Publications by authors named "Faraz Bishehsari"

62 Publications

Gastrointestinal Symptoms Predict the Outcomes From COVID-19 Infection.

J Clin Gastroenterol 2021 Mar 12. Epub 2021 Mar 12.

*Division of Gastroenterology, Department of Internal Medicine †Department of Internal Medicine ‡Rush Institute for Healthy Aging §Division of Allergy and Immunology, Department of Internal Medicine, Rush University Medical Center, Chicago, IL.

Coronavirus disease 2019 (COVID-19) has taken hundreds of thousands of lives globally. Besides the respiratory tract, the virus can affect the gastrointestinal (GI) tract. Data regarding the significance of GI symptoms in the COVID-19 course are limited. In this largest US study to date, the authors reviewed electronic encounters of 1003 consecutive patients who were tested positive for the virus between March 12 and April 3, 2020. Initial GI symptoms were present in up to 22.4% of patients and were associated with worse outcomes after adjustment for demographics, comorbidities, and other clinical symptoms. COVID-19 with GI involvement may define a more severe phenotype.
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http://dx.doi.org/10.1097/MCG.0000000000001513DOI Listing
March 2021

Opioid use as a potential risk factor for pancreatic cancer in the United States: An analysis of state and national level databases.

PLoS One 2021 6;16(1):e0244285. Epub 2021 Jan 6.

Division of Gastroenterology, Department of Internal Medicine, Rush University Medical Center, Chicago, IL, United States of America.

Pancreatic cancer (PC) rate is increasing in the U.S. The use of prescription and illicit opioids has continued to rise nationally in recent years as well. Opioids have been shown to have a deleterious effect on multiple types of cancer with recent data suggesting opium use as a risk factor for PC. Using national databases, we tested whether opioid usage pattern over time could explain the state and national-based variations in PC rates in the U.S. Opioid death rate (as a surrogate for prescription and illicit opioid use) was extracted from the CDCs Wonder online data through the Vital Statistics Cooperative Program. Incidence of pancreatic cancer was retrieved from the online CDCs data base gathered from the U.S. Cancer Statistics Working Group. Prevalence of obesity, tobacco and alcohol use was collected from Behavioral risk factor surveillance system. Mixed-effects regression models were used to test the association between levels of PC rate and opioid death/use rates during the years 1999-2016. A rise in PC was seen over time at the national and state levels. Similarly, the opioid death rates increased over time. Among other potential PC risk factors, only obesity prevalence showed an increase during the study period. A state's opioid death rate at 4 years prior significantly predicted initial incidence of PC (β = 0.1848, p<0.0001) and had a significant effect on the estimated annual change in the rate of PC (β = -.0193,p<0.0001). Opioid use may be an un-identified risk factor contributing to the increasing incidence of PC in the U.S. These novel findings need to be verified by population-based studies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244285PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787381PMC
January 2021

Response to Rathi et al.

Authors:
Faraz Bishehsari

Clin Transl Gastroenterol 2020 Dec 22;12(1):e00270. Epub 2020 Dec 22.

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

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http://dx.doi.org/10.14309/ctg.0000000000000270DOI Listing
December 2020

Interobserver reliability of methods to determine complete resection of adenomas in colonoscopy.

Endoscopy 2020 Dec 7. Epub 2020 Dec 7.

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

Background:  Forceps margin biopsy and polypectomy specimen margins have both been used to assess for polypectomy resection adequacy. The interobserver reliability of the two methods has not been well described.

Methods:  The interpretability of polypectomy specimens for presence of residual neoplasia at the margin was assessed by two blinded pathologists. Next, the concordance of forceps margin biopsy interpretations between three blinded pathologists was evaluated by calculation of interobserver .

Results:  Rates of polypectomy specimen margin interpretability were low: 24/92 (26 %) for pathologist A, 28/92 (30.4 %) for pathologist B. Concordance of forceps margin biopsy interpretations (n = 129) between pathologists was high. Two internal pathologists showed substantial agreement in margin biopsy interpretations ( 0.779; 95 %CL 0.543, 0.912). The concordance remained strong after biopsies were reviewed by a third, external pathologist ( 0.829; 95 %CL 0.658, 0.924). There was complete agreement on 123/129 (95.3 %) between all three pathologists for presence of neoplasia.

