Patient-Centered Access to IBD Care: A Qualitative Study.

Background: Canada has the highest global age-adjusted incidence and prevalence rates of inflammatory bowel disease (IBD). Due to IBD patient volumes and limited resources, challenges to timely access to specialty care have emerged. To address this gap, the aim of this paper was to understand the experiences and perspectives of persons living with IBD with a focus on accessing health care. Methods: Using a qualitative descriptive approach, patients diagnosed with IBD (≥18 years of age) were purposively sampled from rural and urban gastroenterology clinics and communities across Canada. Co-facilitated by a researcher and patient research partner, 14 focus groups were recorded, transcribed, and coded for themes. Thematic analysis was used to ascertain the congruence or discordance of IBD specialty care access experiences. Results: A total of 63 individuals participated in the study. The majority of participants were female (41/63, 65%) and from urban/suburban regions (33/63, 52%), with a mean age of 48.39 (range 16-77 years). The analysis generated three main themes: (1) need for patient to be partner, (2) adapting IBD care access to individual context, and (3) patient-defined care priorities should guide access to IBD care. Conclusions: The complexity of specialty care access for IBD patients cannot be underestimated. It is vital to possess a robust understanding of healthcare system structures, processes, and the impact of these factors on accessing care. Using a patient-centered exploration of barriers and facilitators, IBD specialty care access in Canada can be better understood and improved on provincial and national levels.

Histological improvement of non-alcoholic steatohepatitis with a prebiotic: a pilot clinical trial.

PURPOSE: In obesity and diabetes the liver is highly susceptible to abnormal uptake and storage of fat. In certain individuals hepatic steatosis predisposes to the development of non-alcoholic steatohepatitis (NASH), a disease marked by hepatic inflammation and fibrosis. Although the precise pathophysiology of NASH is unknown, it is believed that the gut microbiota-liver axis influences the development of this disease. With few treatment strategies available for NASH, exploration of gut microbiota-targeted interventions is warranted. We investigated the therapeutic potential of a prebiotic supplement to improve histological parameters of NASH. METHODS: In a placebo-controlled, randomized pilot trial, 14 individuals with liver-biopsy-confirmed NASH [non-alcoholic fatty liver activity score (NAS) ≥ 5] were randomized to receive oligofructose (8 g/day for 12 weeks followed by 16 g/day for 24 weeks) or isocaloric placebo for 9 months. The primary outcome measure was the change in liver biopsy NAS score and the secondary outcomes included changes in body weight, body composition, glucose tolerance, inflammatory markers, and gut microbiota. RESULTS: Independent of weight loss, oligofructose improved liver steatosis relative to placebo and improved overall NAS score (P = 0.016). Bifidobacterium was enhanced by oligofructose, whereas bacteria within Clostridium cluster XI and I were reduced with oligofructose (P < 0.05). There were no adverse side effects that deterred individuals from consuming oligofructose for treatment of this disease. CONCLUSIONS: Independent of other lifestyle changes, prebiotic supplementation reduced histologically-confirmed steatosis in patients with NASH. Larger follow-up studies are warranted. CLINICAL TRIAL: This trial was registered at Clinicaltrials.com as NCT03184376.

An intact microbiota is required for the gastrointestinal toxicity of the immunosuppressant mycophenolate mofetil.

