Gut enterochromaffin cells drive visceral pain and anxiety.

Gastrointestinal (GI) discomfort is a hallmark of most gut disorders and represents an important component of chronic visceral pain1. For the growing population afflicted by irritable bowel syndrome, GI hypersensitivity and pain persist long after tissue injury has resolved2. Irritable bowel syndrome also exhibits a strong sex bias, afflicting women three times more than men1. Here, we focus on enterochromaffin (EC) cells, which are rare excitable, serotonergic neuroendocrine cells in the gut epithelium3-5. EC cells detect and transduce noxious stimuli to nearby mucosal nerve endings3,6 but involvement of this signalling pathway in visceral pain and attendant sex differences has not been assessed. By enhancing or suppressing EC cell function in vivo, we show that these cells are sufficient to elicit hypersensitivity to gut distension and necessary for the sensitizing actions of isovalerate, a bacterial short-chain fatty acid associated with GI inflammation7,8. Remarkably, prolonged EC cell activation produced persistent visceral hypersensitivity, even in the absence of an instigating inflammatory episode. Furthermore, perturbing EC cell activity promoted anxiety-like behaviours which normalized after blockade of serotonergic signalling. Sex differences were noted across a range of paradigms, indicating that the EC cell-mucosal afferent circuit is tonically engaged in females. Our findings validate a critical role for EC cell-mucosal afferent signalling in acute and persistent GI pain, in addition to highlighting genetic models for studying visceral hypersensitivity and the sex bias of gut pain.

Collective nuclear behavior shapes bilateral nuclear symmetry for subsequent left-right asymmetric morphogenesis in Drosophila.

Proper organ development often requires nuclei to move to a specific position within the cell. To determine how nuclear positioning affects left-right (LR) development in the Drosophila anterior midgut (AMG), we developed a surface-modeling method to measure and describe nuclear behavior at stages 13-14, captured in three-dimensional time-lapse movies. We describe the distinctive positioning and a novel collective nuclear behavior by which nuclei align LR symmetrically along the anterior-posterior axis in the visceral muscles that overlie the midgut and are responsible for the LR-asymmetric development of this organ. Wnt4 signaling is crucial for the collective behavior and proper positioning of the nuclei, as are myosin II and the LINC complex, without which the nuclei fail to align LR symmetrically. The LR-symmetric positioning of the nuclei is important for the subsequent LR-asymmetric development of the AMG. We propose that the bilaterally symmetrical positioning of these nuclei may be mechanically coupled with subsequent LR-asymmetric morphogenesis.

Effects of weight change on all causes, digestive system and other causes mortality in Southern Italy: a competing risk approach.

Weight change is associated with all causes of death, cardiovascular, and cancer mortality and a heterogeneous group of other causes of death. We aimed to estimate the effect of weight change on all causes and cause-specific mortality in a cohort with a high prevalence of deaths due to diseases of the digestive system.MethodsIn this prospective cohort study, 2230 subjects aged 30 to 50 years were examined. The study consisted of a 32-year longitudinal study period (January 1985 to December 2017) and mortality follow-up. Outcomes were mortality from all causes and deaths from gastrointestinal disease. Root Mean Squared Error (RMSE) was evaluated to capture individual residual variation in Body Mass Index (BMI) after adjustment for baseline BMI, and the relationship of residual variation with mortality was calculated as cumulative incidence function and cause-specific hazard (CSH) rate.ResultsIn total, 793 participants died during the follow-up, 96 of them due to Digestive system causes. Magnitude of residual variation weight in the last quintile was associated with all-cause mortality (relative risk, 2.00; 95% CI, 1.54-2.59) and Digestive system causes (relative risk, 3.82; 95% CI, 1.86-7.81).ConclusionThe findings suggest an association between weight change and gastrointestinal disease mortality. Epidemiological works studying the correlation between weight change and mortality should consider this aspect.

The male mosquito contribution towards malaria transmission: Mating influences the Anopheles female midgut transcriptome and increases female susceptibility to human malaria parasites.

