Publications by authors named "Ece A Mutlu"

40 Publications

Patient Perspectives on Medical Trauma Related to Inflammatory Bowel Disease.

J Clin Psychol Med Settings 2021 Jul 22. Epub 2021 Jul 22.

Northwestern University Feinberg School of Medicine, 676 N. Saint Clair Street, Suite 1400, Chicago, IL, 60611, USA.

Post-traumatic stress symptoms (PTSS) in response to medical trauma are understudied in inflammatory bowel disease (IBD). Two studies identify surgery, hospitalizations, and disease severity as risk factors. We aimed to document IBD-related patient experiences and how these relate to PTSS via a qualitative study. Adult patients with confirmed IBD recruited from two gastroenterology clinics underwent a semi-structured interview with a psychologist and completed the Post Traumatic Stress Disorder Symptom Scale for DSM5 (PSSI-5). Interviews were analyzed using an interpretive phenomenological approach. Themes and subthemes with representative quotations were documented based on thematic saturation. 16 participants, five met PSSI-5 criteria for PTSD. Five themes emerged: disease uncertainty, information exchange/quality, medical procedures, surgery, and coping. Patients with IBD may experience medical PTSS from several sources. Information, communication, and trust in clinicians is vital but may be sub-optimal. Both adaptive and maladaptive coping strategies are used to mitigate PTSS.
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http://dx.doi.org/10.1007/s10880-021-09805-0DOI Listing
July 2021

Posttraumatic Stress in Patients With Inflammatory Bowel Disease: Prevalence and Relationships to Patient-Reported Outcomes.

Inflamm Bowel Dis 2021 Jun 17. Epub 2021 Jun 17.

Northwestern University Feinberg School of Medicine, Division of Gastroenterology and Hepatology, Chicago, Illinois, USA.

Background: Patients with chronic illness are at increased risk for traumatic stress because of medical trauma. Initial studies of posttraumatic stress (PTS) in patients with inflammatory bowel disease (IBD) have found that approximately one-third of patients may experience significant PTS symptoms including flashbacks, nightmares, hypervigilance, disrupted sleep, and low mood. We aim to better characterize PTS in IBD and its relationship with patient outcomes in a large cohort of patients with IBD.

Methods: Adult patients registered with the Crohn's & Colitis Foundation/University of North Carolina IBD Partners database were invited to complete a supplementary survey between February and July 2020. The Post Traumatic Stress Disorder Checklist-5th edition was administered as a supplemental survey. Additional data from IBD Partners included disease severity, surgery and hospital history, demographics, and health care utilization.

Results: A total of 797 patients participated (452 with Crohn disease, 345 with ulcerative colitis). No impacts on response patterns because of the COVID-19 pandemic were found. Although 5.6% of the sample reported an existing PTS diagnosis because of IBD experiences, 9.6% of participants met the full IBD-related PTS diagnostic criteria per the Post Traumatic Stress Disorder Checklist-5th edition. Female patients, younger patients, those with less educational attainment, non-White patients, and Hispanic patients reported higher levels of PTS symptoms. Patients with higher PTS symptoms were more likely to have been hospitalized, have had surgery, have more severe symptoms, and not be in remission. Increased PTS was also associated with increased anxiety, depression, pain interference, fatigue, and health care utilization.

Conclusions: The present findings support prior research that approximately one-quarter to one-third of patients with IBD report significant symptoms of PTS directly from their disease experiences, and certain demographic groups are at higher risk. In addition, PTS is associated with several IBD outcomes. Patients with higher PTS symptoms are less likely to be in remission and may utilize more outpatient gastrointestinal services. Intervention trials to mitigate PTS symptoms in patients with IBD are warranted.
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http://dx.doi.org/10.1093/ibd/izab152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8344426PMC
June 2021

IBD Development After Diverticulitis May Hold Clues to IBD Pathogenesis.

Authors:
Ece A Mutlu

Inflamm Bowel Dis 2021 06;27(7):1172-1173

Rush University, Department of Medicine, Section of Gastroenterology and Nutrition, Rush University Medical Center, 1725 W. Harrison St, Professional Building Suite 206, Chicago, IL 60612,, USA.

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http://dx.doi.org/10.1093/ibd/izaa300DOI Listing
June 2021

IL-6 Inhibition in Critically Ill COVID-19 Patients Is Associated With Increased Secondary Infections.

Front Med (Lausanne) 2020 28;7:583897. Epub 2020 Oct 28.

Department of Medicine, University of Chicago, Chicago, IL, United States.

Anti-inflammatory therapies such as IL-6 inhibition have been proposed for COVID-19 in a vacuum of evidence-based treatment. However, abrogating the inflammatory response in infectious diseases may impair a desired host response and pre-dispose to secondary infections. We retrospectively reviewed the medical record of critically ill COVID-19 patients during an 8-week span and compared the prevalence of secondary infection and outcomes in patients who did and did not receive tocilizumab. Additionally, we included representative histopathologic post-mortem findings from several COVID-19 cases that underwent autopsy at our institution. One hundred eleven patients were identified, of which 54 had received tocilizumab while 57 had not. Receiving tocilizumab was associated with a higher risk of secondary bacterial (48.1 vs. 28.1%; = 0.029 and fungal (5.6 vs. 0%; = 0.112) infections. Consistent with higher number of infections, patients who received tocilizumab had higher mortality (35.2 vs. 19.3%; = 0.020). Seven cases underwent autopsy. In three cases who received tocilizumab, there was evidence of pneumonia on pathology. Of the four cases that had not been given tocilizumab, two showed evidence of aspiration pneumonia and two exhibited diffuse alveolar damage. Experimental therapies are currently being applied to COVID-19 outside of clinical trials. Anti-inflammatory therapies such as anti-IL-6 therapy have the potential to impair viral clearance, pre-dispose to secondary infection, and cause harm. We seek to raise physician awareness of these issues and highlight the need to better understand the immune response in COVID-19.
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http://dx.doi.org/10.3389/fmed.2020.583897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655919PMC
October 2020

IL6 inhibition in critically ill COVID-19 patients is associated with increased secondary infections.

medRxiv 2020 Sep 12. Epub 2020 Sep 12.