BACKGROUND: Mycophenolate mofetil (MMF) is commonly prescribed after transplantation and has major advantages over other immunosuppressive drugs, but frequent gastrointestinal (GI) side-effects limit its use. The mechanism(s) underlying MMF-related GI toxicity have yet to be elucidated. METHODS: To investigate MMF-related GI toxicity, experimental mice were fed chow containing MMF (0.563%) and multiple indices of toxicity, including weight loss and colonic inflammation, were measured. Changes in intestinal microbial composition were detected using 16S rRNA Illumina sequencing, and downstream PICRUSt analysis was used to predict metagenomic pathways involved. Germ-free (GF) mice and mice treated with orally administered broad-spectrum antibiotics (ABX) were utilized to interrogate the importance of the microbiota in MMF-induced GI toxicity. RESULTS: Mice treated with MMF exhibited significant weight loss, related to loss of body fat and muscle, and marked colonic inflammation. MMF exposure was associated with changes in gut microbial composition, as demonstrated by a loss of overall diversity, expansion of Proteobacteria (specifically Escherichia/Shigella), and enrichment of genes involved in lipopolysaccharide (LPS) biosynthesis, which paralleled increased levels of LPS in the feces and serum. MMF-related GI toxicity was dependent on the intestinal microbiota, as MMF did not induce weight loss or colonic inflammation in GF mice. Furthermore, ABX prevented and reversed MMF-induced weight loss and colonic inflammation. CONCLUSIONS: An intact intestinal microbiota is required to initiate and sustain the GI toxicity of MMF. MMF treatment causes dynamic changes in the composition of the intestinal microbiota that may be a targetable driver of the GI side-effects of MMF.

Effect of Oral Capsule- vs Colonoscopy-Delivered Fecal Microbiota Transplantation on Recurrent Clostridium difficile Infection: A Randomized Clinical Trial.

Importance: Fecal microbiota transplantation (FMT) is effective in preventing recurrent Clostridium difficile infection (RCDI). However, it is not known whether clinical efficacy differs by route of delivery. Objective: To determine whether FMT by oral capsule is noninferior to colonoscopy delivery in efficacy. Design, Setting, and Participants: Noninferiority, unblinded, randomized trial conducted in 3 academic centers in Alberta, Canada. A total of 116 adult patients with RCDI were enrolled between October 2014 and September 2016, with follow-up to December 2016. The noninferiority margin was 15%. Interventions: Participants were randomly assigned to FMT by capsule or by colonoscopy at a 1:1 ratio. Main Outcomes and Measures: The primary outcome was the proportion of patients without RCDI 12 weeks after FMT. Secondary outcomes included (1) serious and minor adverse events, (2) changes in quality of life by the 36-Item Short Form Survey on a scale of 0 (worst possible quality of life) to 100 (best quality of life), and (3) patient perception on a scale of 1 (not at all unpleasant) to 10 (extremely unpleasant) and satisfaction on a scale of 1 (best) to 10 (worst). Results: Among 116 patients randomized (mean [SD] age, 58 [19] years; 79 women [68%]), 105 (91%) completed the trial, with 57 patients randomized to the capsule group and 59 to the colonoscopy group. In per-protocol analysis, prevention of RCDI after a single treatment was achieved in 96.2% in both the capsule group (51/53) and the colonoscopy group (50/52) (difference, 0%; 1-sided 95% CI, -6.1% to infinity; P < .001), meeting the criterion for noninferiority. One patient in each group died of underlying cardiopulmonary illness unrelated to FMT. Rates of minor adverse events were 5.4% for the capsule group vs 12.5% for the colonoscopy group. There was no significant between-group difference in improvement in quality of life. A significantly greater proportion of participants receiving capsules rated their experience as "not at all unpleasant" (66% vs 44%; difference, 22% [95% CI, 3%-40%]; P = .01). Conclusions and Relevance: Among adults with RCDI, FMT via oral capsules was not inferior to delivery by colonoscopy for preventing recurrent infection over 12 weeks. Treatment with oral capsules may be an effective approach to treating RCDI. Trial Registration: clinicaltrials.gov Identifier: NCT02254811.

Changes in Composition of the Gut Bacterial Microbiome after Fecal Microbiota Transplantation for Recurrent Clostridium difficile Infection in a Pediatric Heart Transplant Patient.

