline treatment. [ABSTRACT FROM AUTHOR]

Background: The Motilis 3D‐Transit system allows ambulatory description of transit patterns throughout the gastrointestinal tract and offers an alternative method for studying gastric motility. We aimed to establish normative values for gastric motility assessed with the method. Method: A total of 132 healthy volunteers ingested the 3D‐Transit capsule for assessment of gastrointestinal transit times. Recordings from 125 subjects were used for definition of normative values. Forty‐six subjects were studied on two consecutive days. Recordings were reanalyzed using newly developed software providing information on gastric emptying (GE) as well as contraction frequency and movement during gastric contractions. Results: The median GE time was 2.7 hours (range 0.1‐21.2). In 89% of subjects, the capsule passed the pylorus within a postingestion period of 6 hours. The median frequency of gastric contractions was 3.1 per minute (range 2.6‐3.8). The frequency was higher in women (3.2, range 2.7‐3.8) than in men (3.0, range 2.6‐3.5) and increased with age (0.004 per year) (P <.05). The median amplitudes were 35° (range 4‐85) when based on rotation of the capsule and 11 mm (range 6‐31) when based on capsule change in position. The rotation amplitude was higher in women and decreased with increasing BMI (P <.05). The position amplitude was also higher in women and increased with the amount of calories in the test meal, but decreased with increasing BMI and age (P <.05). Day‐to‐day variation (P >.05) was considerable while inter‐rater variability was small. Conclusion and Inferences: We have established normative values for gastric motility assessed with the 3D‐Transit system. [ABSTRACT FROM AUTHOR]

Background: Dystonia musculorum (Dstdt) is a murine disease caused by recessive mutations in the dystonin (Dst) gene. Loss of dorsal root ganglion (DRG) sensory neurons, ataxia, and dystonic postures before death by postnatal day 18 (P18) is a hallmark feature. Recently we observed gas accumulation and discoloration in the small intestine and cecum in Dstdt mice by P15. The human disease resulting from dystonin loss‐of‐function, known as hereditary sensory and autonomic neuropathy type VI (HSAN‐VI), has also been associated with gastrointestinal (GI) symptoms including chronic diarrhea and abdominal pain. As neuronal dystonin isoforms are expressed in the GI tract, we hypothesized that dystonin loss‐of‐function in Dstdt‐27J enteric nervous system (ENS) neurons resulted in neurodegeneration associated with the GI abnormalities. Methods: We characterized the nature of the GI abnormalities observed in Dstdt mice through histological analysis of the gut, assessing the ENS for signs of neurodegeneration, evaluation of GI motility and absorption, and by profiling the microbiome. Key results: Though gut histology, ENS viability, and GI absorption were normal, slowed GI motility, thinning of the colon mucous layer, and reduced microbial richness/evenness were apparent in Dstdt‐27J mice by P15. Parasympathetic GI input showed signs of neurodegeneration, while sympathetic did not. Conclusions & Inferences: Dstdt‐27J GI defects are not linked to ENS neurodegeneration, but are likely a result of an imbalance in autonomic control over the gut. Further characterization of HSAN‐VI patient GI symptoms is necessary to determine potential treatments targeting symptom relief. [ABSTRACT FROM AUTHOR]

Background: Parasympathetic neuropathy is a key feature in many common disorders, including diabetes, neurological disorders, and cancers, but few objective methods exist for assessing damage to the parasympathetic nervous system, particularly in the gastrointestinal system. This study aimed to validate the use of 11C‐donepezil positron emission tomography (PET) to assess parasympathetic integrity in a group of vagotomized patients. Methods: Sixteen healthy controls and 12 patients, vagotomized due to esophagectomy, underwent 11C‐donepezil PET, measurement of colonic transit time, quantification of plasma pancreatic polypeptide (PP), and assessment of subjective long‐term symptoms. Key Results: Vagotomized patients had significantly decreased PET signal in the small intestine and colon compared with healthy controls (5.7 [4.4‐7.9] vs 7.4 [4.5‐11.3], P =.01 and 1.4 [1.1‐2.1] vs 1.6 [1.4‐2.4], P <.01, respectively). Vagotomized patients also displayed a significantly increased colonic transit time (2.9 ± 0.9 h vs 1.9 ± 0.8 h), P <.01 and increased volumes of the small intestine and colon (715 ccm [544‐1177] vs 443 ccm [307‐613], P <.01 and 971 ccm [713‐1389] vs 711 ccm [486‐1394], P =.01, respectively). Patients and controls did not differ in PP ratio levels after sham feeding, but PP ratio at 10 minutes. after sham feeding and PET signal intensity in the small intestine was positively correlated (P =.03). Conclusions and Inferences: We found significantly decreased 11C‐donepezil signal in the intestine of vagotomized patients, supporting that 11C‐donepezil PET is a valid measure of intestinal parasympathetic denervation. [ABSTRACT FROM AUTHOR]

