Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal tract that is associated with changes in the gut microbiome. Here, we sought to identify ...strain-specific functional correlates with IBD outcomes.
We performed metagenomic sequencing of monthly stool samples from 20 IBD patients and 12 controls (266 total samples). These were taxonomically profiled with MetaPhlAn2 and functionally profiled using HUMAnN2. Differentially abundant species were identified using MaAsLin and strain-specific pangenome haplotypes were analyzed using PanPhlAn.
We found a significantly higher abundance in patients of facultative anaerobes that can tolerate the increased oxidative stress of the IBD gut. We also detected dramatic, yet transient, blooms of Ruminococcus gnavus in IBD patients, often co-occurring with increased disease activity. We identified two distinct clades of R. gnavus strains, one of which is enriched in IBD patients. To study functional differences between these two clades, we augmented the R. gnavus pangenome by sequencing nine isolates from IBD patients. We identified 199 IBD-specific, strain-specific genes involved in oxidative stress responses, adhesion, iron-acquisition, and mucus utilization, potentially conferring an adaptive advantage for this R. gnavus clade in the IBD gut.
This study adds further evidence to the hypothesis that increased oxidative stress may be a major factor shaping the dysbiosis of the microbiome observed in IBD and suggests that R. gnavus may be an important member of the altered gut community in IBD.
Fecal microbiota transplantation (FMT) has been shown to be safe and effective in treating refractory or relapsing C. difficile infection (CDI), but its use has been limited by practical barriers. We ...recently reported a small preliminary feasibility study using orally administered frozen fecal capsules. Following these early results, we now report our clinical experience in a large cohort with structured follow-up.
We prospectively followed a cohort of patients with recurrent or refractory CDI who were treated with frozen, encapsulated FMT at our institution. The primary endpoint was defined as clinical resolution whilst off antibiotics for CDI at 8 weeks after last capsule ingestion. Safety was defined as any FMT-related adverse event grade 2 or above.
Overall, 180 patients aged 7-95 years with a minimal follow-up of 8 weeks were included in the analysis. CDI resolved in 82 % of patients after a single treatment, rising to a 91 % cure rate with two treatments. Three adverse events Grade 2 or above, deemed related or possibly related to FMT, were observed.
We confirm the effectiveness and safety of oral administration of frozen encapsulated fecal material, prepared from unrelated donors, in treating recurrent CDI. Randomized studies and FMT registries are still needed to ascertain long-term safety.
Mortality concern is a frequent driver of care seeking in patients with irritable bowel syndrome (IBS). Data on mortality in IBS are scarce, and population-based studies have been limited in size. We ...examined mortality in IBS.
A nationwide, matched, population-based cohort study was conducted in Sweden. We identified 45,524 patients undergoing a colorectal biopsy at any of Sweden's 28 pathology departments and with a diagnosis of IBS from 2002 to 2016 according to the National Patient Register, a nationwide registry of inpatient and outpatient specialty care. We compared the mortality risk between these individuals with IBS and age- and sex-matched reference individuals (n = 217,316) from the general population and siblings (n = 53,228). In separate analyses, we examined the role of mucosal appearance for mortality in IBS. Finally, we examined mortality in 41,427 patients with IBS not undergoing a colorectal biopsy. Cox regression estimated hazard ratios (HRs) for death.
During follow-up, there were 3,290 deaths in individuals with IBS (9.4/1,000 person-years) compared with 13,255 deaths in reference individuals (7.9/1,000 person-years), resulting in an HR of 1.10 (95% confidence interval CI = 1.05-1.14). After adjustment for confounders, IBS was not linked to mortality (HR = 0.96; 95% CI = 0.92-1.00). The risk estimates were neutral when patients with IBS were compared with their siblings. The underlying mucosal appearance on biopsy had only a marginal impact on mortality, and patients with IBS not undergoing a colorectal biopsy were at no increased risk of death (HR = 1.02; 95% CI = 0.99-1.06).
IBS does not seem to confer an increased risk of death.
