Meenakshi Bewtra

Linking Long-Term Dietary Patterns with Gut Microbial Enterotypes

The basic composition of the human gut microbiome is influenced by long-term diet: high fat and protein versus high fiber. Diet strongly affects human health, partly by modulating gut microbiome composition. We used diet inventories and 16S rDNA sequencing to characterize fecal samples from 98 individuals. Fecal communities clustered into enterotypes distinguished primarily by levels of Bacteroides and Prevotella. Enterotypes were strongly associated with long-term diets, particularly protein and animal fat (Bacteroides) versus carbohydrates (Prevotella). A controlled-feeding study of 10 subjects showed that microbiome composition changed detectably within 24 hours of initiating a high-fat/low-fiber or low-fat/high-fiber diet, but that enterotype identity remained stable during the 10-day study. Thus, alternative enterotype states are associated with long-term diet.

Histone deacetylase 3 coordinates commensal-bacteria-dependent intestinal homeostasis

The development and severity of inflammatory bowel diseases and other chronic inflammatory conditions can be influenced by host genetic and environmental factors, including signals derived from commensal bacteria. However, the mechanisms that integrate these diverse cues remain undefined. Here we demonstrate that mice with an intestinal epithelial cell (IEC)-specific deletion of the epigenome-modifying enzyme histone deacetylase 3 (HDAC3ΔIEC mice) exhibited extensive dysregulation of IEC-intrinsic gene expression, including decreased basal expression of genes associated with antimicrobial defence. Critically, conventionally housed HDAC3ΔIEC mice demonstrated loss of Paneth cells, impaired IEC function and alterations in the composition of intestinal commensal bacteria. In addition, HDAC3ΔIEC mice showed significantly increased susceptibility to intestinal damage and inflammation, indicating that epithelial expression of HDAC3 has a central role in maintaining intestinal homeostasis. Re-derivation of HDAC3ΔIEC mice into germ-free conditions revealed that dysregulated IEC gene expression, Paneth cell homeostasis and intestinal barrier function were largely restored in the absence of commensal bacteria. Although the specific mechanisms through which IEC-intrinsic HDAC3 expression regulates these complex phenotypes remain to be determined, these data indicate that HDAC3 is a critical factor that integrates commensal-bacteria-derived signals to calibrate epithelial cell responses required to establish normal host–commensal relationships and maintain intestinal homeostasis.

Comparative Effectiveness of Infliximab and Adalimumab for Crohn's Disease

BACKGROUND & AIMS Antibodies against tumor necrosis factor-α are widely used to treat patients with Crohns disease (CD). This study compared the effectiveness of infliximab and adalimumab, the 2 most commonly used anti-tumor necrosis factor agents, in patients with CD. METHODS We conducted a retrospective cohort study by using U.S. Medicare data from 2006 through 2010. Patients with CD who were new users of infliximab (n = 1459) or adalimumab (n = 871) after January 31, 2007, were included. Patients older than age 85 and those with rheumatoid arthritis, psoriasis, psoriatic arthritis, or ankylosing spondylitis were excluded. The primary outcome measures were disease persistence on therapy at week 26, surgery (including bowel resection, creation of an ostomy, or surgical treatment of a perforation or abscess), and hospitalization for CD. Propensity score-adjusted logistic and Cox regression were used to compute adjusted odds ratios or hazard ratios and 95% confidence intervals (CIs). RESULTS After 26 weeks of treatment, 49% of patients receiving infliximab remained on drug, compared with 47% of those receiving adalimumab (odds ratio, 0.98; 95% CI, 0.81-1.19). Fewer patients treated with infliximab underwent surgery than those treated with adalimumab, but this difference was not statistically significant (5.5 vs 6.9 surgeries per 100 person-years; hazard ratio, 0.79; 95% CI, 0.60-1.05). Rates of hospitalization did not differ between groups (hazard ratio, 0.88; 95% CI, 0.72-1.07). CONCLUSIONS We observed similar effectiveness of infliximab and adalimumab for CD on the basis of 3 clinically important outcome measures.