Mating causes dramatic changes in female physiology, behaviour, and immunity in many insects, inducing oogenesis, oviposition, and refractoriness to further mating. Females from the Anopheles gambiae species complex typically mate only once in their lifetime during which they receive sperm and seminal fluid proteins as well as a mating plug that contains the steroid hormone 20-hydroxyecdysone. This hormone, which is also induced by blood-feeding, plays a major role in activating vitellogenesis for egg production. Here we show that female Anopheles coluzzii susceptibility to Plasmodium falciparum infection is significantly higher in mated females compared to virgins. We also find that mating status has a major impact on the midgut transcriptome, detectable only under sugar-fed conditions: once females have blood-fed, the transcriptional changes that are induced by mating are likely masked by the widespread effects of blood-feeding on gene expression. To determine whether increased susceptibility to parasites could be driven by the additional 20E that mated females receive from males, we mimicked mating by injecting virgin females with 20E, finding that these females are significantly more susceptible to human malaria parasites than virgin females injected with the control 20E carrier. Further RNAseq was carried out to examine whether the genes that change upon 20E injection in the midgut are similar to those that change upon mating. We find that 79 midgut-expressed genes are regulated in common by both mating and 20E, and 96% (n = 76) of these are regulated in the same direction (up vs down in 20E/mated). Together, these findings show that male Anopheles mosquitoes induce changes in the female midgut that can affect female susceptibility to P. falciparum. This implies that in nature, males might contribute to malaria transmission in previously unappreciated ways, and that vector control strategies that target males may have additional benefits towards reducing transmission.

Selective digestive decontamination, a seemingly effective regimen with individual benefit or a flawed concept with population harm?

Selective digestive decontamination (SDD) regimens, variously constituted with topical antibiotic prophylaxis (TAP) and protocolized parenteral antibiotic prophylaxis (PPAP), appear highly effective for preventing ICU-acquired infections but only within randomized concurrent control trials (RCCT's). Confusingly, SDD is also a concept which, if true, implies population benefit. The SDD concept can finally be reified  in humans using the broad accumulated evidence base, including studies of TAP and PPAP that used non-concurrent controls (NCC), as a natural experiment. However, this test implicates overall population harm with higher event rates associated with SDD use within the ICU context.

Gut-liver-axis: Barrier function of liver sinusoidal endothelial cell.

Liver diseases are associated with the leaky gut via the gut-liver-axis. Previous studies have paid much attention to the effect of gut barrier damage. Notably, clinical observations and basic research reveal that the gut barrier damage seldom leads to liver injury independently but aggravates pre-existing liver diseases such as non-alcoholic fatty liver disease and drug-induced liver injury. These evidences suggest that there is a hepatic barrier in the gut-liver-axis, protecting the liver against gut-derived pathogenic factors. However, it has never been investigated which type of liver cell plays the role of hepatic barrier. Under physiological conditions, liver sinusoidal endothelial cell (LSEC) can take up and eliminate virus, bacteriophage, microbial products, and metabolic wastes. LSEC also keeps the homeostasis of liver immune environment via tolerance-inducing and anti-inflammatory functions. In contrast, under pathological conditions, the clearance function of LSEC is impaired, and LSEC turns into a pro-inflammatory pattern. Given its anatomical position and physiological functions, LSEC is proposed as the hepatic barrier in the gut-liver-axis. In this review, we aim to further understand the role of LSEC as the hepatic barrier. Future studies are warranted to seek effective treatments to improve LSEC health, which appears to be a promising approach to prevent gut-derived liver injury.

The Way to Man's Heart Is through the Stomach.

Organ systems do not exist in a vacuum. However, in an era of increasingly specialized medicine, the focus is often on the organ system alone. Many symptoms are associated with differential diagnoses from upper gastrointestinal (GI) and cardiovascular medical and surgical specialties. Furthermore, a large number of rare but deadly conditions cross paths between the upper GI tract and cardiovascular system; a significant proportion of these are iatrogenic injuries from a parallel specialty. These include unusual fistulae, herniae, and embolisms that transcend specialties. This review highlights these conditions and the shared anatomy and embryology of the two organ systems.