Conclusion:  The majority of polypectomy specimen margins were uninterpretable by pathologists for presence of residual neoplasia. Forceps margin biopsy shows strong interobserver reliability in adenomatous lesions.
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http://dx.doi.org/10.1055/a-1331-4446DOI Listing
December 2020

Abnormal food timing and predisposition to weight gain: Role of barrier dysfunction and microbiota.

Transl Res 2021 May 20;231:113-123. Epub 2020 Nov 20.

Department of Internal Medicine, Division of Gastroenterology, Rush University Medical Center, Chicago, Illinois; Department of Physiology, Rush University Medical Center, Chicago, Illinois; Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands.

Obesity has become a common rising health care problem, especially in "modern" societies. Obesity is considered a low-grade systemic inflammation, partly linked to leaky gut. Circadian rhythm disruption, a common habit in modern life, has been reported to cause gut barrier impairment. Abnormal time of eating, defined by eating close to or during rest time, is shown to cause circadian rhythm disruption. Here, using a non-obesogenic diet, we found that abnormal feeding time facilitated weight gain and induced metabolic dysregulation in mice. The effect of abnormal time of eating was associated with increased gut permeability, estimated by sucralose and/or lactulose ratio and disrupted intestinal barrier marker. Analysis of gut microbiota and their metabolites, as important regulators of barrier homeostasis, revealed that abnormal food timing reduced relative abundance of butyrate-producing bacteria, and the colonic butyrate level. Overall, our data supported that dysbiosis was characterized by increased intestinal permeability and decreased beneficial barrier butyrate-producing bacteria and/or metabolite to mechanistically link the time of eating to obesity. This data provides basis for noninvasive microbial-targeted interventions to improve intestinal barrier function as new opportunities for combating circadian rhythm disruption induced metabolic dysfunction.
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http://dx.doi.org/10.1016/j.trsl.2020.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016699PMC
May 2021

Circadian rhythms and the gut microbiota: from the metabolic syndrome to cancer.

Nat Rev Endocrinol 2020 12 26;16(12):731-739. Epub 2020 Oct 26.

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

The metabolic syndrome is prevalent in developed nations and accounts for the largest burden of non-communicable diseases worldwide. The metabolic syndrome has direct effects on health and increases the risk of developing cancer. Lifestyle factors that are known to promote the metabolic syndrome generally cause pro-inflammatory alterations in microbiota communities in the intestine. Indeed, alterations to the structure and function of intestinal microbiota are sufficient to promote the metabolic syndrome, inflammation and cancer. Among the lifestyle factors that are associated with the metabolic syndrome, disruption of the circadian system, known as circadian dysrhythmia, is increasingly common. Disruption of the circadian system can alter microbiome communities and can perturb host metabolism, energy homeostasis and inflammatory pathways, which leads to the metabolic syndrome. This Perspective discusses the role of intestinal microbiota and microbial metabolites in mediating the effects of disruption of circadian rhythms on human health.
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http://dx.doi.org/10.1038/s41574-020-00427-4DOI Listing
December 2020

Abnormal Food Timing Promotes Alcohol-Associated Dysbiosis and Colon Carcinogenesis Pathways.

Front Oncol 2020 17;10:1029. Epub 2020 Jul 17.

Department of Mathematics, Statistics, and Computer Science, University of Illinois at Chicago, Chicago, IL, United States.

