Covering the Cover

Abstract

Tobacco remains the most preventable cause of death in the world. Evidence supporting a carcinogenic role for tobacco has now expanded to 18 cancers. In this issue of Gastroenterology, 2 studies provide evidence that tobacco use, mainly in the form of cigarette smoking, increases the risk of colorectal adenoma formation in patients with the Lynch syndrome, and the development of high-grade dysplasia and cancer among patients with Barrett's esophagus. The 2 studies indicate that lifestyle changes such as abstention from tobacco use can affect predisposed individuals. Winkels et al evaluated colorectal adenoma risk in tobacco users in a prospective study of 386 patients with Lynch syndrome. Lynch syndrome is characterized by defects in DNA mismatch repair, which is largely represented by mutations in the MSH2 and MLH1 genes. Patients that harbor these mutations carry a cumulative risk of 70%–80% of acquiring colorectal cancer. Winkels et al prospectively followed 386 patients for a median of 10 months and determined the hazard ratios for current and former smokers to be 6.13 and 3.03, respectively, compared with never smokers for developing colorectal adenomas. A trend for developing adenomas was also observed based on the degree of pack-years. The authors concluded that the risk of developing colorectal adenomas in Lynch syndrome patients could be reduced by tobacco abstention. A second paper by Coleman et al describes a retrospective study that examined the impact of tobacco use among 3167 patients with Barrett’s esophagus on the development of high-grade dysplasia or cancer. The strength of this study was the large study population compiled by the Northern Ireland Barrett’s esophagus registry. Although a retrospective study that utilized medical record review, information on smoking status was available for >90% of the Barrett’s esophagus patients. The mean follow-up period was 7.5 years (range, 0.5–16), which resulted in the identification of 117 cases of high-grade dysplasia or cancer. Patients who were current smokers of any form of tobacco exhibited double the risk of developing high-grade dysplasia or cancer compared with patients who had never smoked. Former cigarette smokers also displayed a higher risk of progression compared with never smokers, but at a lower level (hazard ratio = 1.53; [Figure 1]). Thus, both studies were able to show a potentially beneficial role for abstention from tobacco use for gastrointestinal cancers. Therefore, both studies suggest that a focus on tobacco cessation or abstention can significantly improve risk in 2 patient populations susceptible to the development of cancer. See pages 233 and 241. The medical and economic impact of complications of diverticular disease, including diverticulitis and diverticular bleeding, are substantial. Any decrease in the risks and cost of its complications first requires an understanding of the etiology of diverticulosis. Low-fiber diet, physical inactivity, nonsteroidal anti-inflammatory drug use, and constipation have all been considered to be risk factors for the development of diverticulosis. However, previous studies have been limited by methodologic and other factors. Peery et al, in this issue of Gastroenterology, analyze detailed information on diet, physical activity, and bowel habits collected as part of the colonoscopy-based Diet and Health Studies conducted at the University of North Carolina Hospitals from 1998 to 2010 to better determine risk factors for the development of diverticulosis. As expected, the prevalence of diverticulosis increased with age. However, a high intake of fiber was associated with a higher rather than lower prevalence of diverticulosis. Furthermore, constipation was not a risk factor for diverticulosis. A frequency of >15 bowel movements per week was associated with a 70% greater risk for diverticulosis when compared with a frequency of <7 bowel movements per week (Table 1). Physical activity, high dietary intake of red meat or fat, and nonsteroidal anti-inflammatory drug use were not associated with diverticulosis. These findings suggest a need for a reevaluation of previously held views on the mechanisms for the formation of diverticula as well as dietary recommendations for the management of diverticulosis.Table 1Crude and Adjusted (95% CI) Prevalence Ratios for Diverticulosis by Bowel HabitsBowel habitsP for trend<7 BM/week7 BM/week8−14 BM/week>15 BM/weekCrude1.00 (referent)1.33 (1.13−1.58)1.50 (1.25−1.80)1.57 (1.26−1.95)AdjustedaAdjusted