The microbiome is increasingly recognized as an important influence on human health and many of the comorbidities that affect patients after solid organ transplantation (SOT) have been shown to involve changes in gut bacterial populations. Thus, microbiome changes in an individual patient may have important health implications after SOT but this area remains understudied. We describe changes in the composition of the fecal microbiome from a pediatric heart transplant recipient before and >2.5 years after he underwent repeated fecal microbiota transplantation (FMT) for recurrent Clostridium difficile infection (CDI). With both documented episodes of CDI, there was marked loss of bacterial diversity with overgrowth of Proteobacteria (>98.9% of phyla identified) associated with symptomatic colitis that was corrected after FMT. We hypothesize that a second CDI occurring after FMT was related to incomplete restoration of normal bowel flora post-FMT with relative deficiencies of the phyla Firmicutes and Bacteroidetes and the families Lachnospiraceae and Ruminococcaceae. Following the second FMT, there was a gradual shift in gut bacterial composition coincident with the recipient developing lymphonodular hyperplasia of the colon and painless hematochezia that resolved with discontinuation of mycophenolate mofetil (MMF). This case documents dynamic changes in the bacterial microbiome after FMT and suggests that MMF may influence the gut microbiome with consequences for the patient.

Constitutive androstane receptor regulates the intestinal mucosal response to injury.

BACKGROUND AND PURPOSE: The pathogenesis of the inflammatory bowel diseases (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), involves aberrant interactions between a genetically susceptible individual, their microbiota and environmental factors. Alterations in xenobiotic receptor expression and function are associated with increased risk for IBD. Here, we have assessed the role of the constitutive androstane receptor (CAR), a xenobiotic receptor closely related to the pregnane X receptor, in the regulation of intestinal mucosal homeostasis. EXPERIMENTAL APPROACH: CAR expression was assessed in intestinal mucosal biopsies obtained from CD and UC patients, and in C57/Bl6 mice exposed to dextran sulphate sodium (DSS; 3.5% w/v in drinking water) to evoke intestinal inflammation and tissue damage. CAR-deficient mice were exposed to DSS and mucosal healing assessed. Modulation of wound healing by CAR was assessed in vitro. The therapeutic potential of CAR activation was evaluated, using 3,3',5,5'-tetrachloro-1,4-bis(pyridyloxy)benzene (TCPOBOP), a selective rodent CAR agonist. KEY RESULTS: CAR expression was reduced in CD and UC samples, compared with expression in healthy controls. This was reproduced in our DSS studies, where CAR expression was reduced in colitic mice. CAR-deficient mice exhibited reduced healing following DSS exposure. In vitro, CAR activation accelerated intestinal epithelial wound healing by enhancing cell migration. Lastly, treating mice with TCPOBOP, following induction of colitis, enhanced mucosal healing. CONCLUSION AND IMPLICATIONS: Our results support the notion that xenobiotic sensing is altered during intestinal inflammation, and suggest that CAR activation may prove effective in enhancing mucosal healing in patients with IBD.

Giardia duodenalis induces pathogenic dysbiosis of human intestinal microbiota biofilms.

Giardia duodenalis is a prevalent cause of acute diarrheal disease worldwide. However, recent outbreaks in Italy and Norway have revealed a link between giardiasis and the subsequent development of chronic post-infectious irritable bowel syndrome. While the mechanisms underlying the causation of post-infectious irritable bowel syndrome remain obscure, recent findings suggest that alterations in gut microbiota communities are linked to the pathophysiology of irritable bowel syndrome. In the present study, we use a laboratory biofilm system to culture and enrich mucosal microbiota from human intestinal biopsies. Subsequently, we show that co-culture with Giardia induces disturbances in biofilm species composition and biofilm structure resulting in microbiota communities that are intrinsically dysbiotic - even after the clearance of Giardia. These microbiota abnormalities were mediated in part by secretory-excretory Giardia cysteine proteases. Using in vitro cell culture and germ-free murine infection models, we show that Giardia-induced disruptions of microbiota promote bacterial invasion, resulting in epithelial apoptosis, tight junctional disruption, and bacterial translocation across an intestinal epithelial barrier. Additionally, these dysbiotic microbiota communities resulted in increased activation of the Toll-like receptor 4 signalling pathway, and overproduction of the pro-inflammatory cytokine IL-1beta in humanized germ-free mice. Previous studies that have sought explanations and risk factors for the development of post-infectious irritable bowel syndrome have focused on features of enteropathogens and attributes of the infected host. We propose that polymicrobial interactions involving Giardia and gut microbiota may cause persistent dysbiosis, offering a new interpretation of the reasons why those afflicted with giardiasis are predisposed to gastrointestinal disorders post-infection.

