Special Issue: The Gut Microbiome

Gastroenterology is proud to present a special issue devoted to ‘The Gut Microbiome in Health and Disease’.

The human body contains over 10 times more microbial cells than human cells. This microbiome (the commensal, symbiotic, and pathogenic microorganisms that share our body space) maintains the health and function of many tissues, and its disruption contributes to the pathogenesis of many diseases. Gastroenterology has therefore devoted an entire issue—14 review and perspective articles—to this rapidly developing area of research.

In an introduction to the special issue, editors Chung Owyang and Gary Wu explain the particular importance of the most densely populated and diverse of our microbial communities, the intestinal microbiome. Intestinal microorganisms interact with almost all body systems (immune, nervous, metabolic, etc). The effectiveness of fecal microbiota transplantation in the treatment of refractory Clostridium difficile infection has demonstrated how modification of the intestinal microbiome can be used to treat gastrointestinal disorders.

Articles published in this special issue cover the basic concepts of the mammalian gut microbiome and its potential roles in development of various disorders including inflammatory bowel diseases, cancer, and liver disease. Others discuss how the microbiome might be modified to maintain health or treat disease, such as through transplantation of fecal microbiota or with diet and pre or probiotics. Articles cover the latest technologies used to characterize the composition of the microbiome and its metabolic products, as well as the activities of nonbacterial organisms, such as the virome and mycobiome.

This issue is a must-read for anyone interested in learning more about how our microbiota contributes to our health and disease.

Video: Gastric to Esophageal Mucosal Transplantation

In the April issue of Gastroenterology, researchers report transplantation of mucosa from a patient’s stomach to esophagus, to prevent stricture formation after circumferential endoscopic mucosal dissection of early-stage esophageal cancer.

Endoscopic submucosal resection and dissection are used to remove areas of dysplasia and cancer from the esophagus. However, stricture formation is a major drawback for resections of more than 60% of the esophageal circumference.

In the issue’s “Gastroenterology in Motion section,” Juergen Hochberger et al. describe transplanting mucosa from a patient’s stomach to esophagus after endoscopic submucosal dissection for early squamous cell cancer of the cervical esophagus.

A video from the authors shows the circumferential spread of the lesion in the cervical esophagus through the sphincter area into the hypopharynx.

Marking of the upper and lower resection field is followed by submucosal injection of hydroxyethylic starch, with subsequent circumferential caudal and cervical incision.

A tubular caudocranial resection is performed using a 1.5-mm Flushknife and the esophageal specimen is set free, dropping down toward the stomach to be retrieved.

A dissection is performed in the gastric antrum and the specimen is cut into 3 slices. These are attached to the muscular layer of the denuded area in the cervical esophagus by means of clips and a noncovered metal stent.

Hochberger et al. report that within 5 months of the procedure, the area of mucosal transplant had grown nearly circumferentially in the cervical esophagus. Biopsies confirmed the presence of gastric antral mucosa. The patient has been followed for more than 32 months without complaints.

The authors conclude that gastro–esophageal mucosal transplantation provides a new approach for preventing stricture formation following widespread endoscopic submucosal resection or submucosal dissection, and provides excellent long-term results.

 

How Many People Have Eosinophilic Esophagitis?

Eosinophilic esophagitis (EoE), which was barely recognized 20 years ago, affects at least 150,000 people in the United States, with three-quarters being adults, report Evan Dellon et al. in the April issue of Clinical Gastroenterology and Hepatology.

EoE, also known as allergic esophagitis, is an allergic inflammatory disease characterized by increased numbers eosinophils in the esophagus. Symptoms include difficulty swallowing, food impaction, and heartburn.

EoE is a newly recognized disease that has been increasingly diagnosed over the past decade, in children and adults. It is rare, but is believed to be increasing in prevalence.

Although some aspects of the epidemiology of EoE are understood, it has been a challenge to quantify the prevalence of EoE in the US, due to the lack of a central medical record system, inconsistent application of EoE diagnostic definitions, and difficulties in conducting population-based research at tertiary care referral centers.

Evan Dellon et al. set out to investigate the prevalence of EoE in the US, using health insurance claim data from 2009 through 2011 and methods not previously possible in this field.

