Chronic constipation is a highly prevalent condition characterized by infrequent bowel movements with hard stool consistency, straining during evacuation, and abdominal discomfort and bloating. Traditionally, chronic constipation is managed by life style and dietary modifications, with addition of laxatives and stool softeners in many cases. More recently, lubiprostone, a chloride channel activator, was shown to be effective in the treatment of chronic constipation. Despite these modalities, a large proportion of patients remains incompletely relieved with currently available therapeutic approaches. Linaclotide is a minimally absorbed, 14-amino acid peptide that increases intestinal fluid secretion and transit through its binding to the guanylate cyclase-C receptor on the luminal surface of intestinal enterocytes. Activation of this receptor results in increased fluid secretion and acceleration of transit, through a cyclic guanosine 3′, 5′-monophosphate–mediated stimulation of chloride secretion by the cystic fibrosis transmembrane conductance regulator. In addition, in animal models, linaclotide administration was shown to decrease sensitivity to visceral distention. In this issue of Gastroenterology, Lembo et al report the results of a placebo-controlled study evaluating the efficacy of a 4-week treatment with linaclotide in chronic constipation. In this multicenter study from the United States, eligible patients were randomized to treatment with placebo or linaclotide 75, 150, 300, or 600 μg orally once daily. Patients fulfilling Rome criteria for the irritable bowel syndrome were excluded from the study. The primary endpoint of the study was the change in mean weekly spontaneous bowel movements (SBM) frequency from the 14-day pretreatment baseline period to the 4-week treatment period. Secondary end points included stool consistency, abdominal discomfort and bloating, overall evaluation of relief of constipation and treatment satisfaction, and a constipation-specific quality-of-life questionnaire A total of 310 patients (84% Caucasian; 92% female; mean age, 47 years) were randomized to one of the five study arms. Linaclotide dose-dependently and significantly increased the frequency of weekly SBMs (Figure 1), and the number of patients with a SBM on the first treatment day was also dose-dependently and significantly enhanced by linaclotide. These effects were associated with dose-dependent improvement of straining at defecation, stool consistency, abdominal discomfort and bloating, and constipation-associated quality of life. Overall evaluation of constipation severity by the patient, reporting of relief of constipation and treatment satisfaction were all higher with linaclotide than with placebo. Linaclotide was well tolerated and the most commonly reported adverse event was diarrhea, usually transient and mild, and related to the mode of action of the drug. This study demonstrates that linaclotide, a minimally absorbed peptide which is a guanylate cyclase-C receptor agonist, significantly improves bowel habits and abdominal symptoms in patients with chronic constipation. The drug has a rapid onset of activity and is well tolerated. The 150- and 300-μg doses seemed to provide the best benefit/adverse event ratio and will be further tested in phase III clinical trials. Seepage 886. Proton-pump inhibitors (PPIs) are among the most commonly prescribed drugs, and a large number of patients use these on a daily basis as maintenance therapy for gastroesophageal reflux disease. Although PPIs are generally considered safe and approved for long-term use, a number of concerns have been raised. Recently, a number of epidemiologic studies reported a significant association between chronic PPI use and the risk of hip fracture. It is unclear whether this is attributable to an effect of these medications on bone mineral density (BMD), or whether PPI use is a marker of a number of comorbidities that may associate with osteoporosis. In this issue of Gastroenterology, Targownik et al report the results of 2 studies analyzing the effects of PPI therapy on BMD and changes in BMD. The authors analyzed data in the Population Health Research Data Repository and the Drug Programs Information Network and the Provincial Bone Mineral Density Database in Manitoba, Canada. This database contains data sets that capture information on patient demographics, outpatient and hospital visits, and diagnoses since April 1984. The Drug Programs Information Network contains the drug name, date, quantity, and dose dispensed for all prescription drugs used outside of hospitals