Point Mutations in Exon 1B of APC Reveal Gastric Adenocarcinoma and Proximal Polyposis of the Stomach as a Familial Adenomatous Polyposis Variant.

Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is an autosomal-dominant cancer-predisposition syndrome with a significant risk of gastric, but not colorectal, adenocarcinoma. We mapped the gene to 5q22 and found loss of the wild-type allele on 5q in fundic gland polyps from affected individuals. Whole-exome and -genome sequencing failed to find causal mutations but, through Sanger sequencing, we identified point mutations in APC promoter 1B that co-segregated with disease in all six families. The mutations reduced binding of the YY1 transcription factor and impaired activity of the APC promoter 1B in luciferase assays. Analysis of blood and saliva from carriers showed allelic imbalance of APC, suggesting that these mutations lead to decreased allele-specific expression in vivo. Similar mutations in APC promoter 1B occur in rare families with familial adenomatous polyposis (FAP). Promoter 1A is methylated in GAPPS and sporadic FGPs and in normal stomach, which suggests that 1B transcripts are more important than 1A in gastric mucosa. This might explain why all known GAPPS-affected families carry promoter 1B point mutations but only rare FAP-affected families carry similar mutations, the colonic cells usually being protected by the expression of the 1A isoform. Gastric polyposis and cancer have been previously described in some FAP-affected individuals with large deletions around promoter 1B. Our finding that GAPPS is caused by point mutations in the same promoter suggests that families with mutations affecting the promoter 1B are at risk of gastric adenocarcinoma, regardless of whether or not colorectal polyps are present.

Ulcerative Colitis Patients With Clostridium difficile are at Increased Risk of Death, Colectomy, and Postoperative Complications: A Population-Based Inception Cohort Study.

OBJECTIVES: Clostridium difficile (C. difficile) may worsen the prognosis of ulcerative colitis (UC). The objectives of this study were to: (i) validate the International Classification of Diseases-10 (ICD-10) code for C. difficile; (ii) determine the risk of C. difficile infection after diagnosis of UC; (iii) evaluate the effect of C. difficile infection on the risk of colectomy; and (iv) assess the association between C. difficile and postoperative complications. METHODS: The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated by comparing ICD-10 codes for C. difficile with stool toxin tests. A population-based surveillance cohort of newly diagnosed UC patients living in Alberta, Canada were identified from 2003 to 2009 (n=1,754). The effect of a C. difficile infection on colectomy was modeled using competing risk survival regression after adjusting for covariates. The effect of a C. difficile infection on postoperative complications was assessed using a mixed effects logistic regression model. RESULTS: The sensitivity, specificity, PPV, and NPV of the ICD-10 code for C. difficile were 82.1%, 99.4%, 88.4%, and 99.1%, respectively. The risk of C. difficile infection within 5 years of diagnosis with UC was 3.4% (95% confidence interval (CI): 2.5-4.6%). The risk of colectomy was higher among UC patients diagnosed with C. difficile (sub-hazard ratio (sHR)=2.36; 95% CI: 1.47-3.80). C. difficile increased the risk of postoperative complications (odds ratio=4.84; 95% CI: 1.28-18.35). C. difficile was associated with mortality (sHR=2.56 times; 95% CI: 1.28-5.10). CONCLUSIONS: C. difficile diagnosis worsens the prognosis of newly diagnosed patients with UC by increasing the risk of colectomy, postoperative complications, and death.

Lead Poisoning From a Ceramic Jug Presenting as Recurrent Abdominal Pain and Jaundice.

Lead poisoning may present with non-specific symptoms that may result in unnecessary investigations. We report a case of acute lead poisoning in a previously healthy 28-year-old man who presented with recurrent abdominal pain, jaundice, constipation, and weight loss. An extensive diagnostic work-up was completed with inconclusive results. A detailed history revealed an unusual source of lead exposure. Chelation therapy resulted in substantial clinical and biochemical improvement.

Gut microbiota manipulation with prebiotics in patients with non-alcoholic fatty liver disease: a randomized controlled trial protocol.