Alcohol consumption is an established risk factor for colorectal cancer (CRC). Identifying cofactor(s) that modulate the effect of alcohol on colon inflammation and carcinogenesis could help risk stratification for CRC. Disruption of circadian rhythm by light/dark shift promotes alcohol-induced colonic inflammation and cancer. More recently, we found that abnormal food timing causes circadian rhythm disruption and promotes alcohol associated colon carcinogenesis. In this study, we examined the interaction of wrong-time feeding (WTF) and alcohol on CRC-related pathways, in relation to changes in microbial community structure. Polyposis mice (TS4Cre ×) underwent four conditions: alcohol or water and feeding during the light (wrong-time fed/WTF) or during the dark (right-time fed). Colonic cecum mucosal gene expression was analyzed by RNA-seq. Microbiota 16S ribosomal RNA sequencing analysis was used to examine colonic feces. Modeling was used to estimate the extent of the gene expression changes that could be related to the changes in the colonic microbial composition. The circadian rhythm pathway was the most altered pathway by the WTF treatment, indicating that WTF is disruptive to the colonic circadian rhythm. Pathway analysis revealed interaction of WTF with alcohol in dysregulating pathways related to colon carcinogenesis. Similarly, the interaction of alcohol and WTF was detected at multiple parameters of the colonic microbiota including α and β diversity, as well as the community structure. Our modeling revealed that almost a third of total gene alterations induced by our treatments could be related to alterations in the abundance of the microbial taxa. These data support the promoting effect of abnormal food timing alcohol-associated CRC-related pathways in the colon and suggest colon dysbiosis as a targetable mechanism.
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http://dx.doi.org/10.3389/fonc.2020.01029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396506PMC
July 2020

Pancreatic Fat Infiltration Is Associated with a Higher Risk of Pancreatic Ductal Adenocarcinoma.

Visc Med 2020 Jun 5;36(3):220-226. Epub 2020 May 5.

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

Background: Pancreatic ductal adenocarcinoma (PDAC) has a poor survival rate, partly due to delayed diagnosis. Identifying high-risk individuals could lead to early detection and improve survival. A number of risk factors such as alcohol consumption and metabolic syndrome are associated with fatty infiltration of the pancreas. Experimental models show that a fatty pancreas promotes tissue inflammation and fibrosis, which could promote PDAC.

Methods: We conducted a case-control study in a single-university tertiary hospital. Sixty-eight PDAC cases with recent non-contrast computed tomography (CT) and 235 controls were studied. The controls had no history of malignancy and underwent CT colonography for cancer screening in the same period. Pancreatic fat was estimated by calculating pancreatic (P) attenuation, corrected to splenic (S) attenuation, measured in three 1.0-cm regions of the pancreas. The P.S100 value calculated was used to estimate fatty infiltration of the pancreas (FIP), with a lower P.S100 representing a higher FIP.

Results: The PDAC patients had a lower BMI and a higher rate of type 2 diabetes mellitus. The P.S100 was lower in cases than in controls (86.452 vs. 92.414, = 4.016e-06), suggesting that FIP is higher with PDAC. The risk of developing PDAC steadily increased significantly for the quartiles with a higher FIP compared to the low FIP quartile. No correlation between BMI and FIP ( = -0.1031179; 95% confidence interval [CI] -0.22267106 to 0.01949092) was found. Adjusting for confounders (age, sex, BMI, and DM), the risk of developing PDAC according to the FIP was estimated to be 3.75 (95% CI 1.9234408-7.993337; = 0.000171). FIP was stable before and after the diagnosis of PDAC in 9 cases with prior CT scans when no pancreatic tumor was identifiable.

Conclusion: Fatty pancreas is associated with an increased risk of pancreatic cancer. Once confirmed in larger-scale studies, these findings could help to identify at-risk individuals, particularly in high-risk groups such as chronic alcohol consumers.
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http://dx.doi.org/10.1159/000507457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383241PMC
June 2020

Alcohol-Induced Immune Dysregulation in the Colon Is Diurnally Variable.

Visc Med 2020 Jun 21;36(3):212-219. Epub 2020 Apr 21.

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

Introduction: Alcohol increases the risk of colon cancer. Colonic inflammation mediates the effects of alcohol on colon carcinogenesis. Circadian rhythm disruption enhances the alcohol's effect on colonic inflammation and cancer.

Objective: Here, we investigate the diurnal variation of lymphocyte infiltration in the colonic mucosa in response to alcohol.

Methods: Sixty C57BL6/J mice were fed a chow diet, and gavaged with alcohol at a specific time once per day for 3 consecutive days. Immunohistochemistry and immunofluorescence staining were used to quantify total, effector, and regulatory T cells in the colon. Student's test, one-way ANOVA, and two-way ANOVA were used to determine significance.