Lectin-type oxidized LDL receptor-1 distinguishes population of human polymorphonuclear myeloid-derived suppressor cells in cancer patients

PMN-MDSC in cancer patients can be distinguished from neutrophils by a genomic signature and by expression of the LOX-1 receptor. Stressing myeloid-derived suppressor cells in cancer Immunotherapies for cancer have shown promising results in part because they overcome the suppressive effects of the tumor microenvironment on immune cells. Condamine et al. now report that polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) can be distinguished from neutrophils in the same cancer patient by the expression of the lipid metabolism–related molecule lectin-type oxidized LDL receptor-1 (LOX-1). LOX-1–expressing neutrophils were nearly undetectable in healthy individuals but were found prominently in tumor tissues. Moreover, exposing neutrophils from healthy individuals to endoplasmic reticulum stress resulted in up-regulation of LOX-1 and increased suppressive function. These data support the specific targeting of LOX-1–expressing PMN-MDSC for cancer immunotherapy. Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are important regulators of immune responses in cancer and have been directly implicated in the promotion of tumor progression. However, the heterogeneity of these cells and the lack of distinct markers hamper the progress in understanding the biology and clinical importance of these cells. Using partial enrichment of PMN-MDSC with gradient centrifugation, we determined that low-density PMN-MDSC and high-density neutrophils from the same cancer patients had a distinct gene profile. The most prominent changes were observed in the expression of genes associated with endoplasmic reticulum (ER) stress. Unexpectedly, low-density lipoprotein (LDL) was one of the most increased regulators, and its receptor oxidized LDL receptor 1 (OLR1) was one of the most overexpressed genes in PMN-MDSC. Lectin-type oxidized LDL receptor-1 (LOX-1) encoded by OLR1 was practically undetectable in neutrophils in peripheral blood of healthy donors, whereas 5 to 15% of total neutrophils in cancer patients and 15 to 50% of neutrophils in tumor tissues were LOX-1+. In contrast to their LOX-1− counterparts, LOX-1+ neutrophils had gene signature, potent immunosuppressive activity, up-regulation of ER stress, and other biochemical characteristics of PMN-MDSCs. Moreover, induction of ER stress in neutrophils from healthy donors up-regulated LOX-1 expression and converted these cells to suppressive PMN-MDSCs. Thus, we identified a specific marker of human PMN-MDSC associated with ER stress and lipid metabolism, which provides new insights into the biology and potential therapeutic targeting of these cells.

Crohn’s Disease and Ulcerative Colitis Are Associated With Elevated Standardized Mortality Ratios: A Meta-Analysis

Background:Evidence regarding all-cause and cause-specific mortality in inflammatory bowel disease (IBD) is conflicting, and debate exists over appropriate study design to examine these important outcomes. We conducted a comprehensive meta-analysis of all-cause and cause-specific mortality in both Crohn’s disease (CD) and ulcerative colitis (UC), and additionally examined various effects of study design on this outcome. Methods:A systematic search of PubMed and EMBASE was conducted to identify studies examining mortality rates relative to the general population. Pooled summary standardized mortality ratios (SMR) were calculated using random effect models. Results:Overall, 35 original articles fulfilled the inclusion and exclusion criteria, reporting all-cause mortality SMRs varying from 0.44 to 7.14 for UC and 0.71 to 3.20 for CD. The all-cause mortality summary SMR for inception cohort and population cohort UC studies was 1.19 (95% confidence interval, 1.06–1.35). The all-cause mortality summary SMR for inception cohort and population cohort CD studies was 1.38 (95% confidence interval, 1.23–1.55). Mortality from colorectal cancer, pulmonary disease, and nonalcoholic liver disease was increased, whereas mortality from cardiovascular disease was decreased. Conclusions:Patients with UC and CD have higher rates of death from all causes, colorectal-cancer, pulmonary disease, and nonalcoholic liver disease.