COVID-19 and the Digestive System.

The outbreak of novel coronavirus pneumonia in 2019 (Coronavirus disease 2019 [COVID-19]) is now threatening global public health. Although COVID-19 is principally defined by its respiratory symptoms, it is now clear that the virus can also affect the digestive system. In this review, we elaborate on the close relationship between COVID-19 and the digestive system, focusing on both the clinical findings and potential underlying mechanisms of COVID-19 gastrointestinal pathogenesis.

Effects of the DASH Diet and Sodium Intake on Bloating: Results From the DASH-Sodium Trial.

INTRODUCTION: Bloating is one of the most common gastrointestinal complaints. Evidence has linked fiber and sodium to bloating; however, randomized trials examining these diet components are lacking. Here, we used a randomized trial to examine the effects of the high-fiber DASH diet and dietary sodium intake on abdominal bloating. We hypothesized that both the high-fiber DASH diet and higher sodium intake would increase bloating. METHODS: The DASH-Sodium trial (1998-1999) randomized healthy adults to a high-fiber (32 g/d) DASH or low-fiber (11 g/d) Western diet (control). On their assigned diet, participants ate 3 sodium levels (50, 100, and 150 mmol/d at 2100 kcal) in 30-day periods in random order, with 5-day breaks between each period. The participants reported the presence of bloating at baseline and after each feeding period. Statistical analyses included log-binomial models to evaluate the risk of bloating. RESULTS: Of 412 participants (mean age 48 years; 57% women; 57% black), 36.7% reported bloating at baseline. Regardless of the diet, high sodium intake increased the risk of bloating (risk ratio = 1.27; 95% confidence interval: 1.06-1.52; P = 0.01). The high-fiber DASH diet also increased the risk of bloating over all sodium levels (risk ratio = 1.41; 95% confidence interval: 1.22-1.64; P < 0.001). The effect of high-fiber DASH on bloating was greater in men than in women (P for interaction = 0.001). DISCUSSION: Higher dietary sodium increased bloating, as did the high-fiber DASH diet. Although healthful high-fiber diets may increase bloating, these effects may be partially mitigated by decreasing dietary sodium intake. Future research is needed to explore mechanisms by which sodium intake and diet can influence bloating.

SP and KLF Transcription Factors in Digestive Physiology and Diseases.

Specificity proteins (SPs) and Krüppel-like factors (KLFs) belong to the family of transcription factors that contain conserved zinc finger domains involved in binding to target DNA sequences. Many of these proteins are expressed in different tissues and have distinct tissue-specific activities and functions. Studies have shown that SPs and KLFs regulate not only physiological processes such as growth, development, differentiation, proliferation, and embryogenesis, but pathogenesis of many diseases, including cancer and inflammatory disorders. Consistently, these proteins have been shown to regulate normal functions and pathobiology in the digestive system. We review recent findings on the tissue- and organ-specific functions of SPs and KLFs in the digestive system including the oral cavity, esophagus, stomach, small and large intestines, pancreas, and liver. We provide a list of agents under development to target these proteins.

Insulo-opercular cortex generates oroalimentary automatisms in temporal seizures.