Type 2 diabetes (T2D) is a risk factor for hepatocellular carcinoma (HCC). However, it is unknown whether T2D duration or additional metabolic comorbidities further contribute to HCC risk. From the ...Nurses' Health Study (NHS), 120,826 women were enrolled in 1980, and from the Health Professionals Follow‐up Study (HPFS), 50,284 men were enrolled in 1986 and followed through 2012. Physician‐diagnosed T2D was ascertained at baseline and updated biennially. Cox proportional hazards regression models were used to calculate age‐ and multivariable‐adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for incident HCC. Over 32 years of follow‐up (4,488,410 person‐years), we documented 112 cases of HCC (69 women, 43 men). T2D was associated with an increased HCC risk (multivariable HR, 4.59; 95% CI, 2.98‐7.07), as was an increasing T2D duration (Ptrend < 0.001). Compared to nondiabetics, the multivariable HRs for HCC were 2.96 (95% CI, 1.57‐5.60) for 0‐<2 years; 6.08 (95% CI, 2.96‐12.50) for 2‐<10 years; and 7.52 (95% CI, 3.88‐14.58) for ≥10 years. Increasing number of metabolic comorbidities (T2D, obesity, hypertension, and dyslipidemia) was associated with increased HCC risk (Ptrend < 0.001); compared to individuals without metabolic comorbidity, those with four metabolic comorbidities had an 8.1‐fold increased HCC risk (95% CI, 2.48‐26.7). In T2D, neither insulin use nor oral hypoglycemic use was significantly associated with HCC risk (HR, 2.04 95% CI, 0.69‐6.09 and HR, 1.45 95% CI, 0.69‐3.07, respectively). Conclusion: T2D is independently associated with increased risk for HCC in two prospective cohorts of U.S. men and women. This risk is enhanced with prolonged diabetes duration and with comorbid metabolic conditions, suggesting the importance of insulin resistance in the pathogenesis of HCC. (Hepatology 2018;67:1797‐1806)
Long-term data on the influence of cigarette smoking, especially cessation, on the risk of Crohn's disease (CD) and ulcerative colitis (UC) are limited.
We conducted a prospective study of 229,111 ...women in the Nurses' Health Study (NHS) and Nurses' Health Study II (NHS II). Biennially, we collected updated data on cigarette smoking, other risk factors, and diagnoses of CD or UC confirmed by medical record review.
Over 32 years in NHS and 18 years in NHS II, we documented 336 incident cases of CD and 400 incident cases of UC. Compared with never smokers, the multivariate hazard ratio (HR) of CD was 1.90 (95% confidence interval (CI), 1.42-2.53) among current smokers and 1.35 (95% CI, 1.05-1.73) among former smokers. Increasing pack-years was associated with increasing risk of CD (Ptrend < 0.0001), whereas smoking cessation was associated with an attenuation of risk. By contrast, the multivariate HR of UC was 0.86 (95% CI, 0.61-1.20) among current smokers and 1.56 (95% CI, 1.26-1.93) among former smokers. The risk of UC was significantly increased within 2-5 years of smoking cessation (HR, 3.06; 95% CI, 2.00-4.67) and remained persistently elevated over 20 years.
Current smoking is associated with an increased risk of CD, but not UC. By contrast, former smoking is associated with an increased risk of UC, with risk persisting over two decades after cessation.
Summary
Background
There appear to be differences in risk factor profiles for IBD between Asia‐Pacific and Western populations, which might suggest idiosyncrasies in pathogenesis. Recently, sex‐based ...differences in IBD according to the age of diagnosis have been described in Western populations.
Aim
To identify whether sex‐based differences in IBD incidence similarly exist across the age spectrum for Asia‐Pacific populations.
Methods
We identified Asia‐Pacific population‐based cohorts where IBD incidence data stratified by sex were available for the full age spectrum. Cohorts were included only if IBD diagnoses were confirmed and validated. We calculated incidence rate ratios of Crohn's disease (CD) and ulcerative colitis (UC) according to age and compared differences between males and females using random‐effects meta‐analysis.
Results
Among 567.8 million people from 11 Asia‐Pacific countries/provinces/nations, we identified 10 553 incident CD cases (7060 males; 3493 females) and 16 946 incident UC cases (9754 males; 7192 females). Starting in early adolescence until age 50 years, there was a 36%‐64% higher incidence of CD in males vs females (P < 0.001). UC incidence ranged from 20%‐42% higher in males vs females in the age groups between 15 and 65 years (P < 0.05).
Conclusions
In a pooled analysis of population‐based studies from the Asia‐Pacific region, we found a male predominance of both CD and UC for the majority of the age spectrum from adolescence to middle/late‐middle age. Additional studies are needed to clarify biological and nonbiological determinants of sex differences in IBD, which might be distinct between Asia‐Pacific and Western populations.
Studies have reported associations between proton pump inhibitor (PPI) use and dementia. However, data are lacking on long-term PPI use and cognitive function. We therefore examined associations ...between PPI use and performance in tests of cognitive function. Because of shared clinical indications, we examined associations for H2 receptor antagonists (H2RAs) as a secondary aim.
We used prospectively collected data on medication use and other potential risk factors from 13,864 participants in the Nurses’ Health Study II who had completed a self-administered computerized neuropsychological test battery. Multivariable linear regression models were used to examine associations between medication use and composite scores of psychomotor speed and attention, learning and working memory, and overall cognition.
