Bile acid diarrhea is one of the most frequently undiagnosed causes of chronic diarrhea. A variety of different pathophysiologic causes can underlie chronic diarrhea. Even after exclusion of the more frequent causes, up to 5 % of the population remains affected by unexplained chronic diarrhea. In up to 50 % within this cohort, bile acid diarrhea is the underlying cause.The various pathophysiologies leading to bile acid diarrhea are well characterized. In this way, bile acid diarrhea can be divided into primary, secondary and tertiary subtypes. Common to all causes is the increased amount of bile acids in the colon and in the faeces and the resulting secretory-osmotic diarrhea, in more severe forms in combination with steatorrhea. The diagnosis of bile acid diarrhea follows a clear algorithm which, in addition to the search for the cause and possibly a therapeutic trial, recognizes the 75SeHCAT test as the reference method for the detection of an increased loss of bile acids. In view of the chronic nature of the symptoms and the need for permanent, lifelong therapy, the use of a one-time, reliable diagnostic test is justified, though the test is currently only available at a few centers. In addition to the treatment of identifiable underlying diseases, the current treatment includes the use of drugs that bind bile acids, with additional nutritional recommendations and vitamin substitutions.The present review article summarizes the pathophysiology and importance of bile acid diarrhea and discusses the current approach towards diagnosis and treatment.

An increasing number of children and adults are currently suffering symptoms due to FODMAP (Fermentable Oligosaccharides, Disaccharides, Monosaccharides and Polyols) consumption. These carbohydrates are poorly digested in the human gastrointestinal tract, exerting an osmotic effect in the small intestine. In the colon, they become substrates to the microbiota. Microbial fermentation explains symptoms such as abdominal distention (postprandial fullness), bloating and flatulence, abdominal pain and loose feces or diarrhea. There are no standardized methods to measure them in daily clinical work. Daily tolerance and the no-effect doses are unclear. How to diagnose and treat FODMAP associated symptoms is also controversial. In this review, we aim to define FODMAP, their associated symptoms and the current techniques for assessing them. The low-FODMAP diet is described and how to implement it.

Studies of fluid secretion by the small intestine are dominated by the coupling with ATP-dependent generation of ion gradients, whereas the contribution of filtration secretion has been overlooked, possibly by the lack of a known mechanistic basis. We measured apical fluid flow and generation of hydrostatic pressure gradients by epithelia of cultured mouse enterocytes, Caco-2 and T-84 cells, and fibroblasts exposed to mechanical force provided by vigorous aeration and in response to ion gradients, inhibitors of ion channels and transporters and in vitro using intact mouse and rat small intestine. We describe herein a paracellular pathway for unidirectional filtration secretion that is driven by mechanical force, requires tight junctions, is independent of ionic and osmotic gradients, generates persistent hydrostatic pressure gradients, and would contribute to the fluid shifts that occur during digestion and diarrhea. Zinc inhibits the flow of fluid and the paracellular marker fluorescein isothyocyanate conjugated dextran (MW = 4 kD) across epithelia of cultured enterocytes (>95%; p < 0.001) and intact small intestine (>40%; p = 0.03). We propose that mechanical force drives fluid secretion through the tight junction complex via a "one-way check valve" that can be regulated. This pathway of filtration secretion complements chloride-coupled fluid secretion during high-volume fluid flow. The role of filtration secretion in the genesis of diarrhea in intact animals needs further study. Our findings may explain a potential linkage between intestinal motility and intestinal fluid dynamics.

WNT2B is a member of the Wnt family, a group of signal transduction proteins involved in embryologic development and stem cell renewal and maintenance. We recently reported homozygous nonsense variants in WNT2B in three individuals with severe, neonatal-onset diarrhea, and intestinal failure. Here we present a fourth case, from a separate family, with neonatal diarrhea associated with novel compound heterozygous WNT2B variants. One of the two variants was a frameshift variant (c.423del [p.Phe141fs]), while the other was a missense change (c.722 G > A [p.G241D]) that we predict through homology modeling to be deleterious, disrupting post-translational acylation. This patient presented as a neonate with severe diet-induced (osmotic) diarrhea and growth failure resulting in dependence on parenteral nutrition. Her gastrointestinal histology revealed abnormal cellular architecture particularly in the stomach and colon, including oxyntic atrophy, abnormal distribution of enteroendocrine cells, and a paucity of colonic crypt glands. In addition to her gastrointestinal findings, she had bilateral corneal clouding and atypical genital development later identified as a testicular 46,XX difference/disorder of sexual development. Upon review of the previously reported cases, two others also had anterior segment ocular anomalies though none had atypical genital development. This growing case series suggests that variants in WNT2B are associated with an oculo-intestinal (and possibly gonadal) syndrome, due to the protein's putative involvement in multiple developmental and stem cell maintenance pathways.