OBJECTIVE: Oroalimentary automatisms (OAAs) resembling normal alimentary behavior are stereotyped complex movements that may occur during epileptic seizures. They are considered common clinical signs in temporal lobe seizures, but their anatomofunctional mechanisms are not established. We took the opportunity of presurgical intracerebral recordings to study the relations between the occurrence of OAAs and temporal/spatial features of ictal activities. METHODS: We retrospectively reviewed patients with medically intractable medial temporal lobe epilepsy who underwent stereoelectroencephalography (SEEG) at Cleveland Clinic between 2009 and 2016. Patients presenting oroalimentary automatisms during seizures, with intracerebral electrodes spanning temporal and extratemporal areas, were selected. SEEG-clinical correlations with latency measurements were done. Coherence analyses were performed on regions of interest as defined by the areas involved at the onset of oroalimentary automatisms. RESULTS: Fifteen patients (115 seizures) were analyzed. Sixty-nine seizures exhibited overt oroalimentary automatisms. Only insulo-opercular cortex ictal involvement was consistently related to the occurrence of OAAs, with a linear correlation between OAA onset and ictal oscillatory activity onset in the insulo-opercular cortex. SEEG signal processing showed an increase in theta coherence preceding oroalimentary automatism onset between mediobasal-temporal structures and insulo-opercular cortex, as well as between the 2 insulo-opercular regions. SIGNIFICANCE: The underlying mechanism for the production of oroalimentary automatisms in medial temporal seizures is based on temporal-insulo-opercular theta coherence leading to a synchronous state generating rhythmic patterned outputs from the cortical masticatory area.

Intermediate filament proteins of digestive organs: physiology and pathophysiology.

Intermediate filament proteins (IFs), such as cytoplasmic keratins in epithelial cells and vimentin in mesenchymal cells and the nuclear lamins, make up one of the three major cytoskeletal protein families. Whether in digestive organs or other tissues, IFs share several unique features including stress-inducible overexpression, abundance, cell-selective and differentiation state expression, and association with >80 human diseases when mutated. Whereas most IF mutations cause disease, mutations in simple epithelial keratins 8, 18, or 19 or in lamin A/C predispose to liver disease with or without other tissue manifestations. Keratins serve major functions including protection from apoptosis, providing cellular and subcellular mechanical integrity, protein targeting to subcellular compartments, and scaffolding and regulation of cell-signaling processes. Keratins are essential for Mallory-Denk body aggregate formation that occurs in association with several liver diseases, whereas an alternate type of keratin and lamin aggregation occurs upon liver involvement in porphyria. IF-associated diseases have no known directed therapy, but high-throughput drug screening to identify potential therapies is an appealing ongoing approach. Despite the extensive current knowledge base, much remains to be discovered regarding IF physiology and pathophysiology in digestive and nondigestive organs.

The Role of Extracellular Adenosine Triphosphate in Ischemic Organ Injury.

OBJECTIVES: Ischemic tissue injury contributes to significant morbidity and mortality and is implicated in a range of pathologic conditions, including but not limited to myocardial infarction, ischemic stroke, and acute kidney injury. The associated reperfusion phase is responsible for the activation of the innate and adaptive immune system, further accentuating inflammation. Adenosine triphosphate molecule has been implicated in various ischemic conditions, including stroke and myocardial infarction. STUDY SELECTION: Adenosine triphosphate is a well-defined intracellular energy transfer and is commonly referred to as the body's "energy currency." However, Laboratory studies have demonstrated that extracellular adenosine triphosphate has the ability to initiate inflammation and is therefore referred to as a damage-associated molecular pattern. Purinergic receptors-dependent signaling, proinflammatory cytokine release, increased Ca influx into cells, and subsequent apoptosis have been shown to form a common underlying extracellular adenosine triphosphate molecular mechanism in ischemic organ injury. CONCLUSIONS: In this review, we aim to discuss the molecular mechanisms behind adenosine triphosphate-mediated ischemic tissue injury and evaluate the role of extracellular adenosine triphosphate in ischemic injury in specific organs, in order to provide a greater understanding of the pathophysiology of this complex process. We also appraise potential future therapeutic strategies to limit damage in various organs, including the heart, brain, kidneys, and lungs.

Follow-up in Childhood Functional Constipation: A Randomized, Controlled Clinical Trial.