Passive smoking and inflammatory bowel disease: a meta-analysis.

OBJECTIVES:Active smoking has a well-documented role in the etiology of inflammatory bowel disease (IBD), but the role of passive smoking has been unclear. This meta-analysis examined the relationship between prenatal smoke exposure and childhood passive smoke exposure and the development of IBD.METHODS:We searched the MEDLINE and EMBASE databases to identify observational studies regarding the relationship between prenatal and/or childhood passive smoke exposure and the development of Crohns disease (CD) and/or ulcerative colitis (UC). Pooled odds ratios (OR) were calculated for each relationship.RESULTS:A total of 534 and 699 potential studies were identified from the MEDLINE and EMBASE databases, respectively, of which 13 met all of our inclusion criteria. Overall, we did not observe a positive relationship between childhood passive smoke exposure and CD (OR 1.10, 95% confidence interval [CI] 0.92–1.30) or UC (OR 1.01, 95% CI 0.85–1.20). Likewise, we did not observe an association between prenatal smoke exposure and CD (OR 1.10, 95% CI 0.67–1.80), or prenatal smoke exposure and UC (OR 1.11, 95% CI 0.63–1.97).CONCLUSIONS:Our meta-analysis suggests that there is not a strong association between childhood passive smoke exposure and the development of CD. We found no evidence that childhood passive smoke exposure exerts a protective effect against UC, as is the case in active smoke exposure. The heterogeneity among the small number of studies limited the ability to draw conclusions about prenatal smoke exposure.

Acute-on-chronic liver failure before liver transplantation: impact on posttransplant outcomes.

Background. Acute decompensation in patients with chronic liver disease, resulting from acute kidney injury and infections, leads to significant morbidity and mortality. It is unclear whether patients who develop acute-on-chronic liver failure (ACLF) have poor outcomes after liver transplantation. Methods. We performed a single-center retrospective cohort study of 332 patients to evaluate the effect of ACLF, defined as an acute rise in the Model for End-Stage Liver Disease score of more than 5 within 4 weeks before transplantation, on posttransplant outcomes including stage 4 chronic kidney disease, death, recurrent cirrhosis, or graft failure requiring retransplantation. Results and Conclusions. One hundred fifty-seven patients in the study had ACLF and 175 patients had no ACLF (non-ACLF) pretransplant. Thirty-four patients in the entire cohort received dual organs, 10 of them (29.4%) had ACLF. Seventy-six percent of the patients with ACLF had acute kidney injury as their reason for decompensation and 23.6% had an infection. Mean Model for End-Stage Liver Disease score at transplant was significantly different between the groups (ACLF 28.77 vs. non-ACLF 21.23, P<0.0001). A total of 16.6% of the patients achieved an estimated glomerular filtration rate (eGFR) less than 30 mL/min, 21% of patients died, 12.3% developed cirrhosis, and 7.5% received a second transplant. There was no difference in mean eGFR between the ACLF and non-ACLF cohorts at 3 years posttransplant (56.35 mL/min vs. 59.93 mL/min, respectively, P=0.27). On multivariate analysis, ACLF was not significantly associated with eGFR less than 30 mL/min, death, recurrent cirrhosis, or retransplantation when adjusted for potential confounders.

