Kathleen M. Schieffer

Review article: the pathogenesis of pouchitis

A total proctocolectomy followed by ileal pouch‐anal anastomosis is a potentially curative surgery for ulcerative colitis or familial adenomatous polyposis. About 5–35% of patients with ulcerative colitis and 0–11% of patients with familial adenomatous polyposis develop subsequent inflammation of the ileal pouch termed pouchitis.

Bacterial and Fungal Microbiota Changes Distinguish C. difficile Infection from Other Forms of Diarrhea: Results of a Prospective Inpatient Study

This study sought to characterize the bacterial and fungal microbiota changes associated with Clostridium difficile infection (CDI) among inpatients with diarrhea, in order to further explain the pathogenesis of this infection as well as to potentially guide new CDI therapies. Twenty-four inpatients with diarrhea were enrolled, 12 of whom had CDI. Each patient underwent stool testing for CDI prior to being treated with difficile-directed antibiotics, when appropriate. Clinical data was obtained from the medical record, while each stool sample underwent 16S rRNA and ITS sequencing for bacterial and fungal elements. An analysis of microbial community structures distinct to the CDI population was also performed. The results demonstrated no difference between the CDI and non-CDI cohorts with respect to any previously reported CDI risk factors. Butyrogenic bacteria were enriched in both CDI and non-CDI patients. A previously unreported finding of increased numbers of Akkermansia muciniphila in CDI patients was observed, an organism which degrades mucin and which therefore may provide a selective advantage toward CDI. Fungal elements of the genus Penicillium were predominant in CDI; these organisms produce antibacterial chemicals which may resist recovery of healthy microbiota. The most frequent CDI microbial community networks involved Peptostreptococcaceae and Enterococcus, with decreased population density of Bacteroides. These results suggest that the development of CDI is associated with microbiota changes which are consistently associated with CDI in human subjects. These gut taxa contribute to the intestinal dysbiosis associated with C. difficile infection.

Association of Iron Deficiency Anemia With Hearing Loss in US Adults

Importance Hearing loss in the US adult population is linked to hospitalization, poorer self-reported health, hypertension, diabetes, and tobacco use. Because iron deficiency anemia (IDA) is a common and easily correctable condition, further understanding of the association between IDA and all types of hearing loss in a population of US adults may help to open new possibilities for early identification and appropriate treatment. Objective To evaluate the association between sensorineural hearing loss (SNHL) and conductive hearing loss and IDA in adults aged 21 to 90 years in the United States. Design, Setting, and Participants The prevalence of IDA and hearing loss (International Classification of Diseases, Ninth Revision codes 389.1 [SNHL], 389.0 [conductive hearing loss], and 389 [combined hearing loss]) was identified in this retrospective cohort study at the Penn State Milton S. Hershey Medical Center, Hershey, Pennsylvania. Iron deficiency anemia was determined by low hemoglobin and ferritin levels for age and sex in 305 339 adults aged 21 to 90 years. Associations between hearing loss and IDA were evaluated using &khgr;2 testing, and logistic regression was used to model the risk of hearing loss among those with IDA. The study was conducted from January 1, 2011, to October 1, 2015. Main Outcomes and Measures Hearing loss. Results Of 305 339 patients in the study population, 132 551 were men (43.4%); mean (SD) age was 50.1 (18.5) years. There was a 1.6% (n = 4807) prevalence of combined hearing loss and 0.7% (n = 2274) prevalence of IDA. Both SNHL (present in 26 of 2274 individuals [1.1%] with IDA; P = .005) and combined hearing loss (present in 77 [3.4%]; P < .001) were significantly associated with IDA. Logistic regression analysis confirmed increased odds of SNHL (adjusted odds ratio [OR], 1.82; 95% CI, 1.18-2.66) and combined hearing loss (adjusted OR, 2.41; 95% CI, 1.90-3.01) among adults with IDA, after adjusting for sex. Conclusions and Relevance Iron deficiency anemia was associated with SNHL and combined hearing loss in a population of adult patients. Further research is needed to better understand the potential links between IDA and hearing loss and whether screening and treatment of IDA in adults could have clinical implications in patients with hearing loss.