They found that despite its relatively recent description, EoE is frequently diagnosed in the US, with an estimated prevalence of 56.7/100,000 persons. The mean age of patients, surprisingly, was 33.5 years; 65% were male, 55.8% had dysphagia, and 52.8% had at least 1 other allergic condition. Prevalence peaked in men 35–39 years old (see figure).

Prevalence of EoE based on sex and age

Dellon et al. identified patients based on the International Classification of Diseases (ICD), 9th revision code for EoE (530.13). They state that this prevalence could be an underestimate, because knowledge of the code and recognition of EoE are increasing.

The authors observed that the prevalence of EoE decreases after age 45, which was unexpected, because other chronic and nonfatal diseases increase in prevalence with age. This observation could implicate early life exposure as an etiologic factor.

In an editorial that accompanies the article, Andrew J. Gawron says that future studies are needed to determine why middle-aged men appear to be more affected than other populations and why EoE is uncommon among certain ethnic groups. It will also be interesting to investigate whether there a possible birth cohort effect, due to undefined previous common exposures among patients, and what the reasons are for regional variations of EoE prevalence.

Gawron warns that it is important to recognize potential bias and to promote accurate use studies based on ICD-9 codes, to avoid false-alarms and pseudo-epidemics.

How Does Vitamin D Lower Cholesterol?

Researchers have identified a mechanism by which vitamin D reduces levels of cholesterol. In a mouse study published in the April issue of Gastroenterology, Edwin Chow et al. show that activation of the vitamin D receptor increases cholesterol 7α-hydroxylase (CYP7A1)—an enzyme that metabolizes cholesterol—by downregulating its repressor, SHP.

Vitamin D

Studies have reported different effects of vitamin D treatment on lipid profiles and cholesterol levels. However, it has not been clear how vitamin D signaling affects cholesterol homeostasis.

Cholesterol is metabolized to bile acids by CYP7A1. In a negative-feedback mechanism, bile acids such as chenodeoxycholic acid activate the farnesoid X receptor (FXR), leading to repression of CYP7A1.

The vitamin D receptor (VDR) binds to its endogenous ligand, 1α,25-dihydroxyvitamin D₃ (1,25[OH]₂D₃) or lithocholic acid (alternate VDR ligand), to activate the transcription of genes.

Chow et al. investigated the interaction between these pathways with various knockout mice given intraperitoneal injections of 1α,25-dihydroxyvitamin D₃ (1,25[OH]₂D₃).

Thee showed that 1,25(OH)₂D₃ traveled rapidly to the liver, which expressed VDR. There, 1,25(OH)₂D₃ downregulated the transcriptional repressor SHP, leading to upregulation of CYP7A1. Chromatin immunoprecipitation analysis of livers from mice showed that 1,25(OH)₂D₃ increased recruitment of VDR and rodent retinoid X receptor to the Shp promoter.

Chow et al. also found that 1,25(OH)2D3 increased expression of CYP7A1 and another VDR target gene, CYP24A1, but reduced Shp mRNA in mouse and human primary hepatocytes.

These findings provide a direct role for VDR in the repression of SHP to upregulate CYP7A1, and a mechanism for reported cholesterol-lowering effects of vitamin D.

Interestingly, Chow et al. observed time-dependent changes in CYP7A1 expression. They say that the involvement of SHP in this pathway might have been previously missed because SHP mRNA has a short half-life (<30 minutes)—it undergoes proteasome degradation, controlled by the extracellular signal-regulated kinase pathway.

The authors propose that the longer-term effects of steady-state doses of 1,25(OH)₂D₃ that they observed are likely to represent physiologic responses, and that the observed upregulation of CYP7A1 after 1,25(OH)₂D₃ exposure indicates that the VDR could be a therapeutic target for cholesterol lowering.

However, the utility of this mechanism to treat hypercholesterolemia is limited because 1,25(OH)₂D₃ and its precursor, 1α-hydroxyvitamin D_3, can produce hypercalcemia. Also, it is not clear how dietary vitamin D might be used to lower cholesterol in humans, because only low levels of 1,25(OH)₂D₃ are synthesized after ingestion. The authors state that vitamin D deficiency could affect cholesterol levels.

Chow et al. propose that the interaction between the VDR and cholesterol homeostasis in humans requires further investigation—especially studies of VDR ligands that do not induce hypercalcemia.

What is the Best Way to Care for Patients with Alcoholic Hepatitis?