Background: Anti-inflammatory therapies such as IL-6 inhibition have been proposed for COVID-19 in a vacuum of evidence-based treatment. However, abrogating the inflammatory response in infectious diseases may impair a desired host response and predispose to secondary infections.

Methods: We retrospectively reviewed the medical record of critically ill COVID-19 patients during an 8-week span and compared the prevalence of secondary infection and outcomes in patients who did and did not receive tocilizumab. Additionally, we included representative histopathologic post-mortem findings from several COVID-19 cases that underwent autopsy at our institution.

Results: 111 patients were identified, of which 54 had received tocilizumab while 57 had not. Receiving tocilizumab was associated with a higher risk of secondary bacterial (48.1% vs. 28.1%, p=0.029 and fungal (5.6% vs. 0%, p=0.112) infections. Consistent with higher number of infections, patients who received tocilizumab had higher mortality (35.2% vs. 19.3%, p=0.020). Seven cases underwent autopsy. In 3 cases who received tocilizumab, there was evidence of pneumonia on pathology. Of the 4 cases that had not been given tocilizumab, 2 showed evidence of aspiration pneumonia and 2 exhibited diffuse alveolar damage.

Conclusions: Experimental therapies are currently being applied to COVID-19 outside of clinical trials. Anti-inflammatory therapies such as anti-IL-6 therapy have the potential to impair viral clearance, predispose to secondary infection, and cause harm. We seek to raise physician awareness of these issues and highlight the need to better understand the immune response in COVID-19.
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http://dx.doi.org/10.1101/2020.05.15.20103531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7491533PMC
September 2020

Diet Therapy for Inflammatory Bowel Diseases: A Call to the Dining Table.

Inflamm Bowel Dis 2020 03;26(4):510-514

Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

There is vigorous interest among patients, caregivers, clinicians, and scientists to identify useful dietary interventions for inflammatory bowel diseases (IBD). Through the Cochrane Collaboration, we recently performed a systematic review and meta-analysis of dietary interventions for the induction or maintenance of remission in Crohn's disease (CD) and ulcerative colitis (UC) to assess the latest state of research. The current quality of evidence was formally graded to be low or very low for various methodological reasons, such as small sample sizes, heterogeneity among studies, and incomplete reporting. There are nonetheless emerging observational studies that progressively advance our knowledge and provide hope for a role of diet among traditional therapies to improve inflammation and symptoms. Further investments and concerted efforts in research are needed to significantly move the needle in identifying effective dietary therapies for IBD.
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http://dx.doi.org/10.1093/ibd/izz297DOI Listing
March 2020

Development of collagenous colitis in inflammatory bowel disease: two case reports and a review of the literature.

Gastroenterol Rep (Oxf) 2019 Jun 19;7(3):218-222. Epub 2017 Jul 19.

Department of Medicine, Division of Gastroenterology and Nutrition, Rush University, Chicago, IL, USA.

The occurrence of collagenous colitis (CC) in patients with pre-existing inflammatory bowel diseases (IBD) is rare, with only seven cases reported in the past. Herein, we report two IBD cases who developed CC after successful treatment of their IBD with two different tumor necrosis factor (TNF)-α inhibitors, which have been previously reported to successfully treat refractory CC. This report highlights the need to do random biopsies of the colon for CC diagnosis in IBD patients with symptoms of diarrhea after complete mucosal healing. The report also reviews plausible mechanisms as to how CC may develop, including the role of multiple medications.
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http://dx.doi.org/10.1093/gastro/gox026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6573798PMC
June 2019

Food-related quality of life in patients with inflammatory bowel disease and irritable bowel syndrome.

Qual Life Res 2019 Aug 21;28(8):2195-2205. Epub 2019 Mar 21.

Division of Gastroenterology & Hepatology, Northwestern University Feinberg School of Medicine, 676 N. Saint Clair Street Suite 1400, Chicago, IL, 60611, USA.

Background: Food-related quality of life (FRQoL) evaluates the impact of diet, eating behaviors, and food-related anxiety on a person's quality of life. This is the first study to evaluate FRQoL in inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS), two illnesses where food and diet are of importance.

Methods: One hundred seventy-five participants (80 IBS, 95 IBD) participated in the study by completing measures evaluating FRQoL, psychological distress, and health-related quality of life. Primary analyses evaluated differences in FRQoL between IBD and IBS patients. Secondary analyses compared differences based on remission status, dietary use, and dietary consultation, as well as evaluated potential predictors of FRQoL.

Results: IBD patients in remission report the highest FRQoL (IBD-remission: 91.2 (26.5) vs. IBD-active: 67.7 (19.6) and IBS-active: 67.6 (18.3), p < .001). Using more dietary treatments is associated with decreased FRQoL for IBS (r = - 0.23, p < .05) and IBD patients (r = - 0.31, p < .01). IBS patients are more likely to use dietary treatments than IBD (IBS = 81% vs. IBD = 64%, p < .01), with self-directed diets being the most commonly used approach. Symptom severity is the strongest predictor of FRQoL in both groups (IBD: R = .27, p < .01; IBS: R = .23, p < .001).

Conclusion: FRQoL is a unique construct for IBD and IBS patients that can be influenced by several clinical and dietary factors, including number of diets and type of diet used, depending on the diagnosis. Thus, FRQoL should be considered when working with both IBD and IBS patients.
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http://dx.doi.org/10.1007/s11136-019-02170-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625837PMC
August 2019

Collagenous colitis development occurs after long standing mucosal healing in IBD with TNF-α inhibitors, and could be due to exaggerated healing response from excess TNF-α inhibition.