BACKGROUND: Evidence for the role of the gut microbiome in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) is emerging. Strategies to manipulate the gut microbiota towards a healthier community structure are actively being investigated. Based on their ability to favorably modulate the gut microbiota, prebiotics may provide an inexpensive yet effective dietary treatment for NAFLD. Additionally, prebiotics have established benefits for glucose control and potentially weight control, both advantageous in managing fatty liver disease. Our objective is to evaluate the effects of prebiotic supplementation, adjunct to those achieved with diet-induced weight loss, on heptic injury and liver fat, the gut microbiota, inflammation, glucose tolerance, and satiety in patients with NAFLD. METHODS/DESIGN: In a double blind, placebo controlled, parallel group study, adults (BMI ≥25) with confirmed NAFLD will be randomized to either a 16 g/d prebiotic supplemented group or isocaloric placebo group for 24 weeks (n = 30/group). All participants will receive individualized dietary counseling sessions with a registered dietitian to achieve 10 % weight loss. Primary outcome measures include change in hepatic injury (fibrosis and inflammation) and liver fat. Secondary outcomes include change in body composition, appetite and dietary adherence, glycemic and insulinemic responses and inflammatory cytokines. Mechanisms related to prebiotic-induced changes in gut microbiota (shot-gun sequencing) and their metabolic by-products (volatile organic compounds) and de novo lipogenesis (using deuterium incorporation) will also be investigated. DISCUSSION: There are currently no medications or surgical procedures approved for the treatment of NAFLD and weight loss via lifestyle modification remains the cornerstone of current care recommendations. Given that prebiotics target multiple metabolic impairments associated with NAFLD, investigating their ability to modulate the gut microbiota and hepatic health in patients with NAFLD is warranted. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02568605) Registered 30 September 2015.

Giardia duodenalis-induced alterations of commensal bacteria kill Caenorhabditis elegans: a new model to study microbial-microbial interactions in the gut.

Giardia duodenalis is the most common cause of parasitic diarrhea worldwide and a well-established risk factor for postinfectious irritable bowel syndrome. We hypothesized that Giardia-induced disruptions in host-microbiota interactions may play a role in the pathogenesis of giardiasis and in postgiardiasis disease. Functional changes induced by Giardia in commensal bacteria and the resulting effects on Caenorhabditis elegans were determined. Although Giardia or bacteria alone did not affect worm viability, combining commensal Escherichia coli bacteria with Giardia became lethal to C. elegans. Giardia also induced killing of C. elegans with attenuated Citrobacter rodentium espF and map mutant strains, human microbiota from a healthy donor, and microbiota from inflamed colonic sites of ulcerative colitis patient. In contrast, combinations of Giardia with microbiota from noninflamed sites of the same patient allowed for worm survival. The synergistic lethal effects of Giardia and E. coli required the presence of live bacteria and were associated with the facilitation of bacterial colonization in the C. elegans intestine. Exposure to C. elegans and/or Giardia altered the expression of 172 genes in E. coli. The genes affected by Giardia included hydrogen sulfide biosynthesis (HSB) genes, and deletion of a positive regulator of HSB genes, cysB, was sufficient to kill C. elegans even in the absence of Giardia. Our findings indicate that Giardia induces functional changes in commensal bacteria, possibly making them opportunistic pathogens, and alters host-microbe homeostatic interactions. This report describes the use of a novel in vivo model to assess the toxicity of human microbiota.

A novel method to identify fat malabsorption: the Serum Retinyl Palmitate Test.