Although alcohol-related liver disease is the 8th most common cause of mortality in the US and the 2nd leading cause of mortality among all gastrointestinal diseases, there are few therapeutic options for patients or resources to support identification of new therapies. However, treatment approaches are being developed; a review in the April issue of Clinical Gastroenterology and Hepatology, discusses therapeutic targets and treatment options for patients with alcoholic hepatitis (AH).

Most of the US population consumes alcohol, and 1 in 10 people report heavy drinking (≥3 drinks/day). Fortunately, only a minority of these heavy drinkers develop significant liver disease. The reasons for this are unclear, but are likely to involve genetic factors (such as polymorphisms in patatin-like phospholipase 3) as well as an individual’s sex, ethnicity, binge drinking (5 or more drinks at a time), nutrition status (obesity), or co-existing liver diseases, such as hepatitis C.

Younger people, women, and binge drinkers are more prone to develop AH, characterized by hepatic decompensation and portal hypertension. In the review article, Ashwani K. Singal, et al. describe factors that contribute to development of AH and challenges related to management.

The pathogenesis of AH is believed to involve disrupted gut barrier function that leads to translocation of bacteria and endotoxin, activation of the innate immune response in the liver, and hepatocellular apoptosis, necrosis, and injury. Researchers are working on approaches to alter specific steps in the pathogenic process (see figure).

AH develops because alcohol increases gut permeability and allows translocation of bacteria and molecules (DAMPs) that activate the toll-like receptor (TLR)4 in liver. Kupffer cells stimulate production of cytokines such as IL1, IL6, and TNFα, which promote inflammation and cell death. Caspase or IL1 inhibitors might slow or block this process.

Singal, et al. discuss methods to assess disease activity, help patients maintain abstinence from alcohol, and provide supportive care and nutrition. Potential therapies reviewed in include corticosteroids, pentoxifylline, tumor necrosis factor (TNF) inhibitors, antioxidants, oxandrolone, granulocytapheresis, and albumin dialysis. Singal, et al. also discuss the controversies over liver transplantation for patients with AH.

The National Institute on Alcohol Abuse and Alcoholism has created a multi-institutional consortia to identify new therapeutic targets and perform early-phase clinical studies to develop and test new drugs for management of AH (U01 AA021883 and U01 AA021902)

Increasing resources are therefore being allocated to advance management approaches for alcoholic liver disease, especially AH.

Preventing Hypoglycemia After Gastric Bypass

Many patients who undergo gastric bypass surgery experience hypoglycemia after meals. Researchers report in the March issue of Gastroenterology that they can correct this condition with an agent that blocks the receptor for the glucagon-like peptide 1 (GLP1).

Roux-en-Y gastric bypass surgery, widely used to treat obesity, alters glucose metabolism in some individuals. Although the procedure provides many benefits, some patients experience high levels of insulin and low levels of blood sugar after meals (postprandial hyperinsulinemic hypoglycemia). This can lead to palpitations, lightheadedness, sweating, confusion, decreased attentiveness, and even seizures or loss of consciousness. In the patients who experience these symptoms, they occur within 1–3 hours after meals—particularly those rich in simple carbohydrates.

Although multiple mechanisms are likely to contribute to this form of hypoglycemia, several studies have indicated a role for increased levels of GLP1, which is released from intestinal L-cells in response to meals. GLP1 binds to receptors on beta cells to stimulate insulin secretion in a glucose-dependent manner. Postprandial levels of GLP1 were reported to increase more than 10-fold in patients who underwent bypass surgery.

Marzieh Salehi et al. investigated whether a blocker of the GLP1 receptor, called exendin (9–39), affected hyperinsulinemic hypoglycemia after gastric bypass. Their clinical trial included 9 patients with recurrent hypoglycemia after gastric bypass, 7 patients who were asymptomatic after gastric bypass, and 8 healthy individuals (controls). The subjects ate the same meal, and their glucose was traced.

Salehi et al. found that infusion of exendin (9–39) corrected glycemia in all patients with recurrent hypoglycemia after gastric bypass, reducing postprandial insulin secretion by 50%. In comparison, postprandial insulin secretion was reduced by only 13% in subjects who were asymptomatic after gastric bypass and 14% in controls.

Exendin (9–39) also increased the rate at which meal-derived glucose increased in hypoglycemic patients, compared with controls, whereas hepatic glucose production did not differ significantly between groups.