Med Hypotheses 2019 Feb 7;123:90-94. Epub 2019 Jan 7.

Section of Gastroenterology, Hepatology & Nutrition, Rush University Medical Center, Chicago, IL, United States. Electronic address:

Collagenous colitis is a relatively rare disorder affecting mainly middle-aged women where they present with chronic non-bloody diarrhea. Both with lymphocytic colitis they compose microscopic colitis. The exact cause of collagenous colitis is still unknown however; many potential pathophysiologic mechanisms have been proposed but no convincing mechanism has been identified. Collagenous colitis has been linked to medications mainly NSAIDs, SSRIs, and PPIs. It is also believed that collagenous colitis is autoimmune disease and there are weak believe it could have some genetic inheritance. We reported before two cases of collagenous colitis developed in patients with Crohn's disease and ulcerative colitis while they were in complete mucosal remission after being treated with tumor necrosis factors-α inhibitors. In this article we will try to explain how collagenous colitis can develop in patients with inflammatory bowel disease especially those on tumor necrosis factors-α inhibitors.
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http://dx.doi.org/10.1016/j.mehy.2019.01.004DOI Listing
February 2019

The Potential Role of Vedolizumab in Concomitant Eosinophilic Esophagitis and Crohn's Disease.

Clin Gastroenterol Hepatol 2018 11;16(11):1840-1841

Section of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Rush University Medical Center, Chicago, Illinois.

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http://dx.doi.org/10.1016/j.cgh.2018.06.022DOI Listing
November 2018

A descriptive analysis of real-world treatment patterns of innovator (Remicade) and biosimilar infliximab in an infliximab-naïve Turkish population.

Biologics 2018 2;12:97-106. Epub 2018 Oct 2.

Guven Hospital, Department of Rheumatology, Ankara, Turkey.

Purpose: Biosimilar IFX (CT-P13) received marketing approval in Turkey for treatment of rheumatologic diseases, including ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis. Population data on real-world treatment patterns of CT-P13 following marketing approval in European countries are largely unreported. This study examined the prescribing and medication utilization patterns of innovator infliximab (IFX) and CT-P13 in Turkey for patients with RA or IBD naïve to either IFX.

Materials And Methods: Adult patients with ≥1 diagnosis claim for RA or IBD and ≥1 claim for IFX or CT-P13 were identified in the Turkish Ministry of Health database during the following identification periods: 1 Oct 2014-30 May 2015 (RA) and 1 Oct 2014-31 Dec 2015 (IBD). Continuous medical and pharmacy coverage for ≥12 months before and after the date of the first dose (index) IFX or CT-P13 was also required. Separate analyses were done for each population.

Results: Seven hundred and seventy nine adult RA and 581 IBD patients met the selection criteria. The majority of RA (74%; n=575) and IBD patients (87%; n=504) were initiated on IFX. The average study observation period was 16 months for the RA and 12 months for the IBD population. Over the observation periods, discontinuation among RA patients occurred in 42% of IFX and 63% of CT-P13 while discontinuation in the IBD cohort occurred in 38% of IFX; and 62% of CT-P13.

Conclusion: In this population-based study, more IFX-naïve RA and IBD patients were initially treated with IFX than CT-P13. Discontinuation and switching were observed more often and earlier among patients treated with CT-P13 regardless of disease state. Further studies are needed to understand the reasons for these observed differences.
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http://dx.doi.org/10.2147/BTT.S172241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174299PMC
October 2018

Inhalational exposure to particulate matter air pollution alters the composition of the gut microbiome.

Environ Pollut 2018 Sep 18;240:817-830. Epub 2018 May 18.

Section of Pulmonary and Critical Care Medicine, The University of Chicago, Chicago, IL, 60637, USA. Electronic address:

Recent studies suggest an association between particulate matter (PM) air pollution and gastrointestinal (GI) disease. In addition to direct deposition, PM can be indirectly deposited in oropharynx via mucociliary clearance and upon swallowing of saliva and mucus. Within the GI tract, PM may alter the GI epithelium and gut microbiome. Our goal was to determine the effect of PM on gut microbiota in a murine model of PM exposure via inhalation. C57BL/6 mice were exposed via inhalation to either concentrated ambient particles or filtered air for 8-h per day, 5-days a week, for a total of 3-weeks. At exposure's end, GI tract tissues and feces were harvested, and gut microbiota was analyzed. Alpha-diversity was modestly altered with increased richness in PM-exposed mice compared to air-exposed mice in some parts of the GI tract. Most importantly, PM-induced alterations in the microbiota were very apparent in beta-diversity comparisons throughout the GI tract and appeared to increase from the proximal to distal parts. Changes in some genera suggest that distinct bacteria may have the capacity to bloom with PM exposure. Exposure to PM alters the microbiota throughout the GI tract which maybe a potential mechanism that explains PM induced inflammation in the GI tract.
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http://dx.doi.org/10.1016/j.envpol.2018.04.130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400491PMC
September 2018

A compartmentalized type I interferon response in the gut during chronic HIV-1 infection is associated with immunopathogenesis.

AIDS 2018 07;32(12):1599-1611

University of Colorado Anschutz Medical Campus, Aurora, Colorado.

Objective(s): Type I interferon (IFN-I) responses confer both protective and pathogenic effects in persistent virus infections. IFN-I diversity, stage of infection and tissue compartment may account for this dichotomy. The gut is a major site of early HIV-1 replication and microbial translocation, but the nature of the IFN-I response in this compartment remains unclear.

Design: Samples were obtained from two IRB-approved cross-sectional studies. The first study included individuals with chronic, untreated HIV-1 infection (n = 24) and age/sex-balanced uninfected controls (n = 14). The second study included antiretroviral-treated, HIV-1-infected individuals (n = 15) and uninfected controls (n = 15).