Results: Following the alcohol binge, the composition of immune T cell subsets in the mouse colon was time-dependent. Alcohol did not alter the total number of CD3 T cells. However, upon alcohol treatment, T-bet T helper 1 (Th1) cells appeared to dominate the T cell population following a reduction in Foxp3 regulatory T cell (Treg) numbers. Depletion of Tregs was time-dependent, and their numbers were dramatically reduced when alcohol was administered during the rest phase. A reduction in Tregs significantly increased the Th1/Treg ratio, resulting in a more proinflammatory milieu.

Conclusions: Alcohol enhanced the proinflammatory profile in the colon mucosa, as demonstrated by a higher T-bet/Foxp3 ratio, especially during the rest phase. These findings may partly account for the interaction of circadian rhythm disruption with alcohol in colon inflammation and cancer.
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http://dx.doi.org/10.1159/000507124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383251PMC
June 2020

Marked Elevation of Lipase in COVID-19 Disease: A Cohort Study.

Clin Transl Gastroenterol 2020 07;11(7):e00215

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

Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing the pandemic of coronavirus disease 2019 (COVID-19) is a global health crisis. Possible pancreatic involvement has recently been observed in these patients; however, its significance is unclear. The aim of this study was to evaluate the association of significantly elevated lipase with disease outcomes.

Methods: Data about demographics, symptoms, laboratory values, and clinical outcomes were collected for 1,003 consecutive patients testing positive for COVID-19. Elevated lipase was defined as greater than 3 times the upper limit of normal (>3 × ULN). Baseline characteristics among patients with or without elevated lipase were compared using Fisher exact test or Student t-test for categorical or numerical variables, respectively. Logistic regression was used to evaluate the association of lipase levels with primary clinical outcomes (intensive care unit admission and intubation) adjusted for age, sex, body mass index, history of diabetes, and hypertension.

Results: Of 1,003 patients with COVID-19, 83 had available lipase levels and were all admitted to the hospital. Of 83, 14 (16.8%) had elevated lipase (>3 × ULN), which was associated with higher rates of leukocytosis (P < 0.001) and abnormal liver enzymes (P < 0.01). Compared with lower lipase levels (<3 × ULN), patients with elevated lipase had higher rates of ICU admission (92.9% vs 32.8%; P < 0.001) and intubation (78.6% vs 23.5%; P 0.002). In a multivariable-adjusted model, higher lipase levels were significantly associated with admission to the ICU and rate of intubation.

Discussion: Lipase elevation is seen in COVID-19 and is associated with worse disease outcomes.
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http://dx.doi.org/10.14309/ctg.0000000000000215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386395PMC
July 2020

Smell loss is a prognostic factor for lower severity of coronavirus disease 2019.

Ann Allergy Asthma Immunol 2020 10 24;125(4):481-483. Epub 2020 Jul 24.

Division of Allergy and Immunology, Department of Internal Medicine Rush University Medical Center, Chicago, Illinois. Electronic address:

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http://dx.doi.org/10.1016/j.anai.2020.07.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380219PMC
October 2020

Interaction of alcohol with time of eating on markers of circadian dyssynchrony and colon tissue injury.

Chem Biol Interact 2020 Jul 11;325:109132. Epub 2020 May 11.

Department of Internal Medicine, Division of Gastroenterology, Rush University Medical Center, Chicago, IL, USA; Department of Physiology, Rush University Medical Center, Chicago, IL, USA; Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands; Department of Pharmacology, Rush University Medical Center, Chicago, IL, USA.

Background: Alcohol increases the risk of developing colon cancer (CRC), in part via tissue inflammation and impaired barrier integrity. Circadian dyssynchrony (CD) is an understudied but common lifestyle associated factor that increases the risk of multi-organ tissue injury and number of malignancies including CRC. Our prior studies showed that the shift in light-dark cycle exacerbates barrier dysfunction and colonic inflammation in the setting of alcohol treatment, and increases the risk of CRC. Here we studied the interaction of alcohol with an abnormal eating pattern on markers of CD and colonic barrier integrity.

Method: Mice were subjected to day (rest-phase = wrong-time WT) or night-time (active-phase = right-time RT) access to food in combination with access to water or 15% alcohol for total duration of 10 weeks. The food and liquid intake was measured. The locomotor activity data was recorded throughout the study, using a beam-break system. Mice were euthanized at two time points (ZT2 and ZT14). Time variation in the expression of the molecular marker of circadian clock (per2 gene) was measured in the central (hypothalamus) and intestinal (colon) tissue. Colonic protein expression of barrier markers (Occludin and Claudin-1) was studied.