We observed a modest association between duration of PPI use and scores for psychomotor speed and attention (mean score difference for PPI use of 9−14 years vs never users, −0.06; 95% confidence interval, −0.11 to 0.00; Ptrend = .03). After controlling for H2RA use, the magnitude of this score difference was attenuated. Among individuals who did not use PPIs regularly, duration of H2RA use was associated with poorer cognitive scores, with the strongest association apparent for learning and working memory (mean score difference for H2RA users of 9−14 years vs never users, −0.20; 95% confidence interval, −0.32 to −0.08; Ptrend < .001).
In an analysis of data from the Nurses’ Health Study II, we did not observe a convincing association between PPI use and cognitive function. Our data do not support the suggestion that PPI use increases dementia risk. Because our primary hypothesis related to PPI use, our findings for H2RAs should be interpreted with caution.
Diet plays a role in the pathogenesis of Crohn’s disease (CD) and ulcerative colitis (UC). Dietary zinc may influence risk of disease through effects on autophagy, innate and adaptive immune response ...and maintenance of the intestinal barrier.
We analysed data from 170 776 women from the Nurses Health Study I and Nurses Health Study II, who were followed for 26 years. Zinc intake was assessed using semi-quantitative food frequency questionnaires administered every 4 years. Incident CD and UC were ascertained by medical record review. Cox proportional hazards models adjusting for potential confounders determined the independent association between zinc intake and incident disease.
Over 3 317 550 person-years (p-y) of follow-up, we identified 269 incident cases of CD and 338 incident cases of UC. Zinc intake ranged from 9 mg/day in the lowest quintile to 27 mg/day in the highest quintile. Compared with women with the lowest quintile of intake, the multivariate hazard ratios (HR) for CD were 0.92 95% confidence interval (CI), 0.65 – 1.29) for women in the second quintile of intake, 0.60 (95% CI, 0.40 – 0.89) for the third quintile, 0.57 (95% CI, 0.38 – 0.86) for fourth quintile and 0.74 (95% CI, 0.50 – 1.10) for the highest quintile (Ptrend = 0.003). The association was stronger for dietary zinc (HR 0.63, 95% CI, 0.43 – 0.93, comparing extreme quintiles) than for zinc intake from supplements. Neither dietary nor supplemental zinc modified risk of UC.
In two large prospective cohorts of women, intake of zinc was inversely associated with risk of CD but not UC.
Although evidence suggests a persistently decreased risk of colorectal cancer for up to 10 years among individuals with a negative endoscopic biopsy result (i.e., normal mucosa), concerns have been ...raised about other long-term health outcomes among these individuals. In this study, we aimed to explore the long-term risk of inflammatory bowel disease (IBD) after an endoscopic biopsy with normal mucosa.
In the present nationwide cohort study, we identified all individuals in Sweden with a lower or upper gastrointestinal (GI) biopsy of normal mucosa during 1965 to 2016 (exposed, n = 200,495 and 257,192 for lower and upper GI biopsy, respectively), their individually matched population references (n = 989,484 and 1,268,897), and unexposed full siblings (n = 221,179 and 274,529). Flexible parametric model estimated hazard ratio (HR) as an estimate of the association between a GI biopsy of normal mucosa and IBD as well as cumulative incidence of IBD, with 95% confidence interval (CI). The first 6 months after GI biopsy were excluded to avoid detection bias, surveillance bias, or reverse causation. During a median follow-up time of approximately 10 years, 4,853 individuals with a lower GI biopsy of normal mucosa developed IBD (2.4%) compared to 0.4% of the population references. This corresponded to an incidence rate (IR) of 20.39 and 3.39 per 10,000 person-years in the respective groups or 1 extra estimated IBD case among 37 exposed individuals during the 30 years after normal GI biopsy. The exposed individuals had a persistently higher risk of overall IBD (average HR = 5.56; 95% CI: 5.28 to 5.85), ulcerative colitis (UC, average HR = 5.20; 95% CI: 4.85 to 5.59) and Crohn's disease (CD, average HR = 6.99; 95% CI: 6.38 to 7.66) than their matched population references. In the sibling comparison, average HRs were 3.27 (3.05 to 3.51) for overall IBD, 3.27 (2.96 to 3.61) for UC, and 3.77 (3.34 to 4.26) for CD. For individuals with an upper GI biopsy of normal mucosa, the average HR of CD was 2.93 (2.68 to 3.21) and 2.39 (2.10 to 2.73), compared with population references and unexposed full siblings, respectively. The increased risk of IBD persisted at least 30 years after cohort entry. Study limitations include lack of data on indications for biopsy and potential residual confounding from unmeasured risk or protective factors for IBD.
Endoscopic biopsy with normal mucosa was associated with an elevated IBD incidence for at least 30 years. This may suggest a substantial symptomatic period of IBD and incomplete diagnostic examinations in patients with early IBD.
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