Methods: The expression of 12 IFNα subtypes, IFNβ and antiviral IFN-stimulated genes (ISGs) were quantified in peripheral blood mononuclear cells (PBMCs) and colon biopsies using real-time PCR and next-generation sequencing. In untreated HIV-1-infected individuals, associations between IFN-I responses and gut HIV-1 RNA levels as well as previously established measures of colonic and systemic immunological indices were determined.

Results: IFNα1, IFNα2, IFNα4, IFNα5 and IFNα8 were upregulated in PBMCs during untreated chronic HIV-1 infection, but IFNβ was undetectable. By contrast, IFNβ was upregulated and all IFNα subtypes were downregulated in gut tissue. Gut ISG levels positively correlated with gut HIV-1 RNA and immune activation, microbial translocation and inflammation markers. Gut IFN-I responses were not significantly different between HIV-1-infected individuals on antiretroviral treatment and uninfected controls.

Conclusion: The IFN-I response is compartmentalized during chronic untreated HIV-1 infection, with IFNβ being more predominant in the gut. Gut IFN-I responses are associated with immunopathogenesis, and viral replication is likely a major driver of this response.
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http://dx.doi.org/10.1097/QAD.0000000000001863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6054446PMC
July 2018

Complementary and Alternative Treatments Are Needed to Enhance the Care of the Inflammatory Bowel Disease Patient.

Gastroenterol Clin North Am 2017 12 5;46(4):xiii-xiv. Epub 2017 Oct 5.

Rush University Medical Center, Division of Digestive Diseases & Nutrition, 1725 West Harrison Street, Suite 206, Chicago, IL 60612, USA. Electronic address:

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http://dx.doi.org/10.1016/j.gtc.2017.09.001DOI Listing
December 2017

Diet as a Therapeutic Option for Adult Inflammatory Bowel Disease.

Gastroenterol Clin North Am 2017 12;46(4):745-767

Division of Digestive Diseases & Nutrition, Rush University Medical Center, 1725 West Harrison Street, Suite 206, Chicago, IL 60612, USA. Electronic address:

There are many mechanisms to explain how food may drive and ameliorate inflammation. Although there are no consistent macronutrient associations inflammatory bowel disease (IBD) development, many exclusion diets have been described: IgG-4 guided exclusion diet; semivegetarian diet; low-fat, fiber-limited exclusion diet; Paleolithic diet; Maker's diet; vegan diet; Life without Bread diet; exclusive enteral nutrition (EEN), the Specific Carbohydrate Diet (SCD) and the low FODMAP diet. The literature on diet and IBD is reviewed with a particular focus on EEN, SCD, and low FODMAP diets. Lessons learned from the existing observations and strengths and shortcomings of existing data are presented.
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http://dx.doi.org/10.1016/j.gtc.2017.08.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5821251PMC
December 2017

Effect of cytomegalovirus and Epstein-Barr virus replication on intestinal mucosal gene expression and microbiome composition of HIV-infected and uninfected individuals.

AIDS 2017 09;31(15):2059-2067

aDivision of Infectious Diseases, Department of Medicine, University of California, San Diego, La Jolla, California bDivision of Gastroenterology, Department of Internal Medicine cDepartment of Immunology-Microbiology, Rush University Medical Center, Chicago, Illinois, USA. *Sara Gianella and Antoine Chaillon contributed equally to the article.

Background: HIV-infection is associated with dramatic changes in the intestinal mucosa. The impact of other viral pathogens is unclear.

Methods: One hundred and eight (108) biopsies from left and right colon (n = 79) and terminal ileum (n = 29) were collected from 19 HIV-infected and 22 HIV-uninfected participants. Levels of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) DNA were measured by droplet digital PCR. Mucosal gene expression was measured via multiplex-assay. Microbiome analysis was performed using bacterial 16S-rDNA-pyrosequencing. The effect of CMV and EBV replication on the microbiome composition and mRNA-expression of selected cytokines (IL-6, IFN-γ, IL-1β, CCL2, IL-8, and IFN-β1) was evaluated.

Results: Overall, CMV and EBV were detected in at least one intestinal site in 60.5 and 78.9% of participants, respectively. HIV-infected individuals demonstrated less detectable CMV (PB = 0.02); CMV was more frequently detected in terminal ileum than colon (PB = 0.05). Detectable EBV was more frequent among HIV-infected (P B= 0.04) without differences by intestinal site. The number of operational taxonomic units did not differ by CMV or EBV detection status. Among HIV-infected participants, higher CMV was only associated with lower relative abundance of Actinobacteria in the ileum (P = 0.03). Presence of CMV was associated with upregulated expression of all selected cytokines in the ileum (all P < 0.02) and higher expression of IL-8 and IFN-β1 in the colon (all P < 0.05) of HIV-uninfected participants, but not among HIV-infected. EBV had no effect on cytokine expression or microbiome composition whatsoever.

Conclusion: These results illustrate a complex interplay among HIV-infection, intestinal CMV replication, and mucosal gut environment, and highlight a possible modulatory effect of CMV on the microbial and immune homeostasis.
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http://dx.doi.org/10.1097/QAD.0000000000001579DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5654609PMC
September 2017

Relationships between gastrointestinal microbiota and blood group antigens.

Physiol Genomics 2017 Sep 14;49(9):473-483. Epub 2017 Jul 14.