OBJECTIVES: Guidelines recommend close follow-up during the treatment of childhood functional constipation. Only sparse evidence exists on how follow-up is best implemented. Our aim was to evaluate whether follow-up by phone or self-management through Web-based information improved treatment outcomes. METHODS: In this randomized controlled trial, conducted in secondary care, 235 children, ages 2 to 16 years, who fulfilled the Rome III criteria of childhood constipation, were assigned to 1 of the 3 follow-up regimens: control group (no scheduled contact), phone group (2 scheduled phone contacts), and Web group (access to Web-based information). PRIMARY OUTCOME: number of successfully treated children after 3, 6, and 12 months. SECONDARY OUTCOMES: phone contacts, relapse, fecal incontinence, and laxative use. RESULTS: After 3 and 6 months, significantly more children in the Web group (79.7%/75.9%) were successfully treated compared with the control and phone groups (59.7%/63.6% and 63.3%/64.6%) (P = 0.007/P = 0.03). No difference was found after 12 months (control, 72.7%; phone, 68.4%; Web group, 78.5%; P = 0.40). Extra phone consultations were significantly more frequent in the Web group (44.3%) compared with the control group (28.6%) (P = 0.04). Before 3 months, 45.5% of phone consultations were completed in the Web group versus 28.8% and 25.8% in the control and phone groups (P = 0.05/P = 0.02). Relapses, fecal incontinence, and laxative use were not different between interventions. CONCLUSIONS: Improved self-management behavior caused by access to self-motivated Web-based information induced faster short-term recovery during the treatment of functional constipation. Patient empowerment rather than health care-promoted follow-up may be a step toward more effective treatment for childhood constipation.

Age of Onset of Functional Constipation.

In a review of 538 children with functional constipation, we analyzed ages of presentation and onset, symptom duration, and behavioral/developmental problems. We divided the subjects into quartiles (Q1-Q4) based on age of onset. Median onset age was 2.3 years. The oldest group had the shortest symptom duration before referral at 1.8 ±â€Š1.8 years (compared with Q3 to Q1, P = 0.039, P = 0.001, P < 0.001, respectively). Of the Q4 subjects, 22% had a behavioral/developmental problem (P < 0.001 compared with Q1-Q3). We conclude that most children develop functional constipation as infants and toddlers, but those with later onset are more likely to have behavioral/developmental issues and see a specialist sooner.

The Impact of a 24-h Ultra-Marathon on Circulatory Endotoxin and Cytokine Profile.

The study aimed to determine circulatory endotoxin concentration, cytokine profile, and gastrointestinal symptoms of ultra-endurance runners (UER, n=17) in response to a 24-h continuous ultra-marathon competition (total distance range: 122-208 km) conducted in temperate ambient conditions (0-20 °C) in mountainous terrain. Body mass and body temperature were measured, and venous blood samples were taken before and immediately after competition. Samples were analysed for gram-negative bacterial endotoxin, C-reactive protein, cytokine profile, and plasma osmolality. Gastrointestinal symptoms were also monitored throughout competition. Mean exercise-induced body mass loss was (mean±SD) 1.7±1.8% in UER. Pre- and post-competition plasma osmolality in UER was 286±11 mOsmol·kg(-1) and 286±9 mOsmol·kg(-1), respectively. Pre- to post-competition increases (p<0.05) were observed for endotoxin (37%), C-reactive protein (2832%), IL-6 (3 436%), IL-1ß (332%), TNF-α (35%), IL-10 (511%), and IL-8 (239%) concentrations in UER, with no change in the control group (CON; n=12) observed (p>0.05). Gastrointestinal symptoms were reported by 75% of UER, with no symptoms reported by CON. IL-10 (r=0.535) and IL-8 (r=0.503) were positively correlated with gastrointestinal symptoms. A 24-h continuous ultra-marathon competition in temperate ambient conditions resulted in a circulatory endotoxaemia and pro-inflammatory cytokinaemia, counteracted by a compensatory anti-inflammatory response.

The heart and the gut.