Results: No significant differences were present in the weight gain and alcohol intake among the groups over the study period. We observed an interaction of WT eating with alcohol on behavioral markers of circadian rhythm. Compared to the RT + Water treated animals ("reference group"), combination of WT eating and alcohol consumption (WT + Alcohol) significantly changed the per2 oscillatory pattern, that was different between the colon and hypothalamus, indicative of worsening circadian dyssynchrony. This was associated with an overall impaired expression of barrier integrity markers in the colon.

Conclusions: Alcohol induces circadian dyssynchrony which is worsened by abnormal food timing, associated with impaired barrier integrity in the colon. Future studies on the interaction of alcohol and food timing could provide further insights into alcohol associated CRC pathophysiology.
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http://dx.doi.org/10.1016/j.cbi.2020.109132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315934PMC
July 2020

Asthma prolongs intubation in COVID-19.

J Allergy Clin Immunol Pract 2020 Jul - Aug;8(7):2388-2391. Epub 2020 May 14.

Department of Internal Medicine, Rush University Medical Center, Chicago, Ill.

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http://dx.doi.org/10.1016/j.jaip.2020.05.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7224651PMC
July 2020

Summary of the 2019 alcohol and immunology research interest group (AIRIG) meeting: Alcohol-mediated mechanisms of multiple organ injury.

Alcohol 2020 09 28;87:89-95. Epub 2020 Apr 28.

Department of Surgery, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA; Alcohol Research Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA; Immunology Graduate Program, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA.

On November 15, 2019, the 24th annual Alcohol and Immunology Research Interest Group (AIRIG) meeting was held as a satellite conference during the annual Society for Leukocyte Biology meeting in Boston, Massachusetts. The 2019 meeting focused on alcohol, immunity, and organ damage, and included two plenary sessions. The first session highlighted new research exploring the mechanisms of alcohol-induced inflammation and liver disease, including effects on lipidomics and lipophagy, regulatory T cells, epigenetics, epithelial cells, and age-related changes in the gut. The second session covered alcohol-induced injury of other organs, encompassing diverse areas of research ranging from neurodegeneration, to lung barrier function, to colon carcinogenesis, to effects on viral infection. The discussions also highlighted current laboratory and clinical research used to identify biomarkers of alcohol use and disease.
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http://dx.doi.org/10.1016/j.alcohol.2020.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483664PMC
September 2020

Corrigendum to "A gut connection in mucous membrane pemphigoid: Insights into the role of the microbiome" [Ocul Surf 17 (4) (2019) 615-616].

Ocul Surf 2020 04 13;18(2):349. Epub 2020 Feb 13.

Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, United States. Electronic address:

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http://dx.doi.org/10.1016/j.jtos.2020.02.002DOI Listing
April 2020

Abnormal Eating Patterns Cause Circadian Disruption and Promote Alcohol-Associated Colon Carcinogenesis.

Cell Mol Gastroenterol Hepatol 2020 2;9(2):219-237. Epub 2019 Nov 2.

Department of Immunology, Mayo Clinic, Rochester, Minnesota. Electronic address:

Background & Aims: Alcohol intake with circadian rhythm disruption (CRD) increases colon cancer risk. We hypothesized that eating during or around physiologic rest time, a common habit in modern society, causes CRD and investigated the mechanisms by which it promotes alcohol-associated colon carcinogenesis.

Methods: The effect of feeding time on CRD was assessed using B6 mice expressing a fusion protein of PERIOD2 and LUCIFERASE (PER2::LUC) were used to model colon polyposis and to assess the effects of feeding schedules, alcohol consumption, and prebiotic treatment on microbiota composition, short-chain fatty acid levels, colon inflammation, and cancer risk. The relationship between butyrate signaling and a proinflammatory profile was assessed by inactivating the butyrate receptor GPR109A.