Department of Internal Medicine, Section of Gastroenterology, Hepatology and Nutrition, Rush University Medical Center, Chicago, Illinois

FUT2 is a gene for a fucosyltransferase that encodes expression of ABO blood group antigens found on gastrointestinal mucosa and secretions. We hypothesized that the fecal microbiomes of healthy subjects, with blood group antigens A, B, and O, have differing compositions. We analyzed 33 fecal and blood specimens from healthy subjects for FUT2 genotype, and the fecal microbiome was determined by 454 pyrosequencing. Our data show that being a blood group secretor is associated with less diversity at higher orders of taxonomy; and the presence of blood group A antigens in the secretor subjects are associated with an expansion families of bacteria within the gut. Furthermore, our study confirms the previous findings that secretors and nonsecretors have differing bacterial taxa. This extends the previous findings by demonstrating that the impact of being a nonsecretor is higher than that of individual blood group antigens. Additionally, we demonstrate that both secretor status and blood group antigen expression especially affect the Lachnospiraceae family of bacteria within the gut microbiome, with lower abundances noted in nonsecretors and higher abundances in secretors of various blood groups. We further note specific differences in blood group A-secretors demonstrating that the genus is lower in the group A-secretors compared with the non-A-secretors and that this reduction is accompanied by higher abundances of members of the Rikenellaceae, Peptostreptococcaceae, Clostridiales, and This study offers a first insight into the relationship between the fecal microbiome and blood group antigens in secretors.
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http://dx.doi.org/10.1152/physiolgenomics.00043.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5625272PMC
September 2017

Intestinal fungi contribute to development of alcoholic liver disease.

J Clin Invest 2017 Jun 22;127(7):2829-2841. Epub 2017 May 22.

Department of Medicine, UCSD, La Jolla, California, USA.

Chronic liver disease with cirrhosis is the 12th leading cause of death in the United States, and alcoholic liver disease accounts for approximately half of all cirrhosis deaths. Chronic alcohol consumption is associated with intestinal bacterial dysbiosis, yet we understand little about the contribution of intestinal fungi, or mycobiota, to alcoholic liver disease. Here we have demonstrated that chronic alcohol administration increases mycobiota populations and translocation of fungal β-glucan into systemic circulation in mice. Treating mice with antifungal agents reduced intestinal fungal overgrowth, decreased β-glucan translocation, and ameliorated ethanol-induced liver disease. Using bone marrow chimeric mice, we found that β-glucan induces liver inflammation via the C-type lectin-like receptor CLEC7A on Kupffer cells and possibly other bone marrow-derived cells. Subsequent increases in IL-1β expression and secretion contributed to hepatocyte damage and promoted development of ethanol-induced liver disease. We observed that alcohol-dependent patients displayed reduced intestinal fungal diversity and Candida overgrowth. Compared with healthy individuals and patients with non-alcohol-related cirrhosis, alcoholic cirrhosis patients had increased systemic exposure and immune response to mycobiota. Moreover, the levels of extraintestinal exposure and immune response correlated with mortality. Thus, chronic alcohol consumption is associated with an altered mycobiota and translocation of fungal products. Manipulating the intestinal mycobiome might be an effective strategy for attenuating alcohol-related liver disease.
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http://dx.doi.org/10.1172/JCI90562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490775PMC
June 2017

The Potential Role of Gut-Derived Inflammation in Multiple System Atrophy.

J Parkinsons Dis 2017 ;7(2):331-346

Department of Internal Medicine, Division of Gastroenterology, Rush University Medical Center, Chicago, IL, USA.

Background: Recent evidence suggests that Parkinson's disease (PD) is associated with intestinal microbiota dysbiosis, abnormal intestinal permeability, and intestinal inflammation.

Objective: Our study aimed to determine if these gut abnormalities are present in another synucleinopathy, multiple system atrophy (MSA).

Methods: In six MSA and 11 healthy control subjects, we performed immunohistochemistry studies of colonic sigmoid mucosa to evaluate the intestinal barrier marker Zonula Occludens-1 and the endotoxin-related inflammation marker Toll-like-receptor-4 expression. We also assessed colonic sigmoid mucosal and fecal microbiota compositions using high-throughput 16S ribosomal RNA gene amplicon sequencing.

Results: MSA subjects showed disrupted tight junction protein Zonula Occludens-1 structure in sigmoid mucosa tissue suggesting intestinal barrier dysfunction. The lipopolysaccharide specific inflammatory receptor Toll-like-receptor-4 was significantly higher in the colonic sigmoid mucosa in MSA relative to healthy controls. Microbiota analysis suggested high relative abundance of gram-negative, putative "pro-inflammatory" bacteria in various family and genus level taxa, from the phylum Bacteroidetes and Proteobacteria, in MSA feces and mucosa. At the taxonomic level of genus, putative "anti-inflammatory" butyrate-producing bacteria were less abundant in MSA feces. Predictive functional analysis indicated that the relative abundance of a number of genes involved in metabolism were lower in MSA feces, whereas the relative abundance of genes involved in lipopolysaccharide biosynthesis were higher in both MSA feces and mucosa compared to healthy controls.

Conclusions: This proof-of-concept study provides preliminary evidence that like PD, MSA subjects display evidence of disrupted intestinal barrier integrity, increased marker of endotoxin-related intestinal inflammation, and pro-inflammatory colonic microbiota.
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http://dx.doi.org/10.3233/JPD-160991DOI Listing
January 2018

Breath Methane Levels Are Increased Among Patients with Diverticulosis.

Dig Dis Sci 2016 09 29;61(9):2648-54. Epub 2016 Apr 29.

Division of Digestive Diseases and Nutrition, Rush Presbyterian St. Luke's Medical Center, Rush University Medical Center, 1725 W Harrison, Suite 206, Chicago, IL, 60612, USA.

Background: Diverticulosis and its complications are important healthcare problems in the USA and throughout the Western world. While mechanisms as to how diverticulosis occurs have partially been explored, few studies examined the relationship between colonic gases such as methane and diverticulosis in humans.

Aim: This study aimed to demonstrate a significant relationship between methanogenic Archaea and development of diverticulosis.

Methods: Subjects who consecutively underwent hydrogen breath test at Rush University Medical Center between 2003 and 2010 were identified retrospectively through a database. Medical records were reviewed for presence of a colonoscopy report. Two hundred and sixty-four subjects were identified who had both a breath methane level measurement and a colonoscopy result. Additional demographic and clinical data were obtained with chart review.