Background: Swallowing impairment is frequently present in patients with idiopathic inflammatory myopathies (IIMs), and it represents an important cause of morbidity, dramatically reducing the quality of life of patients. Moreover, dysphagia is associated to a worst prognosis. Unfortunately, no standardized instrumental techniques for the assessment of the upper gastrointestinal tract in IIM patients are available. In this study, we explored the characteristics of the alterations in the upper gastrointestinal tract using oro‐pharyngeal‐esophageal scintigraphy (OPES) in a cohort of IIM patients and we correlated the alterations with clinical parameters. Methods: A total of 51 IIM patients were examined with OPES, both with liquids and semisolids, and the data acquired were examined to compute the transit time and the percentage of retention at oral, pharyngeal, and esophageal level. Patient‐reported outcome data (PRO) on dysphagia, disease activity, and clinical parameters were collected. Key results: Oro‐pharyngeal‐esophageal scintigraphy identified at least one alteration in all patients, particularly with the semisolid test and oral and pharyngeal levels presented a higher frequency of involvement compared to the esophageal tract (P < 0.05). A very good correlation between dysphagia severity assessed by PRO and many OPES results was identified. In patients with a shorter disease duration, there was a higher prevalence of alterations at the oral and pharyngeal level and they were correlated to higher swallowing difficulties and higher disease activity parameters. Conclusions & inferences: Our results showed that OPES may represent a novel reproducible tool to assess dysphagia in IIM patients, thus opening new possibilities to evaluate dysphagia in these patients. [ABSTRACT FROM AUTHOR]

Background: The Motilis 3D‐Transit system tracks electromagnetic capsules as they traverse the gastrointestinal tract. The method is minimally invasive and ambulatory. Analysis has previously been limited to regional gut transit times, but new methods may allow detailed analysis of colonic motility. Methods: Parameters of colonic motility were analyzed from 34 3D‐Transit recordings performed in healthy volunteers (median age 28 years; 8 F). Characteristic propulsive velocities and lengths of movement were determined to quantify common movement patterns. Data from seven patients with severe chronic diarrhea were included for comparison. Key Results: Lack of capsule motion accounted for 82% (75%‐87%) of total colonic transit time. Propulsive velocities were distributed with peaks at 0.5 cm/min (antegrade or retrograde) and 50 cm/min (antegrade). Based on velocity and length of propagation, five motor patterns were identified; (a) long fast antegrade, (b) fast antegrade, (c) slow antegrade, (d) slow retrograde, and (e) fast retrograde movements. Long fast antegrade movements were median 21 cm (10‐96 cm). Capsule progression was faster during daytime than at night (5.9 cm/h vs 0.8 cm/h; P < 0.01). Colonic transit was faster in patients with chronic diarrhea than in healthy volunteers (5.4 h vs 18.2 h; P = 0.04), with higher capsule velocity (20.4 cm/h vs 4.4 cm/h; P < 0.01). Conclusions and Inferences: The 3D‐Transit system now allows detailed description of colonic motility and our results are supported by those previously suggested by manometry. It holds promise for future assessment of movement patterns to characterize different diseases and effects of treatment. The ambulatory Motilis 3D‐Transit system tracks electromagnetic capsules as they traverse the gastrointestinal tract. Parameters of colonic motility were analyzed in recordings from 34 healthy volunteers and seven patients with carcinoid diarrhea. [ABSTRACT FROM AUTHOR]