Results: Eating at rest (wrong-time eating [WTE]) shifted the phase of the colon rhythm in PER2::LUC mice. In TS4Cre × APC mice, a combination of WTE and alcohol exposure (WTE + alcohol) decreased the levels of short-chain fatty acid-producing bacteria and of butyrate, reduced colonic densities of regulatory T cells, induced a proinflammatory profile characterized by hyperpermeability and an increased mucosal T-helper cell 17/regulatory T cell ratio, and promoted colorectal cancer. Prebiotic treatment improved the mucosal inflammatory profile and attenuated inflammation and cancer. WTE + alcohol-induced polyposis was associated with increased signal transducer and activator of transcription 3 expression. Decreased butyrate signaling activated the epithelial signal transducer and activator of transcription 3 in vitro. The relationship between butyrate signaling and a proinflammatory profile was confirmed in human colorectal cancers using The Cancer Genome Atlas.

Conclusions: Abnormal timing of food intake caused CRD and interacts with alcohol consumption to promote colon carcinogenesis by inducing a protumorigenic inflammatory profile driven by changes in the colon microbiota and butyrate signaling. Accession number of repository for microbiota sequence data: raw FASTQ data were deposited in the NCBI Sequence Read Archive under project PRJNA523141.
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http://dx.doi.org/10.1016/j.jcmgh.2019.10.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6957855PMC
November 2019

Microbes help to track time.

Science 2019 09;365(6460):1379-1380

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

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http://dx.doi.org/10.1126/science.aaz0224DOI Listing
September 2019

A gut connection in mucous membrane pemphigoid: Insights into the role of the microbiome.

Ocul Surf 2019 10 18;17(4):615-616. Epub 2019 Sep 18.

Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, IL, United States. Electronic address:

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http://dx.doi.org/10.1016/j.jtos.2019.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988187PMC
October 2019

Assessment of the impact of different fecal storage protocols on the microbiota diversity and composition: a pilot study.

BMC Microbiol 2019 06 28;19(1):145. Epub 2019 Jun 28.

Digestive Oncology Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran.

Background: Fecal samples are currently the most commonly studied proxy for gut microbiota. The gold standard of sample handling and storage for microbiota analysis is maintaining the cold chain during sample transfer and immediate storage at - 80 °C. Gut microbiota studies in large-scale, population-based cohorts require a feasible sample collection protocol. We compared the effect of three different storage methods and mock shipment: immediate freezing at - 80 °C, in 95% ethanol stored at room temperature (RT) for 48 h, and on blood collection card stored at RT for 48 h, on the measured composition of fecal microbiota of eight healthy, female volunteers by sequencing the V4 region of the 16S rRNA gene on an Illumina MiSeq.

Results: Shared operational taxonomic units (OTUs) between different methods were 68 and 3% for OTUs > 0.01 and < 0.01% mean relative abundance within each group, respectively. α and β-diversity measures were not significantly impacted by different storage methods. With the exception of Actinobacteria, fecal microbiota profiles at the phylum level were not significantly affected by the storage method. Actinobacteria was significantly higher in samples collected on card compared to immediate freezing (1.6 ± 1.1% vs. 0.4 ± 0.2%, p = 0.005) mainly driven by expansion of Actinobacteria relative abundance in fecal samples stored on card in two individuals. There was no statistically significant difference at lower taxonomic levels tested.

Conclusion: Consistent results of the microbiota composition and structure for different storage methods were observed. Fecal collection on card could be a suitable alternative to immediate freezing for fecal microbiota analysis using 16S rRNA gene amplicon sequencing.
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http://dx.doi.org/10.1186/s12866-019-1519-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599303PMC
June 2019

Alcohol Effects on Colon Epithelium are Time-Dependent.

Alcohol Clin Exp Res 2019 09 22;43(9):1898-1908. Epub 2019 Jul 22.

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

Background: Alcohol intake increases the risk of developing colon cancer. Circadian disruption promotes alcohol's effect on colon carcinogenesis through unknown mechanisms. Alcohol's metabolites induce DNA damage, an early step in carcinogenesis. We assessed the effect of time of alcohol consumption on markers of tissue damage in the colonic epithelium.