Results: Mean breath methane levels were higher in subjects with diverticulosis compared to those without diverticulosis (7.89 vs. 4.94 ppm, p = 0.04). Methane producers (defined as those with baseline fasting breath methane level >5 ppm) were more frequent among subjects with diverticulosis compared to those without diverticulosis (50.9 vs. 34 %, p = 0.0025). When adjusted for confounders, breath methane levels and age were the two independent predictors of diverticulosis on colonoscopy with logistic regression modeling.

Conclusions: Methanogenesis is associated with the presence of diverticulosis. Further studies are needed to confirm our findings and prospectively evaluate a possible etiological role of methanogenesis and methanogenic archaea in diverticulosis.
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http://dx.doi.org/10.1007/s10620-016-4174-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5821261PMC
September 2016

The Effects of Bowel Preparation on Microbiota-Related Metrics Differ in Health and in Inflammatory Bowel Disease and for the Mucosal and Luminal Microbiota Compartments.

Clin Transl Gastroenterol 2016 Feb 11;7:e143. Epub 2016 Feb 11.

Rush University Medical Center, Department of Internal Medicine, Division of Digestive Diseases and Nutrition, Section of Gastroenterology, Chicago, Illinois, USA.

Objectives: Bowel preparations (BPs) taken before colonoscopy may introduce a confounding effect on the results of gastrointestinal microbiota studies. This study aimed to determine the effect of bowel preparation on the mucosa-associated and luminal colonic microbiota in healthy subjects (HC) and inflammatory bowel disease (IBD) patients.

Methods: Biopsy samples (n=36) and fecal samples (n=30) were collected from 10 HC and 8 IBD subjects pre- and post-BP. 16S rRNA gene was pyrosequenced using 454 Titanium protocols. We compared the differences between the pre- and post-BP samples (i.e., comparisons-across-bowel-prep); we examined the effect of BP on the expected separation of the mucosal vs. the luminal compartments (i.e., comparisons-across-compartments). Last, we compared the baseline differences between the HC vs. IBD groups (a secondary analysis), and examined whether the differences between the HC vs. IBD changed after BP.

Results: In comparisons-across-bowel-prep, the Shannon's index (SI) decreased only in the biopsy samples of IBD subjects post-BP (P=0.025) and phylogenetic diversity-whole tree (PD-WT) metric decreased in biopsy samples of HC subjects post-BP (P=0.021). In secondary comparisons, the subtle differences between the fecal samples of the HC vs. IBD groups, in terms of evenness and the SI, were not apparent post-BP. In terms of β-diversity, in comparisons-across-bowel-prep, the proportion of shared operational taxonomic units (OTUs) in pre- and post-BP samples was low (~30%) and unweighted Unifrac distances between pre- and post-BP specimens ranged from 0.52 to 0.66. HC biopsies were affected more than IBD biopsies with BP (P=0.004). In comparisons-across-compartments, the proportion of shared OTUs between biopsy and fecal samples increased and Unifrac distances decreased post-BP in IBD subjects, reducing the differences between the mucosal and luminal compartments of the gut microbiota. Interindividual differences in Unifrac distances were preserved even with BP effects, although the effects were greater on weighted Unifrac distances. Bacteroidetes and its subtypes increased post-BP in both the luminal and mucosal compartments.

Conclusions: Bowel preparations affect the composition and diversity of the fecal and luminal microbiota in the short term, introducing potential bias into experiments examining the gut microbiota. The magnitude of the effect of BP is not greater than that of interindividual variation. Both the luminal and mucosal compartments of the gut microbiota get affected, and samples from controls and IBD subjects may get affected differently. Studies of the colonic microbiota should take into account the direction and the magnitude of the change introduced by BP during the design stage of the experiments, and consider sample sizes so that potential bias is minimized.
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http://dx.doi.org/10.1038/ctg.2015.54DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4817412PMC
February 2016

Longitudinal Survey of Microbiota in Hospitalized Preterm Very-Low-Birth-Weight Infants.

J Pediatr Gastroenterol Nutr 2016 Feb;62(2):292-303

*Rush University Medical Center, Chicago, IL †Texas Department of State Health Services, Austin ‡Research and Testing Laboratory, Lubbock, TX §University of Illinois at Chicago, Chicago ||WakeMed Health and Hospitals, Raleigh, NC.

Objectives: The aim of the present study was to examine the changes in bacteria in hospitalized preterm infants during the first month of life.

Methods: Rectal swabs were collected daily from 12 preterm infants. DNA was extracted from swabs from day of birth and weekly thereafter. Bacterial taxa were identified with next generation sequencing using universal bacterial primers targeted at the 16S ribosomal DNA on a 454 Roche titanium platform. Sequences were clustered into operational taxonomic units, and taxonomy was assigned against the Greengenes databank using Quantitative Insights Into Microbial Ecology version 1.4. Quantitative polymerase chain reaction was used to determine the abundance of Bifidobacterium spp. Functional assessment of the microbiome was performed with Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt).

Results: Average birth weight and gestational age were 1055 g and 28 weeks, respectively. There were 6 to 35 different bacterial families identified in the day-of-birth samples, unrelated to the mode of delivery. Richness decreased through hospitalization (week 1, 16.9 ± 7.7 vs weeks 3-5, 10.7 ± 3.4, P < 0.001). The Shannon diversity index demonstrated the lowest diversity at birth, an increase at week 2, followed by a rapid decline at weeks 3 to 5, suggesting the development of a more uniform microbiota composition after 2 weeks of stay at a neonatal intensive care unit. Enterobacteriaceae, Staphylococcaceae, and Enterococcaceae constituted the majority of the bacterial families. Bifidobacterium spp were infrequently detected at extremely low levels. PICRUSt analysis revealed the enhancement of peroxisome, PPAR, and adipocytokine signaling; plant-pathogen interaction; and aminobenzoate degradation pathways in week 1 samples.