Background: Postoperative ileus (POI) is abdominal surgery‐induced impaired gastrointestinal (GI) motility. We aimed to investigate the effects of DA‐9701, a prokinetic agent formulated from Pharbitis Semen and Corydalis tuber, likely mediated via corticotrophin‐releasing factor (CRF) pathways, in a POI model. Methods: A laparotomy with cecal manipulation was performed to induce POI in guinea pigs. GI transit was measured based on charcoal migration after intragastric administration of DA‐9701 1, 3, and 10 mg kg−1. CRF1 receptor antagonist, CP‐154 526 (subcutaneous) or agonist, human/rat (h/r) CRF (intraperitoneal) was injected. Then, plasma adrenocorticotropic hormone (ACTH) levels were measured, and the average intensity of the CRF expression was analyzed in the proximal colon and hypothalamus, and c‐Fos in the hypothalamus. Key Results: DA‐9701 significantly increased delayed GI transit in POI in a dose‐dependent manner and decreased plasma ACTH levels at 10 mg kg−1. CP‐154 526 significantly decreased plasma ACTH levels but was not as effective on GI transit as DA‐9701 was. h/r CRF did not significantly affect GI transit and plasma ACTH levels. No significant difference was observed in GI transit and plasma ACTH levels in both groups administered DA‐9701 with h/r CRF and h/r CRF alone. CRF expression in the proximal colon decreased after DA‐9701 administration, but not significantly, compared with levels in POI alone. However, CRF expression in the hypothalamus was significantly lower in the DA‐9701‐pretreated POI than in the untreated POI. Conclusions and Inferences: The DA‐9701‐induced improvement in GI transit and inhibition of plasma ACTH levels was mediated by the central CRF pathway. [ABSTRACT FROM AUTHOR]

Neurotrophic factors are traditionally recognized for their roles in differentiation, growth, and survival of specific neurons in the central and peripheral nervous system. Some neurotrophic factors are essential for the development and migration of the enteric nervous system along the fetal and post‐natal gut. Over the last two decades, several non‐developmental functions of neurotrophic factors have been characterized. In the adult gastrointestinal tract, neurotrophic factors regulate gut sensation, motility, epithelial barrier function, and protect enteric neurons and glial cells from damaging insults in the microenvironment of the gut. In this issue of Neurogastroenterology and Motility, Fu et al demonstrate that brain‐derived neurotrophic factor plays a role in the pathogenesis of distention‐induced abdominal pain in bowel obstruction. In light of this interesting finding, this mini‐review highlights some of the recent advances in understanding of the physiological and pathophysiological roles of neurotrophic factors in the adult gut. [ABSTRACT FROM AUTHOR]

Abstract: The use of opioid medications for acute and chronic pain has increased significantly in the past 20 years in the United States. Given the high density of opioid receptors in the gastrointestinal tract, side effects are common in these patients including constipation, dysphagia, bloating, nausea, and vomiting. These side effects, which are experienced by most patients who take opioids, can lead to significant impairment in quality of life. Unlike other side effects from opioids, gastrointestinal side effects do not diminish with continued use, often leading patients to reduce or discontinue their opioid treatment to relieve these side effects. Therefore, physicians must be aware and anticipate potential side effects in patients receiving opioids to ensure appropriate pain management. [ABSTRACT FROM AUTHOR]

Dynamic magnetic resonance imaging ( MRI) of gastrointestinal motility has developed rapidly over the past few years. The non-invasive and non-ionizing character of MRI is an important advantage together with the fact that it is fast and can visualize the entire gastrointestinal tract. Advances in imaging and quantification techniques have facilitated assessment of gastric, small intestinal, and colonic motility in a clinical setting. Automated quantitative motility assessment using dynamic MRI meets the need for non-invasive techniques. Recently, studies have begun to examine this technique in patients, including those with IBD, pseudo-obstruction and functional bowel disorders. Remaining challenges for clinical implementation are processing the large amount of data, standardization and validation of the numerous MRI metrics and subsequently assessment of the potential role of dynamic MRI. This review examines the methods, advances, and remaining challenges of evaluation of gastrointestinal motility with MRI. It accompanies an article by Khalaf et al. in this journal that describes a new protocol for assessment of pan-intestinal motility in fasted and fed state in a single MRI session. [ABSTRACT FROM AUTHOR]