and personal care homes since April 1995. The Provincial Bone Mineral Density Database contains the results of all clinical dual-energy x-ray absorptiometry scans performed since 1990, as well as demographics and comorbidities. In a first, case-control study, the authors identified cases with hip or lumbar spine osteoporosis (T-score < −2.5) and these were matched with up to 3 age- and gender-matched controls with normal BMD. Subjects using medications with known osteoprotective effects, residents of personal care homes and patients on hemodialysis were excluded from the analysis. PPI use in the previous 5 years was compared for both groups. In a second, longitudinal study, the authors included only subjects who underwent 2 BMD assessments between 2001 and 2006, separated by 1–3 years. Then annual change in BMD was compared between PPI users (PPI dose prescribed for ≥50% of the days between the 2 measurements) and non-users. A similar analysis was made for high-intensity PPI use (>1 PPI dose per day). Subjects using osteoprotective medications were not excluded from this study. In the cross-sectional study, hip and lumbar spine osteoporosis were found in 2193 and 3596 subjects, respectively, who were matched with 5527 and 10,257 controls, respectively. In univariate analyses, PPI use was associated with a lower risk of osteoporosis at the lumbar spine for all dosis and with a lower risk of hip osteoporosis for subjects who had been dispensed >1500 standard PPI doses over the previous 5 years. In multivariable logistic regression analysis, after adjusting for potential confounders, no association was found between PPI use and osteoporosis at either the hip or the lumbar spine. In the longitudinal study, 2549 subjects were identified who underwent 2 separate BMD assessments separated by 2.31 ± 0.5 years. The use of PPIs at a rate of >0.5 or >1.0 standard daily doses over the time between both BMD assessments did not have an effect on the rate of BMD decline, either at the lumbar spine or the hip. The use of osteoprotective medicines (bisphosphonates, systemic estrogens, and selective estrogen receptor modulators) was associated with an annual increase in BMD at both sites, while steroid use was associated with a significantly larger annual decrease in BMD at both sites (Figure 2). This study found that a history of chronic PPI use is not associated with an increased likelihood of osteoporosis at either the hip or the lumbar spine, and that the rate of bone mineral loss is also not affected by chronic PPI use. These data are reassuring to patients who require chronic PPI use and to the physicians who are prescribing these drugs. Nevertheless, prospective studies of the effects of PPI use on the bone mineral metabolism and on the development of fracture are needed to further clarify this issue. In the meantime, clinicians should optimize PPI use by accurate selection of patients in need of chronic PPI therapy. Seepage 896. Primary sclerosing cholangitis (PSC) is a chronic, progressive, inflammatory disorder of unknown origin that affects the large and small ducts of the biliary tree, driving hepatic cirrhosis and cholangiocarcinoma development. PSC is strongly associated with the concurrent presence of inflammatory bowel disease, particularly ulcerative colitis (UC), which elevates the colon cancer risk in these patients. There are no known specific genes linked to PSC. In the study by Karlsen et al, a genome-wide association study was performed using 375,487 single nucleotide polymorphisms (SNPs) on a discovery patient panel (consisting of 285 PSC patients and 298 healthy controls) and 3 validation patient panels (panel 1 consisting of 137 PSC and 368 controls; panel 2 consisting of 229 PSC and 735 healthy controls; and panel 3 consisting of 400 PSC and 1832 health controls). Genome-side statistical significance for the discovery panel was only detected for SNPs in the HLA complex on chromosome 6p21, with the strongest association with 2 SNPs centromeric to HLA-B (rs3099844) and rs2844559 (Figure 3), with odds rations of 4.8 and 4.7, respectively. Additionally, rs9524260 in the GPC5/GPC6 (glypican) region on chromosome 13q21 showed associations in both the discovery and validation panels, although refinement of the genetic signal at this locus could not be performed. The function of GPC6 is unknown, but bears similarity to other GPCs and heparan sulfate proteoglycans that is physically linked to outer cell membranes, and is expressed in the liver and, more specifically, cholangiocytes. Silencing Gpc6 in murine cholangiocytes revealed its