In an editorial that accompanies the article, Mary-Elizabeth Patti and Allison Goldfine say that the disproportionately greater response to exendin (9–39) among patients with hypoglycemia syndrome indicates that GLP1 contributes to their excessive insulin secretion and hypoglycemia after meals.

Patti and Goldfine propose that post-bypass hyperinsulinemic hypoglycemia arises from changes that the surgery and its associated weight loss produce in glycemic and hormonal patterns after meals (see figure).

Potential mechanism by which exendin(9–39) reduces GLP1 signaling, insulin secretion, and hypoglycemia in patients with gastric bypass.

Following gastric bypass, food intake and rapid emptying of the gastric pouch lead to excessive increases in glucose and parallel increases in insulin secretion, with subsequent rapid decreases in glucose levels.

Salehi et al. add that the distinct pattern of ingested glucose appearance among subjects with recurrent hypoglycemia after gastric bypass indicates that altered gastrointestinal function contributes to glucose abnormalities in this syndrome. They say that larger studies are needed to determine if these findings are applicable to a broad range of subjects who have undergone gastric bypass.

What Patient Factors Affect Bowel Preparation for Colonoscopy?

Bowel preparation is suboptimal for about one third of adults older than 55 undergoing outpatient colonoscopy, says the March issue of Clinical Gastroenterology and Hepatology. Diabetes and low level of patient engagement in their own health care contribute to less-than-optimal preparation, the researchers show.

Colonoscopy is an important screening tool for colorectal cancer, but its effectiveness requires sufficient detection of adenomas, which depends on the skill of endoscopists and the quality of bowel preparation. Suboptimal quality of bowel preparation can cause endoscopists to miss adenomas, increasing procedure times and the need for repeat examinations. It also increases a patient’s risk for developing colorectal cancer.

Many studies have compared different specific bowel preparation regimens, but few have examined patients’ roles in bowel preparation and colonoscopy quality.

Marina Serper et al. investigated the relationship between health literacy, patient engagement, and bowel preparation quality.

They analyzed results from 462 adults who received outpatient colonoscopies, 55–74 years old, and found that 134 had suboptimal quality of bowel preparation (about one third). After adjusting for demographics and clinical characteristics, diabetes increased risk for inadequate bowel preparation almost 2.5-fold.

Furthermore, Serper et al. found that a low level of patient-reported knowledge, skills, and confidence for self-management of chronic disease (called ‘patient activation’) increased risk for inadequate preparation 2-fold. Serper et al. explain that patients with low levels of activation do not possess the skills or knowledge to actively manage their health.

The authors conclude that a patient’s level of engagement in their personal health is an important factor in colonoscopy preparation. However, because this was a cross-sectional study, they warn that they cannot clearly establish the causes of inadequate cleansing.

Patients with higher levels of activation are more engaged in healthy behaviors, more likely to seek health information and ask questions, and more likely to undergo age-appropriate cancer screening. Low activation has been linked to higher healthcare costs. Health insurers have therefore begun to identify individuals with low levels of activation who could require additional counseling and support.

In an accompanying editorial, Douglas Rex explains that there are 2 sets of factors that affect the quality of bowel cleansing. One set includes medical factors (such as diabetes) which physicians can easily identify. The other includes factors that affect the ability of patients to follow the preparation instructions. He says it would helpful to develop simple surveys for use in endoscopy units to identify these patients. More work is needed to establish tools and techniques to educate and improve adherence to instructions.

Rex also explains that bowel preparation efficacy is also reduced when the cleansing agent is poorly tolerated and cannot be fully ingested. Less efficacious preparations are unsafe, because they impair adenoma or cancer detection and necessitate early repeat procedures. Poorly tolerated preparations reduce patients’ willingness to repeat procedures, reducing efficacy and safety, with regard to cancer prevention.

Interestingly, Serper et al. found that level of health literacy did not affect quality of bowel preparation for colonoscopy, and that health literacy and patient activation do not correlate. They explain that although health literacy (a measure of cognitive skill) and patient activation (a measure of patient engagement) are each associated with health behavior, they are complementary—each captures a unique yet often unmeasured patient trait.

Prospective studies of a diverse population are needed to confirm the relationships between these factors and adequate bowel cleansing. However, interventions to improve colonoscopy quality should consider the importance of patient activation in their design.