Radiofrequency Ablation Is Associated With Decreased Neoplastic Progression in Patients With Barrett's Esophagus and Confirmed Low-Grade Dysplasia

BACKGROUND & AIMS Barretts esophagus (BE) with low-grade dysplasia (LGD) can progress to high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC). Radiofrequency ablation (RFA) has been shown to be an effective treatment for LGD in clinical trials, but its effectiveness in clinical practice is unclear. We compared the rate of progression of LGD after RFA with endoscopic surveillance alone in routine clinical practice. METHODS We performed a retrospective study of patients who either underwent RFA (n = 45) or surveillance endoscopy (n = 125) for LGD, confirmed by at least 1 expert pathologist, from October 1992 through December 2013 at 3 medical centers in the United States. Cox regression analysis was used to assess the association between progression and RFA. RESULTS Data were collected over median follow-up periods of 889 days (interquartile range, 264-1623 days) after RFA and 848 days (interquartile range, 322-2355 days) after surveillance endoscopy (P = .32). The annual rates of progression to HGD or EAC were 6.6% in the surveillance group and 0.77% in the RFA group. The risk of progression to HGD or EAC was significantly lower among patients who underwent RFA than those who underwent surveillance (adjusted hazard ratio = 0.06; 95% confidence interval: 0.008-0.48). CONCLUSIONS Among patients with BE and confirmed LGD, rates of progression to a combined end point of HGD and EAC were lower among those treated with RFA than among untreated patients. Although selection bias cannot be excluded, these findings provide additional evidence for the use of endoscopic ablation therapy for LGD.

Update on the risk of lymphoma following immunosuppressive therapy for inflammatory bowel disease

The care of inflammatory bowel disease has changed considerably with the introduction of a number of immunosuppressants including anti-metabolite and anti-TNF therapies. While efficacious, these medications also carry important risks, notably the potential risk of lymphoma. This risk is one of the most worrisome for both patients and physicians. Our current knowledge is still evolving; however, our understanding of what risks these drugs carry, both individually and synergistically, is critical in allowing informed decision making. In this article, we will describe the known lymphoma risks of commonly used immunosuppressant medications in inflammatory bowel disease, with an emphasis on non-Hodgkin’s lymphoma and hepatosplenic T-cell lymphoma.

Comparative risk of recurrence of dysplasia and carcinoma after endoluminal eradication therapy of high-grade dysplasia versus intramucosal carcinoma in Barrett's esophagus.

BACKGROUND Endoscopic therapy is the preferred approach for the management of Barretts esophagus (BE) patients with high-grade dysplasia (HGD) and intramucosal carcinoma (IMC). Little is known about outcome differences in patients with HGD versus IMC. OBJECTIVE To determine and compare the rate of recurrent dysplasia or neoplasia in patients with HGD or IMC undergoing endoscopic therapy. DESIGN Retrospective cohort study. PATIENTS A total of 246 BE patients with either HGD or IMC referred for endoscopic therapy. INTERVENTION Patients underwent EMR and/or ablation therapy with the goal of complete eradication of all dysplasia/neoplasia and intestinal metaplasia (CE-IM). Patients were assigned to either the HGD or IMC group based on highest pathology grade at the start of therapy. MAIN OUTCOME MEASUREMENTS Complete eradication and recurrence of IM and/or HGD/neoplasia were assessed among patients with HGD versus IMC. Only patients with CE-IM (documented eradication of all dysplasia/neoplasia and IM on a single endoscopy) were included for analysis of recurrence rates and risk factors. RESULTS CE-IM was achieved in 113 of 135 patients (83.7%) with HGD and in 84 of 111 patients (75.7%) with IMC (P = .16). Overall recurrence rates of dysplasia or neoplasia after CE-IM were similar in both groups (HGD, 8.0% vs IMC, 9.5%; P = .44; relative risk, 1.2; 95% confidence interval, 0.5-3.0) and remained similar in patients with 5 years of surveillance after CE-IM (HGD, 13.5% vs IMC, 11.4%; P = .53; relative risk, 0.85; 95% confidence interval, 0.3-2.7). LIMITATIONS Retrospective, observational study and evolution of endoscopic modalities and experience. CONCLUSION Endoluminal therapy can successfully achieve eradication of IM and dysplasia or neoplasia in BE patients with HGD and IMC at comparable rates. There were no differences in the rates of recurrent HGD/IMC in the 2 groups.