protein to be functioning as a regulator of inflammatory cytokines as silencing upregulated lipocalin-2 and the chemokines Cxcl3 and Cxcl5, the mast cell protease Mcpt8, and tissue inhibitor of matrix metallopreinase 3 (Timp3). In evaluating 15 known UC loci, replication was only obtained at 2 loci, rs12612347 on chromosome 2q35 (with circumstantial evidence for representing the bile acid receptor GPBAR1 gene) and rs3197999 at chromosome 3p21 (locus suggestive of the previously linked macrophage-stimulating 1 [MST1] gene). This study identifies the first associated genes to PSC, and includes strong human leukocyte antigen associations, and a subset of genes that regulate the inflammatory response and potentially involve a bile acid receptor that shares linkage with UC. Seepage 1102. Pancreatic intraepithelial neoplasia (PanIN) has identifiable histological features and typically contains mucin. The current classification scheme stages PanIN lesions as 1A, 1B, 2, and 3 based on cell morphology and histology, and are presumed precursors to pancreatic cancer. However, the cells of origin for PanIN lesions, currently thought to be from pancreatic ductal cells, are not clear. In the study by Strobel et al, mouse and human pancreata were examined histologically, for mucin production, and for specific genes that might identify a specific origin for PanIN lesions. From normal pancreata in both species, a separate compartment was identified that appeared as gland-like outpouches residing in the mesenchyme surrounding larger ducts but coming more often off larger ducts near branch points (Figure 4). This compartment, termed pancreatic duct glands (PDG) show cytoplasmic PAS staining (compared with ducts that showed only membranous staining) express Muc1 and Muc6 mucins, and express sonic hedgehog (Shh) that was not present in any other portion of the normal pancreas. In response to cerulein-induced chronic pancreatic injury, PDG increase in number and size by hyperplasia with a more mucinous appearance, become metaplastic (mirroring gastric metaplasia) with up-regulating Muc6 and acquiring expression of Muc5ac, and up-regulating Shh, all PanIN-like features. Indeed, human pancreatic ductal epithelial cells exposed to recombinant Shh demonstrated enhanced mucin expression through up-regulation of Muc6 and Muc5ac, indicating that the hedgehog pathway is responsible for the mucinous metaplasia, with similar findings in Shh-expressing transgenic mice and demonstration of upregulated SHH in human specimens of chronic pancreatitis. The study indicates that the origin of PanIN is likely from a newly identified and distinct compartment in the pancreas, PDG, which undergoes mucinous metaplasia in response to chronic injury through upregulation of Shh signaling. Seepage 1166. Efficacy of Linaclotide for Patients With Chronic ConstipationGastroenterologyVol. 138Issue 3PreviewLinaclotide is a minimally absorbed peptide agonist of the guanylate cyclase-C receptor that stimulates intestinal fluid secretion and transit and reduces pain in animal models. We assessed the safety and efficacy of a range of linaclotide doses in patients with chronic constipation. Full-Text PDF Proton-Pump Inhibitor Use Is Not Associated With Osteoporosis or Accelerated Bone Mineral Density LossGastroenterologyVol. 138Issue 3PreviewRecent studies have shown an association between proton-pump inhibitor use (PPI) and hip fracture. The mechanism by which PPI use promotes the development of hip fracture is uncharacterized. Therefore, we sought to determine whether PPI use is associated with osteoporosis or accelerated bone mineral density (BMD) loss. Full-Text PDF Genome-Wide Association Analysis in Primary Sclerosing CholangitisGastroenterologyVol. 138Issue 3PreviewWe aimed to characterize the genetic susceptibility to primary sclerosing cholangitis (PSC) by means of a genome-wide association analysis of single nucleotide polymorphism (SNP) markers. Full-Text PDF Pancreatic Duct Glands Are Distinct Ductal Compartments That React to Chronic Injury and Mediate Shh-Induced MetaplasiaGastroenterologyVol. 138Issue 3PreviewPancreatic intraepithelial neoplasia (PanIN) are pancreatic cancer precursor lesions of unclear origin and significance. PanIN aberrantly express sonic hedgehog (Shh), an initiator of pancreatic cancer, and gastrointestinal mucins. A majority of PanIN are thought to arise from ducts. We identified a novel ductal compartment that is gathered in gland-like outpouches (pancreatic duct glands [PDG]) of major ducts and characterized its role in injury and metaplasia. Full-Text PDF