The heart and the gut seem to be two organs that do not have much in common. However, there is an obvious and clinically relevant impact of gut functions on the absorption of drugs and oral therapies on the one hand. On the other hand, the gut determines the quantity of nutrient uptake and plays a central role in metabolic diseases. Patients with inflammatory bowel diseases appear to have a higher risk for coronary heart disease despite a lower prevalence of 'classical' risk factors, indicating additional links between the gut and the heart. However, they certainly have a 'leaky' intestinal barrier associated with increased permeability for bacterial wall products. An impaired intestinal barrier function will be followed by bacterial translocation and presence of bacterial products in the circulation, which can contribute to atherosclerosis and chronic heart failure (CHF) as recent data indicate. Impaired cardiac function in CHF vice versa impacts intestinal microcirculation leading to a barrier defect of the intestinal mucosa and increased bacterial translocation. These pathways and the most recent insights into the impact of the gut on acute and chronic heart disease will be discussed in this review.

[SIGNIFICANCE OF MAGNESIUM IN PHISIOLOGY AND PATHOLOGY OF THE DIGESTIVE SYSTEM].

The article describes the physiological role of magnesium in the human body and its importance for metabolic processes. The reasons for the development of magnesium deficiency and hypermagnesaemia and its clinical symptoms are shown. The specialties of magnesium metabolism disturbances in gastroenterological pathology are described. Particular attention paid to the correction of magnesium levels with deviations of its content in the organism.

Catheter-related bloodstream infection in patients with motility disorder of the alimentary tract.

PURPOSE: Catheter-related bloodstream infection (CRBSI) is a serious complication associated with parenteral nutrition (PN). We retrospectively examined the features of CRBSI in patients with motility disorder (MD) by reviewing medical records. METHODS: Patients who received PN for more than 100 days in our hospital between January 2009 and September 2013 were reviewed. They were divided into two groups based on the presence or absence of MD. The frequency of CRBSI and the pathogenic organisms detected were compared. Statistical analysis was performed with the Mann-Whitney U test or Fisher's exact test. P < 0.05 was considered significant. RESULTS: Six patients had MD (MD group) and four patients had short bowels without MD (SB group). The median frequencies of CRBSI were 12.6 per 1,000 catheter-days in the MD group and 2.3 in the SB group (P = 0.027). The percentage of Gram-negative bacilli in all pathogenic organisms was 61% in the MD group and 22% in the SB group (P = 0.036). CONCLUSION: We found CRBSI was more frequent and Gram-negative bacilli were more common in patients with MD. Stasis in the alimentary tract and subsequent bacterial overgrowth appear to be risk factors for CRBSI. Therefore, it is crucial to seek treatments not to cause intestinal stasis.

Relationship between patterns of alcohol consumption and gastrointestinal symptoms among patients with irritable bowel syndrome.

OBJECTIVES: Heavy alcohol intake may exacerbate gastrointestinal (GI) symptoms in adults with irritable bowel syndrome (IBS); however, the role of alcohol in IBS is unclear. We investigated prospective associations between daily patterns of alcohol intake and next day's GI symptoms using daily diaries. METHODS: In an observational study of women aged 18-48 years with IBS and healthy controls, participants recorded daily GI symptoms, alcohol intake, caffeine intake, and cigarette smoking for ≈ 1 month. GI symptoms included abdominal pain, abdominal bloating, intestinal gas, diarrhea, constipation, nausea, stomach pain, heartburn, and indigestion. Binge drinking was defined as 4+ alcohol-containing drinks/day. RESULTS: Patterns of alcohol intake did not differ between IBS patients and controls. Although patterns of drinking were associated with GI symptoms among women with IBS, this was not the case with the healthy controls. The strongest associations for IBS patients were between binge drinking and the next day's GI symptoms (e.g., diarrhea, P=0.006; nausea, P=0.01; stomach pain, P=0.009; and indigestion, P=0.004), whereas moderate and light drinking either were not associated or weakly associated with GI symptoms. Associations between alcohol intake and GI symptoms were stronger for women with IBS-diarrhea than for IBS-constipation or IBS-mixed. Effects of binge drinking on GI symptoms were strongest when comparing between individuals (rather than within individuals). CONCLUSIONS: Our findings indicate that IBS symptoms differ according to the pattern of alcohol intake among IBS patients, suggesting that the pattern of drinking may in part explain the inconsistent findings between alcohol and IBS symptoms.