Diarrhea is a fairly common problem among the elderly that has a higher morbidity and mortality compared with the general population. There are multiple reasons for diarrhea in the elderly that can be stratified by different mechanisms: infectious, osmotic, secretory, inflammatory, and malabsorptive. Oral hydration and dietary management are the basic management principles for all forms of diarrhea but specific treatment should address the root cause of diarrhea in order to improve outcomes.

Cystic fibrosis transmembrane conductance regulator (CFTR) is an unusual ABC transporter. It acts as an anion-selective channel that drives osmotic fluid transport across many epithelia. In the gut, CFTR is crucial for maintaining fluid and acid-base homeostasis, and its activity is tightly controlled by multiple neuro-endocrine factors. However, microbial toxins can disrupt this intricate control mechanism and trigger protracted activation of CFTR. This results in the massive faecal water loss, metabolic acidosis and dehydration that characterize secretory diarrhoeas, a major cause of malnutrition and death of children under 5 years of age. Compounds that inhibit CFTR could improve emergency treatment of diarrhoeal disease. Drawing on recent structural and functional insight, we discuss how existing CFTR inhibitors function at the molecular and cellular level. We compare their mechanisms of action to those of inhibitors of related ABC transporters, revealing some unexpected features of drug action on CFTR. Although challenges remain, especially relating to the practical effectiveness of currently available CFTR inhibitors, we discuss how recent technological advances might help develop therapies to better address this important global health need.

The Rome IV criteria for primary chronic obstipation help to distinguish between short-term ailments and a chronic pattern of complaints 1. In general, there are several causes of defecation disorder in the age group of the elderly. Anamnesis and observance of red flags in addition to a geriatric basic assessment make it possible to narrow down the causes. The distinction between low-transit constipation and normal intestinal function can decisively influence the therapeutic consequence.

FODMAP is an acronym for fermentable oligo-, di- and monosaccharides, and polyols. These short-chain carbohydrates, arranged in descending order, are associated with worsening or induction of functional gastrointestinal symptoms such as cramping, bloating, and diarrhea. Such symptoms are at least partially attributable to the non-absorbable nature of osmotic carbohydrates, which undergo bacterial fermentation in the small intestine.[1] The implementation of this diet is in three phases, with the eventual goal of eating well-tolerated foods with some FODMAP content. Up to three-quarters of patients may show a response in six weeks or less.[2]

Neurons of the enteric submucous plexus are challenged by osmolar fluctuations during digestion and absorption of nutrients. Central neurons are very sensitive to changes in osmolality but knowledge on that issue related to enteric neurons is sparse. The present study focuses on investigation of osmosensitivity of submucosal neurons including potential molecular mediating mechanisms. Results show that submucosal neurons respond to hypoosmolar stimuli with increased activity which is partially mediated by the transient receptor potential vanilloid 4 channel. We provided important information on osmosensitive properties of enteric neurons. These data are fundamental to better explain the nerve-mediated control of the gastrointestinal functions during physiological and pathophysiological (diarrhoea) conditions.

Patients receiving vinca alkaloids for hematological malignancies frequently experience constipation that is unresponsive to laxatives. Research on treatment of vinca alkaloid-induced constipation is limited. This study aimed to determine whether the chloride channel activator lubiprostone ameliorates vinca alkaloid-induced constipation in patients with hematological malignancies. In this retrospective cohort study, vinca alkaloid-induced constipation (grade ≥ 3 using the Common Terminology Criteria for Adverse Events) was investigated in patients treated for hematological malignancies between July 2014 and June 2019 who had already been prescribed osmotic laxatives and additionally received either a stimulant laxative or lubiprostone. Univariate and multivariate analyses were performed to identify the risk factors for persistent constipation after introduction of the second laxative. A propensity score model was used to match 67 patients taking a stimulant laxative and 67 treated with lubiprostone, and the occurrence of intractable constipation was compared between groups. Overall, 203 patients were included, among whom 50 (25%) had constipation. On multivariate analysis, body mass index, opioid use, and addition of lubiprostone were independently associated with constipation. Patients treated with lubiprostone were significantly less likely to experience intractable constipation than did those treated with stimulant laxatives (10% vs. 34%, P = 0.002). Moreover, post-constipation diarrhea was significantly less frequent among patients treated with lubiprostone (42% vs. 63%, P = 0.024). Lubiprostone was more effective than stimulant laxatives at treating vinca alkaloid-induced intractable constipation in patients with hematological malignancies, and its use could enable safe vinca alkaloid chemotherapy.