for age, tobacco use.1.00 (referent)1.34 (1.04−1.72)1.59 (1.22−2.07)1.70 (1.24−2.34)<.001BM, bowel movements.a Adjusted for age, tobacco use. Open table in a new tab BM, bowel movements. See page 266. Essential to the gastrointestinal tract's function is the presence of polarized epithelia that serves a barrier function, and as a means for directional nutrient transport into the body. Protein complexes known as tight junctions provide a permeability barrier between the cells of polarized epithelia. The barrier, however, is not absolute as the tight junction's permeability to ions can be selectively regulated. An essential component of tight junctions are the claudins. The claudins are a large family of membrane proteins that feature 4 transmembrane domains and amino- and carboxy-terminal ends that extend into the cytoplasm. Humans express 23 and mice 24 different claudin genes, many of which are the result of gene duplication. Claudins present on adjacent epithelial cells bind to each via their ectodomains, thereby forming the permeability barrier between cells. The claudins' cytoplasmic domains serve as a binding site for many other tight junction components that modulate barrier function. In this issue of Gastroenterology, 2 papers explore the function of claudins 7 and 18 in the intestine and stomach, respectively. Ding et al produced a CLDN7−/− mutant, which expressed an intestinal phenotype. The CLDN7−/− mice are viable at birth but soon fail to thrive and die by 12 days. Previously published work described a salt-wasting nephropathy observed in null mutants. The present study focused on the intestine, where severe defects such as mucosal ulcerations, epithelial sloughing, and inflammation were observed. Consistent with the inflammatory changes, increased expression of multiple regulatory genes for inflammation were also observed. The authors also demonstrated that expression of the matrix metalloproteinase, MMP3, is also induced in CLDN3’s absence. MMP3 activation has been associated with tissue injury and inflammation. A second paper in this issue by Hayashi et al reports on the phenotype that results from a CLDN18−/− null mutation. CLDN18 is normally highly expressed in the stomach. The CLDN18−/− null mutants are viable at birth, but as they develop into adults, a decrease in the number of parietal and chief cells, and the onset of gastritis is observed. In addition, an expansion of Trefoil Factor 2 (TFF2)–positive cells was observed, which when associated with parietal cells loss is consistent with the development of a metaplasia known as spasmolytic polypeptide expressing metaplasia. Spasmolytic polypeptide expressing metaplasia has been associated with intestinal type gastric cancer. The authors provide data suggesting that the absence of CLDN18 results in diffusion of H+ across the paracellular barrier, which then contributes to the development of inflammation. The 2 studies demonstrate the important role served by claudins in maintaining epithelial cell integrity and the paracellular barrier. Both studies have the potential to provide valuable insights into human disease. See pages 292 and 305. Farnesoid X receptor (FXR) is a member of the steroid/thyroid hormone receptor family of ligand-dependent transcription factors and bile acids are its endogenous ligands. Bile acid homeostasis is regulated through a negative feedback loop that involves hepatic FXR and its inhibition, via small heterodimer partner (SHP), of the hepatic expression of CYP7a1, the enzyme that catalyzes the rate-limiting step in bile acid synthesis, and the hepatocellular uptake of bile acids mediated by the Na+/taurocholate cotransporter. Intestinal FXR is involved in the regulation of bile acid reabsorption in the ileum where it induces the expression of the ileal bile acid protein, involved in intracellular transport of bile acids, and the organic solute transporter α and β (OSTα/β), involved in the basolateral membrane transport of bile acids into the portal circulation. In addition, ileal activation of FXR induces the expression of fibroblast growth factor 19 (FGF19), a hormone secreted into the portal circulation that acts synergistically with SHP to inhibit the expression of CYP7a1. An understanding of the key role that FXR plays as an intracellular bile acid sensor offers the potential for the therapeutic use of FXR agonists, such as obeticholic acid, in cholestatic disorders. In this background, Modica et al, using transgenic mice expressing a constitutively active form