BACKGROUND: Malabsorptive etiologies of chronic diarrhea are important to identify. The 72-h stool for fecal fat test (FFT), the gold standard for diagnosing fat malabsorption, is fraught with limitations that impact its reliability. Vitamin A, a fat-soluble vitamin, parallels the absorption of lipids. We assessed the feasibility and validate a novel clinical test, retinyl palmitate (RP), for the diagnosis of fat malabsorption, and to compare the results to the FFT. METHODS: Using a case-control study design, patients with chronic diarrhea secondary to suspected malabsorption, and healthy control subjects were identified. A Dietitian taught subjects to consume a 100g fat diet for the FFT with measurements of stool fat after 72-h. Serum levels of Vitamin A (retinol) and RP were measured by reversed-phase high pressure liquid chomatography. Two-way comparisons were made between the groups using 2 sample Wilcoxon rank-sum tests. RESULTS: Sixteen patients completed this study (8 cases and 8 control subjects). Fecal fat results were available for 15/16 patients. The sensitivity of the FFT was 100% (identified all cases), but the FFT specificity was 42%, as 4/7 control patients were identified as malabsorbers. Cases with short bowel syndrome had the lowest RP levels but this did not meet statistical significance. There was no significant difference for serum RP levels when comparing cases and control patients' AUC. CONCLUSIONS: Serum RP is useful to identify malabsorption, albeit in severe cases. Furthermore, we have shown that the 72-hour FFT has poor performance characteristics, highlighting the need for more useful diagnostics in identifying malabsorption.

Clostridium difficile infection worsens the prognosis of ulcerative colitis.

BACKGROUND: The impact of Clostridium difficile infections among ulcerative colitis (UC) patients is well characterized. However, there is little knowledge regarding the association between C difficile infections and postoperative complications among UC patients. OBJECTIVE: To determine whether C difficile infection is associated with undergoing an emergent colectomy and experiencing postoperative complications. METHODS: The present population-based case-control study identified UC patients admitted to Calgary Health Zone hospitals for a flare between 2000 and 2009. C difficile toxin tests ordered in hospital or 90 days before hospital admission were provided by Calgary Laboratory Services (Calgary, Alberta). Hospital records were reviewed to confirm diagnoses and to extract clinical data. Multivariate logistic regression analyses were performed among individuals tested for C difficile to examine the association between C difficile infection and emergent colectomy and diagnosis of any postoperative complications and, secondarily, an infectious postoperative complication. Estimates were presented as adjusted ORs with 95% CIs. RESULTS: C difficile was tested in 278 (58%) UC patients and 6.1% were positive. C difficile infection was associated with an increased risk for emergent colectomy (adjusted OR 3.39 [95% CI 1.02 to 11.23]). Additionally, a preoperative diagnosis of C difficile was significantly associated with the development of postoperative infectious complications (OR 4.76 [95% CI 1.10 to 20.63]). CONCLUSION: C difficile diagnosis worsened the prognosis of UC by increasing the risk of colectomy and postoperative infectious complications following colectomy. Future studies are needed to explore whether early detection and aggressive management of C difficile infection will improve UC outcomes.

VSL#3 ® probiotic therapy does not reduce portal pressures in patients with decompensated cirrhosis.

BACKGROUND & AIMS: In patients with decompensated cirrhosis, bacterial translocation can contribute to splanchnic vasodilatation, decreased effective circulating volume, and portal hypertension. The primary objective of this randomized, double blind placebo controlled trial was to evaluate the effect of the probiotic VSL#3(®) on the hepatic venous pressure gradient (HVPG). METHODS: Seventeen patients with decompensated cirrhosis and an HVPG of ≥ 10 mmHg were randomized to receive 2 months of VSL#3(®) or an identical placebo. HVPG, endotoxin, interleukin (IL)-6, IL-8, IL-10, renin, aldosterone, nitric oxide and stool microbiota were measured at baseline and study end. RESULTS: Two of the 17 patients were taken off the trial before completion (one for alcohol abuse and the second for SBP - both in placebo arm). Data were analysed on the remaining 15 patients. The median model for end-stage liver disease score was 12, and 80% of patients had Child Pugh B disease. The treatment arm had a greater decrease in HVPG from baseline to study end than the placebo arm (median change from baseline -11.6% vs +2.8%), although this reduction was not statistically significant in either group. There was a significant reduction in the plasma aldosterone level in the VSL#3(®) group, but no significant changes in the other measured parameters, including the stool microflora analysis. CONCLUSIONS: Within the limitations of our sample size, VSL#3(®) therapy does not appear to have a significant impact on portal pressure reduction in patients with decompensated cirrhosis.