Cancer Cells in Circulation

Pancreatic cancer cells can be detected in patients’ circulation before tumors are discovered, researchers report in the March issue of Gastroenterology.

Cancer cells have long been believed to acquire metastatic potential after large primary tumors are established. However, many patients undergoing pancreatectomy for chronic pancreatitis are found to have disseminated pancreatic ductal adenocarcinomas (PDAC), even though only precancerous pancreatic intraepithelial neoplasias were detected by histologic analysis.

Furthermore, among patients with small primary tumors (<2 cm) with no evidence of metastatic disease, only 18% survive for 5 years after pancreatectomy—most patients still develop recurrent, metastatic disease. Metastatic cancer cells therefore appear to start spreading before large primary tumors develop.

Andrew Rhim et al. investigated whether pancreas-derived epithelial cells might be detected in blood samples from patients with evidence of only precancerous lesions of the pancreas—with no detectable invasive carcinomas.

They collected and analyzed blood samples from patients with intraductal papillary mucinous neoplasm (IPMNs) or mucinous cystic neoplasms but no evidence for tumors or metastases, along with patients with cytology-confirmed PDAC and no cysts or cancer (positive and negative controls, respectively).

Using microfluidic geometrically enhanced differential immunocapture, they found more than 3 circulating pancreas epithelial cells/mL in blood samples from 7 of 21 patients (33%) with cystic lesions and no diagnosis of cancer (Sendai-criteria negative), 8 of 11 patients (73%) with PDAC, and in 0 of 19 patients without cysts or cancer (controls).

Circulating pancreatic epithelial cells (red) and leukocytes (green).

Therefore, pancreas epithelial cells from patients with cystic lesions or cancer enter the bloodstream.

Studies are underway to analyze the genetic features of circulating pancreatic endothelial cells from patients with cystic lesions, to see if the cells already have somatic mutations associated with PDAC. It is not clear whether patients with these cells in their circulation all develop tumors.

If the cells are associated with subsequent tumor formation, their detection in blood samples could be a marker of PDAC risk. Rhim et al. are planning studies to follow patients with cysts to determine if number or genomic features of circulating pancreatic cells can predict the development of PDAC.

In Treating Crohn’s Disease, Earlier is Better

Patients receiving medical therapies when they have more complicated stages of Crohn’s disease (CD) are more likely to require surgery, researchers report in the March issue of Clinical Gastroenterology and Hepatology. The disease is most-effectively treated by drugs at its early, inflammatory stages.

Patients have a 40%–71% risk for requiring intestinal surgery within 10 years of diagnosis of Crohn’s disease. Although many drugs are used to treat this disease, there is controversy over their ability to reduce patients’ need for surgery.

Gordon Moran et al. investigated whether types of Crohn’s disease that patients have when they begin treatment with thiopurines (azathioprine or mercaptopurine) or anti-tumor necrosis factor (TNF) agents affect their need for surgery.

Moran et al. associated the presence of stricturing disease, ileal location, or ileocolonic location at the time patients are first prescribed thiopurines with a need for surgery. However, thiopurines were found to be more likely than other drugs to prevent the need for surgery for patients with only Crohn’s colitis.

Stricturing or penetrating disease at the time of prescription of anti-TNF agents was significantly associated with a need for surgery. Prescription of an anti-TNF agent after prescription of a thiopurine reduced the risk for surgery, compared with prescription of only a thiopurine.

Moran et al. conclude that treatment of Crohn’s disease with thiopurines and/or anti-TNF therapies before the development of complications reduces the risk for surgery. Treatment with these drugs after the development of complicated disease is not as effective—patients are more likely to require intestinal resection. Moran et al. state that the best outcomes are achieved when patients are treated at the early, inflammatory stage of disease development.

Interestingly, surgery before drug prescription reduced the risk for further surgeries among patients who received thiopurines or anti-TNF agents. Moran et al. say that there is evidence that the drugs can be effective after the disease course is reset by surgery.

Moran et al. acknowledge that physicians often face the challenge of whether to begin anti-TNF therapy after a complication develops, or to recommend surgery. The authors say that anti-TNF therapy can reduce the inflammatory component of a strictured segment and thereby prevent the need for surgery, or at least reduce the amount of surgery required. Residual inflammation before surgery has been associated with an increased incidence of complications after surgery.