of FXR in the gut, have examined the protective role of intestinal FXR in cholestatic liver injury. Selective activation of intestinal FXR induced Fgf15, the mouse ortholog of FGF19, Shp, OSTα, and OSTβ, repressed Cyp7a1, and significantly reduced the total bile acid pool size and fecal excretion of bile acids. More important, selective activation of intestinal FXR protected mice from liver injury after bile duct ligation, a model of extrahepatic cholestasis (Figure 2) , both by reducing the size and hydrophobic index of the total bile acid pool and by preserving intestinal architectural integrity, thereby reducing bacterial translocation and inflammation. Similar protection from intestinal FXR activation was observed in response to the administration of α-naphthylisothiocyanate, a model of chemically induced intrahepatic cholestasis, and in Mdr2−/− mice, a model of genetically induced intrahepatic cholestasis. Liver injury after bile duct ligation was also prevented by FGF19 treatment. These findings support the intriguing concept of targeting the intestine with FXR and/or FGF19 agonists to treat cholestatic liver injury. See page 355. A High-Fiber Diet Does Not Protect Against Asymptomatic DiverticulosisGastroenterologyVol. 142Issue 2PreviewThe complications of diverticulosis cause considerable morbidity in the United States; health care expenditures for this disorder are estimated to be $2.5 billion per year. Many physicians and patients believe that a high-fiber diet and frequent bowel movements prevent the development of diverticulosis. Evidence for these associations is poor. We sought to determine whether low-fiber or high-fat diets, diets that include large quantities of red meat, constipation, or physical inactivity increase risk for asymptomatic diverticulosis. Full-Text PDF Deficiency of Claudin-18 Causes Paracellular H+ Leakage, Up-regulation of Interleukin-1β, and Atrophic Gastritis in MiceGastroenterologyVol. 142Issue 2PreviewAlthough defects in tight junction (TJ) epithelial paracellular barrier function are believed to be a primary cause of inflammation, the mechanisms responsible remain largely unknown. Full-Text PDF Selective Activation of Nuclear Bile Acid Receptor FXR in the Intestine Protects Mice Against CholestasisGastroenterologyVol. 142Issue 2PreviewCholestasis is a liver disorder characterized by impaired bile flow, reduction of bile acids (BAs) in the intestine, and retention of BAs in the liver. The farnesoid X receptor (FXR) is the transcriptional regulator of BA homeostasis. Activation of FXR by BAs reduces circulating BA levels in a feedback mechanism, repressing hepatic cholesterol 7α-hydroxylase (Cyp7a1), the rate-limiting enzyme for the conversion of cholesterol to BAs. This mechanism involves the hepatic nuclear receptor small heterodimer partner and the intestinal fibroblast growth factor (FGF) 19 and 15. Full-Text PDF Tobacco Smoking Increases the Risk of High-Grade Dysplasia and Cancer Among Patients With Barrett's EsophagusGastroenterologyVol. 142Issue 2PreviewEsophageal adenocarcinoma arises from Barrett's esophagus (BE); patients with this cancer have a poor prognosis. Identification of modifiable lifestyle factors that affect the risk of progression from BE to esophageal adenocarcinoma might prevent its development. We investigated associations among body size, smoking, and alcohol use with progression of BE to neoplasia. Full-Text PDF Smoking Increases the Risk for Colorectal Adenomas in Patients With Lynch SyndromeGastroenterologyVol. 142Issue 2PreviewIndividuals with Lynch syndrome have a high risk of developing colorectal carcinomas and adenomas at a young age, due to inherited mutations in mismatch repair genes. We investigated whether modifiable lifestyle factors, such as smoking and alcohol intake, increase this risk. Full-Text PDF Inflammation and Disruption of the Mucosal Architecture in Claudin-7–Deficient MiceGastroenterologyVol. 142Issue 2PreviewIntegrity of the intestinal epithelium is required for nutrition absorption and defense against pathogens. Claudins are cell adhesion molecules that localize at tight junctions (TJs); many are expressed in the intestinal tract, but little is known about their functions. Claudin-7 is unique in that it has a stronger basolateral membrane distribution than other claudins, which localize primarily to apical TJs in the intestinal epithelium. We investigated the basolateral functions of claudin-7 and assessed the effects of disruption of Cldn7 in intestines of mice. Full-Text PDF