Risk of surgery for inflammatory bowel diseases has decreased over time: a systematic review and meta-analysis of population-based studies.

BACKGROUND & AIMS: The inflammatory bowel diseases (IBDs) are chronic diseases that often require surgery. However, the risk of requirement of surgery over time has not been well characterized. We performed a systematic review and meta-analysis to establish the cumulative risk of surgery among patients with IBD and evaluated how this risk has changed over time. METHODS: We searched Medline, EMBASE, PubMed, and conference proceedings (2009-2012) on May 8, 2013, for terms related to IBD and intestinal surgery. Two reviewers screened 8338 unique citations to identify 486 for full-text review. The analysis included population-based studies published as articles (n = 26) and abstracts (n = 4) that reported risks of surgery at 1, 5, or 10 years after a diagnosis of Crohn's disease and/or ulcerative colitis. The trend in risk of surgery over time was analyzed by meta-regression using mixed-effect models. RESULTS: Based on all population-based studies, the risk of surgery 1, 5, and 10 years after diagnosis of Crohn's disease was 16.3% (95% confidence interval [CI], 11.4%-23.2%), 33.3% (95% CI, 26.3%-42.1%), and 46.6% (95% CI, 37.7%-57.7%), respectively. The risk of surgery 1, 5, and 10 years after diagnosis of ulcerative colitis was 4.9% (95% CI, 3.8%-6.3%), 11.6% (95% CI, 9.3%-14.4%), and 15.6% (95% CI, 12.5%-19.6%), respectively. The risk of surgery 1, 5, and 10 years after diagnosis of Crohn's disease and 1 and 10 years after diagnosis of ulcerative colitis has decreased significantly over the past 6 decades (P < .05). CONCLUSIONS: Based on systematic review and meta-analysis of population-based studies, the risk of intestinal surgery among patients with IBD has decreased over the past 6 decades.

Environmental particulate matter induces murine intestinal inflammatory responses and alters the gut microbiome.

BACKGROUND: Particulate matter (PM) is a key pollutant in ambient air that has been associated with negative health conditions in urban environments. The aim of this study was to examine the effects of orally administered PM on the gut microbiome and immune function under normal and inflammatory conditions. METHODS: Wild-type 129/SvEv mice were gavaged with Ottawa urban PM10 (EHC-93) for 7-14 days and mucosal gene expression analyzed using Ingenuity Pathways software. Intestinal permeability was measured by lactulose/mannitol excretion in urine. At sacrifice, segments of small and large intestine were cultured and cytokine secretion measured. Splenocytes were isolated and incubated with PM10 for measurement of proliferation. Long-term effects of exposure (35 days) on intestinal cytokine expression were measured in wild-type and IL-10 deficient (IL-10(-/-)) mice. Microbial composition of stool samples was assessed using terminal restriction fragment length polymorphism. Short chain fatty acids were measured in caecum. RESULTS: Short-term treatment of wild-type mice with PM10 altered immune gene expression, enhanced pro-inflammatory cytokine secretion in the small intestine, increased gut permeability, and induced hyporesponsiveness in splenocytes. Long-term treatment of wild-type and IL-10(-/-) mice increased pro-inflammatory cytokine expression in the colon and altered short chain fatty acid concentrations and microbial composition. IL-10(-/-) mice had increased disease as evidenced by enhanced histological damage. CONCLUSIONS: Ingestion of airborne particulate matter alters the gut microbiome and induces acute and chronic inflammatory responses in the intestine.

Fecal microbiome and volatile organic compound metabolome in obese humans with nonalcoholic fatty liver disease.