Background Currently, there are no histological criteria to diagnose irritable bowel syndrome ( IBS). Our aims were (i) to examine the distribution of inflammatory cells in the colon of healthy and IBS subjects and (ii) to find histological diagnosis criteria for IBS. Methods Colonic biopsies were taken from four distinct regions of the colon from 20 controls ( HC) and 11 patients with IBS (4 with constipation ( IBS-C) and 7 with diarrhea ( IBS-D) and embedded in paraffin. Macrophages, mast cells, eosinophils, and T lymphocytes were immunostained and positive cells counted. Key Results In both HC and IBS patients, global cellularity decreased from the cecum to the rectum ( P < .01) which is attributed to reduced number of macrophages ( P < .05) and eosinophils ( P < .001) but not T cells. Mast cells were reduced in IBS ( P < .05) but not in HC, particularly in IBS-D ( P < .05). Results showed higher number of macrophages in the left colon of IBS subjects than HC ( P < .05). Conclusion & Inferences Here we report a decreasing gradient of immune cells from the cecum to the rectum of the human colon. Although global cellularity cannot be used to distinguish between IBS and HC, closer analysis of macrophages and mast cells may be useful markers to confirm IBS histologically and to differentiate between IBS-C and IBS-D when clinical presentation alternates between constipation and diarrhoea. This pilot study remains to be confirmed with greater number of patients. [ABSTRACT FROM AUTHOR]

Background Tacr2 is one of the G protein-coupled receptors( GPCRs) that mediate the biological actions of tachykinins. It is abundantly expressed in the gastrointestinal ( GI) system and is thought to play an important role in GI motility, secretion, and visceral sensitivity. Previously, the physiological and pathophysiological functions of Tacr2 were mainly studied using Tacr2 selective agonists or antagonists. Here, we seek to investigate the effect of Tacr2 disruption in mice to provide further insights. Methods The Tacr2 knockout mice were generated by homologous recombination and the phenotypic changes of the Tacr2-null mice were analyzed and compared with their wild type (wt) littermates. Key Results Increased food retention was detected in Tacr2 −/− mice. The stomach of Tacr2 −/− mice had thinner muscularis externa and less neurons in the myenteric plexus. The stomach and small intestine exhibited longer duration of electrical field stimulation ( EFS)-induced inhibition in the gastric fundus and decreased frequency of migrating motor complex ( MMC), respectively. Neuronal nitric oxide synthase (nNOS) and vasoactive intestinal polypeptide (VIP) were significantly up-regulated due to Tarc2 deficiency, contributing to enhanced nitric oxide (NO) signaling in the stomach of Tacr2 −/− mice. Intraperitoneal application of 7-nitroindazole (7- NI) to Tacr2 −/− mice effectively relieved the gastric emptying disturbance. Moreover, Creb and NF-κB signalings were involved in the regulation of these physiological changes initiated by Tacr2 deficiency. Conclusions & Inferences Tacr2 negatively regulated the expression of nNOS and VIP both in vivo and in vitro. Its ablation in mice elevated the expression of nNOS and VIP, enhanced NO signaling and changed the Creb and NF-κB signalings, finally leading to the gastric emptying disturbance of Tacr2 −/− mice. [ABSTRACT FROM AUTHOR]

Background In the gastrointestinal tract of several species, facilitating 5- HT4 receptors were proposed on myenteric cholinergic neurons innervating smooth muscle by in vitro study of the effect of the selective 5- HT4 receptor agonist prucalopride on submaximal cholinergic contractions. This was not yet established in the murine gastrointestinal tract. Methods In circular smooth muscle strips from murine fundus, jejunum and colon, contractions were induced by electrical field stimulation in the presence of guanethidine, L- NAME and for colon also MRS 2500. Submaximal contractions were induced to study the influence of prucalopride. Key Results Electrical field stimulation at reduced voltage induced reproducible submaximal neurogenic and cholinergic contractions as the contractions were abolished by tetrodotoxin and atropine. Hexamethonium had no systematic inhibitory effect but mecamylamine reduced the responses, suggesting that part of the cholinergic response is due to activation of preganglionic neurons. Prucalopride concentration-dependently increased the submaximal cholinergic contractions in the three tissue types, reaching maximum from 0.03 μmol/L onwards. The facilitation in the different series with 0.03 μmol/L prucalopride ranged from 41% to 104%, 30% to 76% and 24% to 74% in fundus, jejunum, and colon, respectively. The effect of 0.03 μmol/L prucalopride was concentration-dependently inhibited by GR 113808. Conclusions & Inferences In the murine gastrointestinal tract, activation of 5- HT4 receptors with prucalopride enhances cholinergic contractions, illustrating facilitation of myenteric cholinergic neurotransmission. The degree of enhancement with prucalopride is of similar magnitude as previously reported in other species, but the effective concentrations are lower than those needed in the gastrointestinal tract of other species. [ABSTRACT FROM AUTHOR]