Conclusions: Our results suggest that although preterm infants have individualized microbiota that are detectable at birth, the differences decrease during the neonatal intensive care unit hospitalization with increasing prominence of pathogenic microbiota.
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http://dx.doi.org/10.1097/MPG.0000000000000913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4724288PMC
February 2016

Classification methods for the analysis of LH-PCR data associated with inflammatory bowel disease patients.

Int J Bioinform Res Appl 2015 ;11(2):111-29

Microbiome Analysis Centre, Department of Environmental Science and Policy, George Mason University, 4400 University Drive, Fairfax, Virginia, 22030 USA.

The human gut is one of the most densely populated microbial communities in the world. The interaction of microbes with human host cells is responsible for several disease conditions and of criticality to human health. It is imperative to understand the relationships between these microbial communities within the human gut and their roles in disease. In this study we analyse the microbial communities within the human gut and their role in Inflammatory Bowel Disease (IBD). The bacterial communities were interrogated using Length Heterogeneity PCR (LH-PCR) fingerprinting of mucosal and luminal associated microbial communities for a class of healthy and diseases patients.
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http://dx.doi.org/10.1504/IJBRA.2015.068087DOI Listing
October 2015

Disease-specific alterations in the enteric virome in inflammatory bowel disease.

Cell 2015 Jan 22;160(3):447-60. Epub 2015 Jan 22.

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address:

Decreases in the diversity of enteric bacterial populations are observed in patients with Crohn's disease (CD) and ulcerative colitis (UC). Less is known about the virome in these diseases. We show that the enteric virome is abnormal in CD and UC patients. In-depth analysis of preparations enriched for free virions in the intestine revealed that CD and UC were associated with a significant expansion of Caudovirales bacteriophages. The viromes of CD and UC patients were disease and cohort specific. Importantly, it did not appear that expansion and diversification of the enteric virome was secondary to changes in bacterial populations. These data support a model in which changes in the virome may contribute to intestinal inflammation and bacterial dysbiosis. We conclude that the virome is a candidate for contributing to, or being a biomarker for, human inflammatory bowel disease and speculate that the enteric virome may play a role in other diseases.
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http://dx.doi.org/10.1016/j.cell.2015.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4312520PMC
January 2015

Supplementation of saturated long-chain fatty acids maintains intestinal eubiosis and reduces ethanol-induced liver injury in mice.

Gastroenterology 2015 Jan 16;148(1):203-214.e16. Epub 2014 Sep 16.

Department of Medicine, University of California San Diego, La Jolla, California. Electronic address:

Background & Aims: Alcoholic liver disease is a leading cause of mortality. Chronic alcohol consumption is accompanied by intestinal dysbiosis, and development of alcoholic liver disease requires gut-derived bacterial products. However, little is known about how alterations to the microbiome contribute to pathogenesis of alcoholic liver disease.

Methods: We used the Tsukamoto-French mouse model, which involves continuous intragastric feeding of isocaloric diet or alcohol for 3 weeks. Bacterial DNA from the cecum was extracted for deep metagenomic sequencing. Targeted metabolomics assessed concentrations of saturated fatty acids in cecal contents. To maintain intestinal metabolic homeostasis, diets of ethanol-fed and control mice were supplemented with saturated long-chain fatty acids (LCFA). Bacterial genes involved in fatty acid biosynthesis, amounts of lactobacilli, and saturated LCFA were measured in fecal samples of nonalcoholic individuals and patients with active alcohol abuse.

Results: Analyses of intestinal contents from mice revealed alcohol-associated changes to the intestinal metagenome and metabolome, characterized by reduced synthesis of saturated LCFA. Maintaining intestinal levels of saturated fatty acids in mice resulted in eubiosis, stabilized the intestinal gut barrier, and reduced ethanol-induced liver injury. Saturated LCFA are metabolized by commensal Lactobacillus and promote their growth. Proportions of bacterial genes involved in fatty acid biosynthesis were lower in feces from patients with active alcohol abuse than controls. Total levels of LCFA correlated with those of lactobacilli in fecal samples from patients with active alcohol abuse but not in controls.

Conclusions: In humans and mice, alcohol causes intestinal dysbiosis, reducing the capacity of the microbiome to synthesize saturated LCFA and the proportion of Lactobacillus species. Dietary approaches to restore levels of saturated fatty acids in the intestine might reduce ethanol-induced liver injury in patients with alcoholic liver disease.
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http://dx.doi.org/10.1053/j.gastro.2014.09.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4274236PMC
January 2015

TNF inhibitors to treat ulcerative colitis in a metastatic breast cancer patient: a case report and literature review.

World J Gastroenterol 2014 May;20(19):5912-7

Ruwaida Ben Musa, Graduate College, Rush University, Chicago, IL 60612, United States.

Adalimumab (ADA) is a tumor necrosis factor (TNF) inhibitor, used for the treatment of inflammatory bowel disease. Previous studies have reported an increased risk of cancer following exposure to TNF inhibitors, but little has been reported for patients with cancer receiving TNF-inhibitor treatment. We present a female patient with metastatic breast cancer and ulcerative colitis (UC) who was treated with ADA. A 54-year-old African American female with a past history of left-sided breast cancer (BC) diagnosed at age 30 was initially treated with left-breast lumpectomy, axillary dissection, followed by chemotherapy and radiation therapy. Years after initial diagnosis, she developed recurrent, bilateral BC and had bilateral mastectomy. Subsequent restaging computed tomography (CT) scan demonstrated distant metastases to the bone and lymph nodes. Three years into her treatment of metastatic breast cancer, she was diagnosed with UC by colonoscopy. Her UC was not controlled for 5 mo with 5-aminosalicylates. Subcutaneous ADA was started and resulted in dramatic improvement of UC. Four months after starting ADA, along with ongoing chemotherapy, restaging CT scan showed resolution of the previously seen metastatic lymph nodes. Bone scan and follow-up positron emission tomography/CT scans performed every 6 mo indicated the stability of healed metastatic bone lesions for the past 3 years on ADA. While TNF-α inhibitors could theoretically promote further metastases in patients with prior cancer, this is the first report of a patient with metastatic breast cancer in whom the cancer has remained stable for 3 years after ADA initiation for UC.
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http://dx.doi.org/10.3748/wjg.v20.i19.5912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4024802PMC
May 2014

A compositional look at the human gastrointestinal microbiome and immune activation parameters in HIV infected subjects.