BACKGROUND & AIMS: The histopathology of nonalcoholic fatty liver disease (NAFLD) is similar to that of alcoholic liver disease. Colonic bacteria are a source of many metabolic products, including ethanol and other volatile organic compounds (VOC) that may have toxic effects on the human host after intestinal absorption and delivery to the liver via the portal vein. Recent data suggest that the composition of the gut microbiota in obese human beings is different from that of healthy-weight individuals. The aim of this study was to compare the colonic microbiome and VOC metabolome of obese NAFLD patients (n = 30) with healthy controls (n = 30). METHODS: Multitag pyrosequencing was used to characterize the fecal microbiota. Fecal VOC profiles were measured by gas chromatography-mass spectrometry. RESULTS: There were statistically significant differences in liver biochemistry and metabolic parameters in NAFLD. Deep sequencing of the fecal microbiome revealed over-representation of Lactobacillus species and selected members of phylum Firmicutes (Lachnospiraceae; genera, Dorea, Robinsoniella, and Roseburia) in NAFLD patients, which was statistically significant. One member of phylum Firmicutes was under-represented significantly in the fecal microbiome of NAFLD patients (Ruminococcaceae; genus, Oscillibacter). Fecal VOC profiles of the 2 patient groups were different, with a significant increase in fecal ester compounds observed in NAFLD patients. CONCLUSIONS: A significant increase in fecal ester VOC is associated with compositional shifts in the microbiome of obese NAFLD patients. These novel bacterial metabolomic and metagenomic factors are implicated in the etiology and complications of obesity.

The human gut microbiome: current knowledge, challenges, and future directions.

The Human Genome Project was completed a decade ago, leaving a legacy of process, tools, and infrastructure now being turned to the study of the microbes that reside in and on the human body as determinants of health and disease, and has been branded "The Human Microbiome Project." Of the various niches under investigation, the human gut houses the most complex and abundant microbial community and is an arena for important host-microbial interactions that have both local and systemic impact. Initial studies of the human microbiome have been largely descriptive, a testing ground for innovative molecular techniques and new hypotheses. Methods for studying the microbiome have quickly evolved from low-resolution surveys of microbial community structure to high-definition description of composition, function, and ecology. Next-generation sequencing technologies combined with advanced bioinformatics place us at the doorstep of revolutionary insight into the composition, capability, and activity of the human intestinal microbiome. Renewed efforts to cultivate previously "uncultivable" microbes will be important to the overall understanding of gut ecology. There remain numerous methodological challenges to the effective study and understanding of the gut microbiome, largely relating to study design, sample collection, and the number of predictor variables. Strategic collaboration of clinicians, microbiologists, molecular biologists, computational scientists, and bioinformaticians is the ideal paradigm for success in this field. Meaningful interpretation of the gut microbiome requires that host genetic and environmental influences be controlled or accounted for. Understanding the gut microbiome in healthy humans is a foundation for discovering its influence in various important gastrointestinal and nutritional diseases (eg, inflammatory bowel disease, diabetes, and obesity), and for rational translation to human health gains.

Assessment of variables associated with smoking cessation in Crohn's disease.

BACKGROUND: Patients with Crohn's disease (CD) who smoke have a more complicated disease course. AIMS: Our primary objective was to assess smoking related variables that were associated with smoking cessation versus continued smoking in patients with CD. METHODS: A multi-center study identified CD patients who were seen at the University of Chicago and University of Calgary IBD clinics. Patients were categorized into three subgroups: lifetime non-smokers, current smokers, or ex-smokers. Participants completed questionnaires assessing their cigarette smoking behavior. Current smokers were prospectively followed for 6 months to assess smoking status and attempts to quit. Logistic regression analysis was performed to identify factors associated with smoking cessation. RESULTS: Three hundred patients were enrolled with 148 identifying themselves as lifetime non-smokers, 70 as current smokers, and 82 as ex-smokers. Patients who reported their first cigarette within 5 min of waking were more likely to be current smokers (OR = 21; 95% CI 3.94-107.3) as compared to patients who waited greater than 60 min. Current smokers were more likely to have one or more household members who smoked compared to ex-smokers (P < 0.05). Nearly half (49%) of the current smokers were in the precontemplation stage of change (i.e. no intention to quit smoking). At the 6-month follow-up, only 11% reported they quit smoking. CONCLUSIONS: Patients who report a short time to first cigarette in the morning may have more difficulty in smoking cessation. Current smokers were more likely to have another smoker in the household compared to ex-smokers. Current smokers had low levels of motivation to quit smoking and consequently with no intervention, very few quit 6 months after the baseline assessment.