Chronic diarrhea is defined as a predominantly loose stool lasting longer than four weeks. A patient history and physical examination with a complete blood count, C-reactive protein, anti-tissue transglutaminase immunoglobulin A (IgA), total IgA, and a basic metabolic panel are useful to evaluate for pathologies such as celiac disease or inflammatory bowel disease. More targeted testing should be based on the differential diagnosis. When the differential diagnosis is broad, stool studies should be used to categorize diarrhea as watery, fatty, or inflammatory. Some disorders can cause more than one type of diarrhea. Watery diarrhea includes secretory, osmotic, and functional types. Functional disorders such as irritable bowel syndrome and functional diarrhea are common causes of chronic diarrhea. Secretory diarrhea can be caused by bile acid malabsorption, microscopic colitis, endocrine disorders, and some postsurgical states. Osmotic diarrhea can present with carbohydrate malabsorption syndromes and laxative abuse. Fatty diarrhea can be caused by malabsorption or maldigestion and includes disorders such as celiac disease, giardiasis, and pancreatic exocrine insufficiency. Inflammatory diarrhea warrants further evaluation and can be caused by disorders such as inflammatory bowel disease, Clostridioides difficile, colitis, and colorectal cancer.

Irritable bowel syndrome (IBS) is among the most common gastrointestinal disorders encountered in primary and secondary care and is associated with impaired quality of life, increased healthcare utilization, and significant costs to patients and society. There are three primary phenotypes of IBS, categorized according to stool pattern: IBS with diarrhea (IBS-D), IBS with constipation (IBS-C) and IBS with a mixed bowel pattern (IBS-M). The treatment approach to all forms of IBS is typically hierarchal, with initial therapies consisting of dietary and lifestyle modifications. When these interventions are impractical or ineffective, pharmacotherapy with over-the-counter and prescription therapies is often employed. Tenapanor is a locally acting, minimally absorbed, selective small-molecule inhibitor of the intestinal sodium/hydrogen exchanger 3 (NHE3) that was approved in September 2019 by the U.S. Food and Drug Administration (FDA) for IBS-C. This agent works by increasing the sodium level in the intestinal lumen and promoting the efflux of fluid into the gut lumen to maintain osmotic balance in addition to having an antinociceptive effect. Tenapanor has been shown to improve bowel movement frequency/form and abdominal pain in patients with IBS-C. This article will elaborate on the clinical development program for tenapanor for this indication.

The gut microbiome functions like an endocrine organ, generating bioactive metabolites, enzymes or small molecules that can impact host physiology. Gut dysbacteriosis is associated with many intestinal diseases including (but not limited to) inflammatory bowel disease, primary sclerosing cholangitis-IBD, irritable bowel syndrome, chronic constipation, osmotic diarrhoea and colorectal cancer. The potential pathogenic mechanism of gut dysbacteriosis associated with intestinal diseases includes the alteration of composition of gut microbiota as well as the gut microbiota-derived signalling molecules. The many correlations between the latter and the susceptibility for intestinal diseases has placed a spotlight on the gut microbiome as a potential novel target for therapeutics. Currently, faecal microbial transplantation, dietary interventions, use of probiotics, prebiotics and drugs are the major therapeutic tools utilized to impact dysbacteriosis and associated intestinal diseases. In this review, we systematically summarized the role of intestinal microbiome in the occurrence and development of intestinal diseases. The potential mechanism of the complex interplay between gut dysbacteriosis and intestinal diseases, and the treatment methods are also highlighted.

Bacteria use flagella as propellers to move to favorable environments. Escherichia albertii, a growing cause of foodborne illness and diarrhea, is reportedly non-motile and lacks flagella on its surface. Here, we report that 27 out of 59 E. albertii strains, collected mainly from humans and birds, showed swimming motility when cultured at low osmotic pressure. The biosynthesis of flagella in E. albertii cells was induced under ambient temperature and hypoosmotic pressure: conditions which resemble aquatic environments. Flagellar induction increased E. albertii survival in the intestinal epithelial cell culture containing gentamicin. Although genes involved in chemotaxis are not present in the E. albertii genome, the addition of glutamic acid, an amino acid known to regulate the internal cell osmolarity, augmented the proportion of swimming cells by 35-fold. These results suggest that flagellar biosynthesis and motility in E. albertii cells are controlled by their internal and external osmolarity.