The Relationship Between Iron Deficiency Anemia and Sensorineural Hearing Loss in the Pediatric and Adolescent Population

Purpose A correlation between iron deficiency anemia (IDA) and sudden sensorineural hearing loss (SNHL) was described in adults. In this study, we examined if there is a relationship between IDA and hearing loss in the pediatric population. Method This was a retrospective cohort study of data collected from the Informatics for Integrating Biology and the Bedside database from 2011 to 2016. Children and adolescents 4-21 years old seen at Penn State Milton S. Hershey Medical Center, Hershey, PA, were examined for hearing loss and IDA status. Hearing loss was determined by International Classification of Disease-9 and -10 codes, and IDA was determined by both low hemoglobin and serum ferritin levels for age and sex. Results We identified 20,113 patients. Prevalence of hearing loss and IDA was 1.7% and 2.3%, respectively. The prevalence of all hearing loss was 3.0% in the IDA cohort and 1.7% in those without IDA. Children and adolescents with IDA are at increased odds of developing SNHL (adjusted odds ratio: 3.67, 95% CI [1.60-7.30]). Conclusions Children with IDA demonstrate increased likelihood of SNHL. Although correction of IDA in those with hearing loss has yet to be linked to improvements in hearing outcomes, screening for and correcting IDA among pediatric patients will positively affect overall health status. Supplemental Material: https://doi.org/10.23641/asha.5087071.

The Microbial Ecosystem Distinguishes Chronically Diseased Tissue from Adjacent Tissue in the Sigmoid Colon of Chronic, Recurrent Diverticulitis Patients

Diverticular disease is commonly associated with the older population in the United States. As individual’s age, diverticulae, or herniation of the mucosa through the colonic wall, develop. In 10–25% of individuals, the diverticulae become inflamed, resulting in diverticulitis. The gut ecosystem relies on the interaction of bacteria and fungi to maintain homeostasis. Although bacterial dysbiosis has been implicated in the pathogenesis of diverticulitis, associations between the microbial ecosystem and diverticulitis remain largely unstudied. This study investigated how the cooperative network of bacteria and fungi differ between a diseased area of the sigmoid colon chronically affected by diverticulitis and adjacent non-affected tissue. To identify mucosa-associated microbes, bacterial 16S rRNA and fungal ITS sequencing were performed on chronically diseased sigmoid colon tissue (DT) and adjacent tissue (AT) from the same colonic segment. We found that Pseudomonas and Basidiomycota OTUs were associated with AT while Microbacteriaceae and Ascomycota were enriched in DT. Bipartite co-occurrence networks were constructed for each tissue type. The DT and AT networks were distinct for each tissue type, with no microbial relationships maintained after intersection merge of the groups. Our findings indicate that the microbial ecosystem distinguishes chronically diseased tissue from adjacent tissue.

RNA-seq implicates deregulation of the immune system in the pathogenesis of diverticulitis

Individuals with diverticula or outpouchings of the colonic mucosa and submucosa through the colonic wall have diverticulosis, which is usually asymptomatic. In 10-25% of individuals, the diverticula become inflamed, resulting in diverticulitis. Very little is known about the pathophysiology or gene regulatory pathways involved in the development of diverticulitis. To identify these pathways, we deep sequenced RNAs isolated from full-thickness sections of sigmoid colon from diverticulitis patients and control individuals. Specifically for diverticulitis cases, we analyzed tissue adjacent to areas affected by chronic disease. Since the tissue was collected during elective sigmoid resection, the disease was in a quiescent state. A comparison of differentially expressed genes found that gene ontology (GO) pathways associated with the immune response were upregulated in diverticulitis patients compared with nondiverticulosis controls. Next, weighted gene coexpression network analysis was performed to identify the interaction among coexpressed genes. This analysis revealed RASAL3, SASH3, PTPRC, and INPP5D as hub genes within the brown module eigengene, which highly correlated (r = 0.67, P = 0.0004) with diverticulitis. Additionally, we identified elevated expression of downstream interacting genes. In summary, transcripts associated with the immune response were upregulated in adjacent tissue from the sigmoid colons of chronic, recurrent diverticulitis patients. Further elucidating the genetic or epigenetic mechanisms associated with these alterations can help identify those at risk for chronic disease and may assist in clinical decision management.NEW & NOTEWORTHY By using an unbiased approach to analyze transcripts expressed in unaffected colonic tissues adjacent to those affected by chronic diverticulitis, our study implicates that a defect in the immune response may be involved in the development of the disease. This finding expands on the current data that suggest the pathophysiology of diverticulitis is mediated by dietary, age, and obesity-related factors. Further characterizing the immunologic differences in diverticulitis may better inform clinical decision-making.