Background Evidence suggests that patients with irritable bowel syndrome ( IBS) exhibit increases in gut permeability and alterations in tight junction ( TJ) protein expression. Although psychological stress worsens IBS symptoms, the mechanisms by which stress enhances gut permeability and affects TJ protein expression remain to be determined. Here, we test the hypothesis that chronic intermittent psychological stress activates the release of proinflammatory cytokines to alter TJ proteins and promotes increased gut permeability. Methods Male Fischer-344 rats were subjected to 1 hour of water avoidance stress ( WAS) or SHAM stress per day for 7 days. Following the stress protocol, colonic permeability was measured via transepithelial electrical resistance ( TEER) and macromolecular flux of horseradish peroxidase ( HRP). In tissue isolated from rats exposed to the WAS or SHAM stress, TJ proteins claudin-2, junctional adhesion molecule-A ( JAM-A) and zonula occluden-1 ( ZO-1) were measured via Western blotting, histological appearance of the colonic segments was assessed via hematoxylin and eosin staining, and an inflammatory cytokine panel was quantified via quantitative reverse transcription-polymerase chain reaction. Key Results Repetitive daily exposure to WAS decreased the TEER, increased the macromolecular flux of HRP, and altered the expression of claudin-2, JAM-A and ZO-1 proteins within colonic tissue compared to SHAM controls. In the absence of a histologically defined inflammation, the cytokine profiles of WAS-treated animals revealed an increase in interleukin-1β and tumor necrosis factor ( TNF)-α. Subsequent analysis revealed a significant positive correlation between TNF-α and expression of TJ protein claudin-2. Conclusions & Inferences Our findings suggest that chronic stress increases colonic permeability via sub-inflammatory cytokine-mediated remodeling of TJ protein expression. [ABSTRACT FROM AUTHOR]

Enterochromaffin cells were the first endocrine cells of the gastrointestinal tract to be chemically distinguished, almost 150 years ago. It is now known that the chromaffin reaction of these cells was due to their content of the reactive aromatic amine, 5-hydroxytryptamine (5- HT, also known as serotonin). They have commonly been thought to be a special class of gut endocrine cells (enteroendocrine cells) that are distinct from the enteroendocrine cells that contain peptide hormones. The study by Martin et al. in the current issue of this journal reveals that the patterns of expression of nutrient receptors and transporters differ considerably between chromaffin cells of the mouse duodenum and colon. However, even within regions, chromaffin cells differ; in the duodenum there are chromaffin cells that contain both secretin and 5- HT, cholecystokinin and 5- HT, and all three of secretin, cholecystokinin, and 5- HT. Moreover, the ratios of these different cell types differ substantially between species. And, in terms of function, 5- HT has many roles, including in appetite, motility, fluid secretion, release of digestive enzymes and bone metabolism. The paper thus emphasizes the need to define the many different classes of enterochromaffin cells and relate this to their roles. [ABSTRACT FROM AUTHOR]

Background As a traditional method for the assessment of colon dynamics, radio-opaque markers ( ROMs) are limited in clinical use because of their ionizing radiation. We compared the accuracy and applicability of gadolinium-based capsules with ROMs in the measurement of colon dynamics in healthy controls and slow transit constipation ( STC) patients. Methods Seven patients with STC and nine healthy controls under a normal diet orally consumed ROMs and gadolinium-based capsules simultaneously. All subjects underwent X-ray and magnetic resonance imaging ( MRI). Healthy control images were acquired at 12, 24, and 48 h, and STC patient images were acquired at 24, 48, and 72 h. The scores based on the position of the labeling capsules and ROMs in the colon and the colon transit times ( CTTs) in the two groups were compared. Key Results The CTTs obtained via the ROMs were 34.7±17.4 and 67.3±6.5 h in the healthy controls and STC patients, respectively ( P<.05). The CTTs obtained via MRI were 30.9±15.9 and 74.1±7.2 h in the healthy controls and STC patients, respectively ( P<.05). The CTTs of the STC patients were significantly longer than the healthy controls. The correlation ( rs) between the scores based on the position of the labeling capsule and ROMs in the healthy group and the STC patients was .880 ( P<.05) and .889 ( P<.05), respectively. Conclusions and Inferences As a MRI contrast label, gadolinium-based capsules exhibit results comparable to ROMs in colon motility measurements. [ABSTRACT FROM AUTHOR]