The authors explain that treating patients at a late stage reduces drug efficacy, alters the risk–benefit ratio, and can be more expensive.

In a separate article in the March issue of CGH, Jean–Frédéric Colombel et al. report that among patients with moderate to severe ileocolonic Crohn’s disease who received the anti-TNF agent adalimumab as induction and maintenance therapy, those who achieved ‘deep remission’ (the absence of mucosal ulceration and CD Activity Index scores less than 150) appeared to have better 1-year outcomes (fewer hospitalizations and surgeries, lower rates of dosage adjustment, better quality of life, to be more productive and active, and have lower medical costs) than those who did not.

Similar to the findings of Moran et al., Colombel et al. say that anti-TNF agent therapy earlier in the disease course increases the probability of deep remission.

How Does an Antibiotic Reduce Symptoms of IBS?

Rifaximin alters the intestinal microbiota to prevent inflammation and visceral hyperalgesia in stressed rats, according to the February issue of Gastroenterology. These findings could explain the ability of this antibiotic to relieve symptoms of irritable bowel syndrome (IBS) in patients.

Rifaximin is a broad-spectrum antibiotic that has been approved by the FDA for traveler’s diarrhea and minimal hepatic encephalopathy. Interestingly, rifaximin also appears to reduce pain and bloating in patients with IBS, but little is known about the mechanisms of this process.

Low-grade mucosal inflammation and increased intestinal permeability are common in patients with functional bowel disorders. Chronic stress contributes to functional bowel disorders and can predispose patients to gastrointestinal infections or induce visceral hyperalgesia. In animal models of visceral hypersensitivity, psychological stress appears to alter gut microbiota and gut barrier function.

Xu et al. therefore used rat models of visceral hyperalgesia to determine how rifaximin affected intestinal microbiota, inflammation, and function. They found that induction of stress, by water avoidance or repeat restraint, led to visceral hyperalgesia, accompanied by mucosal inflammation and impaired mucosal barrier function.

Oral administration of rifaximin reduced the bacterial load in the intestines of the stressed rats, and altered the composition of bacterial community in the distal ileum (Lactobacillus species became the most abundant, see figure.

Bacterial community composition analyzed with nonmetric multidimensional scaling plots using a θYC distance matrix of operational taxonomic unit−based data. Circles represent distinct bacterial communities identified in luminal contents of terminal ileum of individual rats. Circles that appear larger are closer in the axis not represented and circles that are smaller are farther away in the axis not represented; some circles have been made transparent.

Rifaximin also prevented mucosal inflammation, barrier impairment, and visceral hyperalgesia in response to chronic stress.

A different antibiotic, neomycin, also changed the composition of the ileal bacterial community (Proteobacteria became the most abundant species), but did not prevent intestinal inflammation or induction of visceral hyperalgesia by stress.

The authors propose that development of visceral hyperalgesia is likely, at least in part, mediated by specific interactions between the microbiota and mucosa that lead to inflammation and barrier impairments after exposure to chronic stress.

Preclinical and clinical studies have linked visceral hyperalgesia to increased intestinal permeability. Previous studies have shown that intestinal inflammation induced by chronic stress releases factors such as prostaglandin E₂, and activates ion channels in the dorsal root ganglia that innervate the lower gut.

Psychological stressors have been reported to alter bacterial community structure. Studies have shown that the stress can change the bacterial community structure, reducing species richness and diversity, and facilitating susceptibility to bacterial pathogens.

Although rifaximin appears to alter intestinal bacterial communities, leading to a relative abundance of Lactobacillus that prevents mucosal abnormalities and visceral hyperalgesia induced by chronic stress, direct immunomodulatory effects might also be involved. However, the authors provide evidence that the effects of rifaximin observed are not caused by direct anti-inflammatory action on the mucosa.

Several clinical trials have evaluated the efficacy and safety of rifaximin in patients with IBS. A meta-analysis found rifaximin to be more effective than placebo in improving overall symptoms and bloating in IBS. Rifaximin has been estimated to offer an approximate 10% therapeutic gain for patients with IBS—similar to other available IBS therapies.

Xu et al. warn that rodent models have limited predictive value for IBS treatment in humans, and that the experimental design does not indicate that rifaximin treatment is beneficial for the symptomatic patient but rather that rifaximin prophylaxis can be beneficial in preventing a stress-induced flare.