Reduced total serum bilirubin levels are associated with ulcerative colitis

Chronic inflammation associated with inflammatory bowel disease (IBD) results in increased oxidative stress that damages the colonic microenvironment. Low levels of serum bilirubin, an endogenous antioxidant, have been associated with increased risk for Crohn’s disease (CD). Therefore, the aim of this study was to examine whether total serum bilirubin levels are associated with ulcerative colitis (UC). We identified a retrospective case-control population (n = 6,649) from a single tertiary care center, Penn State Hershey Medical Center (PSU) and a validation cohort (n = 1,996) from Virginia Commonwealth University Medical Center (VCU). Cases were age- and sex-matched to controls (PSU: CD n = 254, UC n = 187; VCU: CD n = 233, UC n = 124). Total serum bilirubin levels were obtained from de-identified medical records and segregated into quartiles. Logistic regression analysis was performed on each quartile of total serum bilirubin compared to the last quartile (highest bilirubin levels) to determine the association of total serum bilirubin with UC. Similar to CD patients, UC patients demonstrated reduced levels of total serum bilirubin compared to controls at PSU and VCU. The lowest quartile of total serum bilirubin was independently associated with UC for the PSU (OR: 1.98 [95% CI: 1.09–3.63]) and VCU cohorts (OR: 6.07 [95% CI: 3.01–12.75]). Lower levels of the antioxidant bilirubin may reduce the capability of UC patients to remove reactive oxygen species leading to an increase in intestinal injury. Therapeutics that reduce oxidative stress may be beneficial for these patients.

Pathophysiology of diverticular disease

ABSTRACT Introduction: Inflammation of diverticula, or outpouchings of the colonic mucosa and submucosa through the muscularis layer, leads to diverticulitis. The development of diverticular disease, encompassing both diverticulosis and diverticulitis, is a result of genetic predisposition, lifestyle, and environmental factors, including the microbiome. Areas covered: Previous reports implicated genetic predisposition, environmental factors, and colonic dysmotility in diverticular disease. Recent studies have associated specific host immune responses and the microbiome as contributors to diverticulitis. To review pertinent literature describing pathophysiological factors associated with diverticulosis or diverticulitis, we searched the PubMed database (March 2018) for articles considering the role of colonic architecture, genetic predisposition, environment, colonic motility, immune response, and the microbiome. Expert commentary: In the recent years, research into the molecular underpinnings of diverticular disease has enhanced our understanding of diverticular disease pathogenesis. Although acute uncomplicated diverticulitis is treated with broad spectrum antibiotics, evaluation of the microbiome has been limited and requires further comprehensive studies. Evidence suggests that a deregulation of the host immune response is associated with both diverticulosis and diverticulitis. Further examining these pathways may reveal proteins that can be therapeutic targets or aid in identifying biological determinants of clinical or surgical decision making.

Associations between Polymorphisms and Haplotypes in the UDPGlucuronosylTransferase 1A Gene Family with Lung Cancer Risk

Title: Associations between polymorphisms and haplotypes in the UDP-Glucuronosyl transferase 1A gene family with lung cancer risk. Background: Over 5,000 compounds have been identified in cigarette smoke, of which 73 are considered carcinogenic to either laboratory animals or humans by the International Agency for Research on Cancer. The UDPglucuronsyl transferases (UGTs) are Phase II drug-metabolizing enzymes that catalyze the metabolism of several cigarette smoke carcinogens for excretion. There are hundreds of genetic variants that span the nine genes in the UGT1A gene cluster, but the effect of UGT1A polymorphisms on lung cancer risk has not been studied in American Caucasians. This study hypothesized that UGT1A variants, either individually or as a haplotype, would be associated with lung cancer risk in American Caucasians. Methods and Findings: To examine the effect of genetic variation in the nine UGT1A genes on lung cancer risk, a comprehensive association and haplotype study was conducted using American Caucasian lung cancer cases and matched healthy controls on ninety-six tagSNPs. Known lung cancer risk factors including age, sex, smoking status, and pack-years of smoking were controlled for in all analyses. Multiple SNPs in the UGT1A gene cluster were associated with lung cancer risk in various stratified analyses before a multiple testing correction was applied. A significant association was found between two haplotypes in the UGT1A haplotype block 2 (rs7569014, rs7421795, rs1817154) and small cell carcinoma risk in American Caucasians. Multiple SNPs were found to affect lung cancer risk that did not remain significant following multiple testing correction. The UGT1A haplotype block 2 may be associated with small cell lung carcinoma. However, single SNP association studies did not yield significant results after multiple testing correction. Conclusions: UGT1A variants may play only a minor role in other lung cancer risk in American Caucasians; however, this needs to be confirmed in larger studies.