PLoS Pathog 2014 Feb 20;10(2):e1003829. Epub 2014 Feb 20.

Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands ; Department of Immunology/Microbiology, Rush University Medical Center, Chicago, Illinois, United States of America.

HIV progression is characterized by immune activation and microbial translocation. One factor that may be contributing to HIV progression could be a dysbiotic microbiome. We therefore hypothesized that the GI mucosal microbiome is altered in HIV patients and this alteration correlates with immune activation in HIV. 121 specimens were collected from 21 HIV positive and 22 control human subjects during colonoscopy. The composition of the lower gastrointestinal tract mucosal and luminal bacterial microbiome was characterized using 16S rDNA pyrosequencing and was correlated to clinical parameters as well as immune activation and circulating bacterial products in HIV patients on ART. The composition of the HIV microbiome was significantly different than that of controls; it was less diverse in the right colon and terminal ileum, and was characterized by loss of bacterial taxa that are typically considered commensals. In HIV samples, there was a gain of some pathogenic bacterial taxa. This is the first report characterizing the terminal ileal and colonic mucosal microbiome in HIV patients with next generation sequencing. Limitations include use of HIV-infected subjects on HAART therapy.
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http://dx.doi.org/10.1371/journal.ppat.1003829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930561PMC
February 2014

Colonic microbiome is altered in alcoholism.

Am J Physiol Gastrointest Liver Physiol 2012 May 12;302(9):G966-78. Epub 2012 Jan 12.

Department of Medicine, Division of Digestive Diseases and Nutrition, Section of Gastroenterology, Rush University Medical Center, Chicago, Illinois 60612, USA.

Several studies indicate the importance of colonic microbiota in metabolic and inflammatory disorders and importance of diet on microbiota composition. The effects of alcohol, one of the prominent components of diet, on colonic bacterial composition is largely unknown. Mounting evidence suggests that gut-derived bacterial endotoxins are cofactors for alcohol-induced tissue injury and organ failure like alcoholic liver disease (ALD) that only occur in a subset of alcoholics. We hypothesized that chronic alcohol consumption results in alterations of the gut microbiome in a subgroup of alcoholics, and this may be responsible for the observed inflammatory state and endotoxemia in alcoholics. Thus we interrogated the mucosa-associated colonic microbiome in 48 alcoholics with and without ALD as well as 18 healthy subjects. Colonic biopsy samples from subjects were analyzed for microbiota composition using length heterogeneity PCR fingerprinting and multitag pyrosequencing. A subgroup of alcoholics have an altered colonic microbiome (dysbiosis). The alcoholics with dysbiosis had lower median abundances of Bacteroidetes and higher ones of Proteobacteria. The observed alterations appear to correlate with high levels of serum endotoxin in a subset of the samples. Network topology analysis indicated that alcohol use is correlated with decreased connectivity of the microbial network, and this alteration is seen even after an extended period of sobriety. We show that the colonic mucosa-associated bacterial microbiome is altered in a subset of alcoholics. The altered microbiota composition is persistent and correlates with endotoxemia in a subgroup of alcoholics.
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http://dx.doi.org/10.1152/ajpgi.00380.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3362077PMC
May 2012

Particulate matter air pollution causes oxidant-mediated increase in gut permeability in mice.

Part Fibre Toxicol 2011 Jun 9;8:19. Epub 2011 Jun 9.

Department of Medicine, Section of Gastroenterology and Nutrition Rush University Medical College, 1725 W Harrison Street, Chicago, IL 60612, USA.

Background: Exposure to particulate matter (PM) air pollution may be an important environmental factor leading to exacerbations of inflammatory illnesses in the GI tract. PM can gain access to the gastrointestinal (GI) tract via swallowing of air or secretions from the upper airways or mucociliary clearance of inhaled particles.

Methods: We measured PM-induced cell death and mitochondrial ROS generation in Caco-2 cells stably expressing oxidant sensitive GFP localized to mitochondria in the absence or presence of an antioxidant. C57BL/6 mice were exposed to a very high dose of urban PM from Washington, DC (200 μg/mouse) or saline via gastric gavage and small bowel and colonic tissue were harvested for histologic evaluation, and RNA isolation up to 48 hours. Permeability to 4 kD dextran was measured at 48 hours.

Results: PM induced mitochondrial ROS generation and cell death in Caco-2 cells. PM also caused oxidant-dependent NF-κB activation, disruption of tight junctions and increased permeability of Caco-2 monolayers. Mice exposed to PM had increased intestinal permeability compared with PBS treated mice. In the small bowel, colocalization of the tight junction protein, ZO-1 was lower in the PM treated animals. In the small bowel and colon, PM exposed mice had higher levels of IL-6 mRNA and reduced levels of ZO-1 mRNA. Increased apoptosis was observed in the colon of PM exposed mice.

Conclusions: Exposure to high doses of urban PM causes oxidant dependent GI epithelial cell death, disruption of tight junction proteins, inflammation and increased permeability in the gut in vitro and in vivo. These PM-induced changes may contribute to exacerbations of inflammatory disorders of the gut.
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http://dx.doi.org/10.1186/1743-8977-8-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3132719PMC
June 2011
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