We describe a 6-year-old boy who presented to the emergency department with the complaint of nausea and vomiting with diarrhea. Workup revealed a glucose level of 1904 mg/dL, and hyperglycemic hyperosmolar syndrome was diagnosed. Hyperglycemic hyperosmolar syndrome is very rare in the pediatric population, but recent published reports suggest that the incidence of this disorder may be increasing.

Neonatal diarrhea remains the primary cause of mortality in dairy calves around the world, and optimal treatment protocols are needed. The main goals of therapy are to restore hydration and electrolyte concentrations, correct strong ion (metabolic) acidemia, and provide nutritional support. Administration of oral electrolyte solutions (OES) has long been the primary method used to treat neonatal diarrhea in humans and calves because OES are capable of addressing each of the primary goals of therapy. In calves with moderate dehydration, we hypothesized that oral electrolytes would be as good as or better than small volumes of intravenous (IV) or subcutaneous (SC) fluids. Therefore, the main goal of this study was to compare the ability of a commercially available oral electrolyte solution (OES) administered alone or in combination with hypertonic saline with small volumes of IV or SC fluid therapy to resuscitate calves with diarrhea. Thirty-three Holstein calves from 5 to 14 d of age were utilized in this clinical trial. Diarrhea and dehydration were induced by adding sucrose to the milk replacer. In addition, hydrochlorothiazide and spironolactone were given orally and furosemide intramuscularly. Depression status, clinical hydration scores, fecal consistency, and body weight were recorded at regular intervals. Treatment began when calves had severe diarrhea and had a decrease in plasma volume of at least 10%. Calves were randomly assigned to 1 of 4 treatment groups of 8 to 9 calves per group: (1) OES; (2) OES with hypertonic saline (4 mL/kg, IV); (3) IV fluids (lactated Ringer's, 2 L); or (4) SC fluids (lactated Ringer's, 2 L). Treatments were given at 0 and 12 h. Changes in plasma volume, blood pH, electrolyte levels, and physical examination scores were determined before therapy and again at 1, 2, 4, 8, and 12 h after each treatment. All 4 treatments were ultimately successful in improving hydration as well as increasing blood pH; however, animals in both groups that received OES had much faster resuscitation than those in either the IV or SC fluid group. In conclusion, oral electrolyte products remain the gold standard for resuscitating diarrheic calves with moderate dehydration and acidemia and will likely perform better than small volumes of IV lactated Ringer's solution. Subcutaneous fluids by themselves are a poor treatment option and should be only be used as supportive therapy following the initial correction of hypovolemia and metabolic acidosis.

There has been no prior application of matched metagenomics and metatranscriptomics in Clostridioides difficile infection (CDI) evaluating the role of fungi in CDI or identifying community functions that contribute to the development of this disease. We collected diarrheal stools from 49 inpatients (18 of whom tested positive for CDI) under stringent inclusion criteria. We utilized a tiered sequencing approach to identify enriched bacterial and fungal taxa, using 16S and internal transcribed spacer (ITS) rRNA gene amplicon sequencing, with matched metagenomics and metatranscriptomics performed on a subset of the population. Distinct bacterial and fungal compositions distinguished CDI-positive and -negative patients, with the greatest differentiation between the cohorts observed based on bacterial metatranscriptomics. Bipartite network analyses demonstrated that Aspergillus and Penicillium taxa shared a strong positive relationship in CDI patients and together formed negative cooccurring relationships with several bacterial taxa, including the Oscillospira, Comamonadaceae, Microbacteriaceae, and Cytophagaceae Metatranscriptomics revealed enriched pathways in CDI patients associated with biofilm production primarily driven by Escherichia coli and Pseudomonas, quorum-sensing proteins, and two-component systems related to functions such as osmotic regulation, linoleic acid metabolism, and flagellar assembly. Differential expression of functional pathways unveiled a mechanism by which the causal dysbiosis of CDI may self-perpetuate, potentially contributing to treatment failures. We propose that CDI has a distinct fungus-associated bacteriome, and this first description of metatranscriptomics in human subjects with CDI demonstrates that inflammation, osmotic changes, and biofilm production are key elements of CDI pathophysiology.IMPORTANCE Our data suggest a potential role for fungi in the most common nosocomial bacterial infection in the United States, introducing the concept of a transkingdom interaction between bacteria and fungi in this disease. We also provide the first direct measure of microbial community function in Clostridioides difficile infection using patient-derived tissue samples, revealing antibiotic-independent mechanisms by which C. difficile infection may resist a return to a healthy gut microbiome.