Given the prevalence of irritable bowel syndrome ( IBS) and the suboptimal response to most therapeutic approaches, there has been increasing interest in and adoption of dietary treatment strategies, such as the low Fermentable Oligo-, Di-, & Mono-Saccharides and Polyols ( FODMAP) diet. FODMAPs are a diverse group of carbohydrates that exert effects in the gastrointestinal tract not only via fermentation but likely via alterations in the microbiota, metabolome, permeability, and intestinal immunity as well. Clinical evidence for efficacy of this diet is mounting, but there are significant questions regarding short- and long-term safety and effects on the microbiota and nutrition that remain unanswered. This review article interprets the recent findings reported in this issue of Neurogastroenterology and Motility and summarizes the mechanistic and clinical efficacy data of the low FODMAP diet in IBS patients to date. [ABSTRACT FROM AUTHOR]

Background The use of the anticancer chemotherapeutic agent 5-fluorouracil (5- FU) is often limited by nausea, vomiting, constipation, and diarrhea; these side-effects persist long after treatment. The effects of 5- FU on enteric neurons have not been studied and may provide insight into the mechanisms underlying 5- FU-induced gastrointestinal dysfunction. Methods Balb/c mice received intraperitoneal injections of 5- FU (23 mg/kg) 3 times/week for 14 days. Gastrointestinal transit was analysed in vivo prior to and following 3, 7, and 14 days of 5- FU treatment via serial x-ray imaging. Following 14 days of 5- FU administration, colons were collected for assessment of ex vivo colonic motility, gross morphological structure, and immunohistochemical analysis of myenteric neurons. Fecal lipocalin-2 and CD45+ leukocytes in the colon were analysed as markers of intestinal inflammation. Key Results Short-term administration of 5- FU (3 days) increased gastrointestinal transit, induced acute intestinal inflammation and reduced the proportion of neuronal nitric oxide synthase-immunoreactive neurons. Long-term treatment (7, 14 days) resulted in delayed gastrointestinal transit, inhibition of colonic migrating motor complexes, increased short and fragmented contractions, myenteric neuronal loss and a reduction in the number of Ch AT-immunoreactive neurons after the inflammation was resolved. Gross morphological damage to the colon was observed following both short- and long-term 5- FU treatment. Conclusions & Inferences Our results indicate that 5- FU induces accelerated gastrointestinal transit associated with acute intestinal inflammation at day 3 after the start of treatment, which may have led to persistent changes in the ENS observed after days 7 and 14 of treatment contributing to delayed gastrointestinal transit and colonic dysmotility. [ABSTRACT FROM AUTHOR]

Background In ancient medicine, extracts of the marijuana plant Cannabis sativa were used against diseases of the gastrointestinal ( GI) tract. Today, our knowledge of the ingredients of the Cannabis plant has remarkably advanced enabling us to use a variety of herbal and synthetic cannabinoid ( CB) compounds to study the endocannabinoid system ( ECS), a physiologic entity that controls tissue homeostasis with the help of endogenously produced CBs and their receptors. After many anecdotal reports suggested beneficial effects of Cannabis in GI disorders, it was not surprising to discover that the GI tract accommodates and expresses all the components of the ECS. Cannabinoid receptors and their endogenous ligands, the endocannabinoids, participate in the regulation of GI motility, secretion, and the maintenance of the epithelial barrier integrity. In addition, other receptors, such as the transient receptor potential cation channel subfamily V member 1 (TRPV1), the peroxisome proliferator-activated receptor alpha (PPARα) and the G-protein coupled receptor 55 (GPR55), are important participants in the actions of CBs in the gut and critically determine the course of bowel inflammation and colon cancer. Purpose The following review summarizes important and recent findings on the role of CB receptors and their ligands in the GI tract with emphasis on GI disorders, such as irritable bowel syndrome, inflammatory bowel disease, and colon cancer. [ABSTRACT FROM AUTHOR]