Methods: Mice were treated by alcohol or phosphate-buffered saline (PBS), at 4-hour intervals for 3 days, and their colons were analyzed for (i) proliferation (Ki67) and antiapoptosis (Bcl-2) markers, (ii) DNA damage (γ-H2AX), and (iii) the major acetaldehyde (AcH)-DNA adduct, N -ethylidene-dG. To model circadian disruption, mice were shifted once weekly for 12 h and then were sacrificed at 4-hour intervals. Samples of mice with a dysfunctional molecular clock were analyzed. The dynamics of DNA damage repair from AcH treatment as well as role of xeroderma pigmentosum, complementation group A (XPA) in their repair were studied in vitro.

Results: Proliferation and survival of colonic epithelium have daily rhythmicity. Alcohol induced colonic epithelium proliferation in a time-dependent manner, with a stronger effect during the light/rest period. Alcohol-associated DNA damage also occurred more when alcohol was given at light. Levels of DNA adduct did not vary by time, suggesting rather lower repair efficiency during the light versus dark. XPA gene expression, a key excision repair gene, was time-dependent, peaking at the beginning of the dark. XPA knockout colon epithelial cells were inefficient in repair of the DNA damage induced by alcohol's metabolite.

Conclusions: Time of day of alcohol intake may be an important determinant of colon tissue damage and carcinogenicity.
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http://dx.doi.org/10.1111/acer.14141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722020PMC
September 2019

Nutraceuticals in colorectal cancer: A mechanistic approach.

Eur J Pharmacol 2018 Aug 20;833:396-402. Epub 2018 Jun 20.

Department of Internal Medicine, Division of Digestive Diseases, Hepatology, and Nutrition, Rush University Medical Center, Chicago, IL 60612, USA. Electronic address:

Colorectal cancer (CRC) is one of the most diagnosed cancers in the world. Even though screening, surgery and oncology have greatly advanced, CRC is still one of the leading causes of cancer deaths, with 700,000 annual mortalities in both men and women. Environmental and lifestyle factors brought up by industrialization, such as an altered diet, lack of physical activity, increase in alcohol consumption, and circadian disruption, have greatly affected the burden of CRC. These factors increase the CRC risk, at least partly, by pathologically altering the colonic environment, including composition of the gut microbiota, referred to as dysbiosis. Colonic dysbiosis can promote pro-carcinogenic immune signaling cascades, leading to pro-tumorigenic inflammation, carcinogen production, and altered cellular responses in susceptible host resulting to development and/or progression of CRC. Nutraceuticals such as prebiotic molecules and probiotic bacterial species can help maintain intestinal microbial homeostasis and thus mitigate this pathological processes. Therefore, prebiotics and probiotics can hinder the effects of dysbiosis by encouraging anti-carcinogenic, anti-inflammatory immunity, the maintenance of the intestinal epithelial barrier, pro-apoptotic mechanisms, and carcinogen inactivation. In addition to its implications in preventing CRC, because of the mechanisms affected, nutraceuticals are being discovered as potential adjuncts to immune checkpoint inhibitors in the treatment of CRC. In this review, we provide an overview of the potential implications of prebiotics and probiotics in the prevention and treatment of CRC.
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http://dx.doi.org/10.1016/j.ejphar.2018.06.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063737PMC
August 2018

Alternative approaches to polyp extraction in colonoscopy: a proof of principle study.

Gastrointest Endosc 2018 09 6;88(3):536-541. Epub 2018 Jun 6.

Department of Gastroenterology, Rush University Medical Center, Chicago, Illinois, USA.

Background And Aims: A limitation of determination of the completeness of resection in polypectomy is polyp fragmentation. When a polyp fragments, the pathologist cannot determine resection completeness. Alternative approaches to reduce polyp fragmentation include reducing shearing forces on the polyp or removing polyps through the instrument channel. The primary aim of this study was to assess fragmentation of polyps extracted using different approaches from conventional polyp retrieval.

Methods: Polyps (5-15 mm) resected by cold snare or cautery by 3 colonoscopists were extracted from the colonoscope using 1 of 4 techniques. Method I was the conventional method of pressing the suction valve button and retrieving the polyp through a trap. Method II involved removing the suction valve, covering the open suction valve cylinder with a finger. Method III used a Roth Net polyp retriever placed through the instrument channel. Method IV involved connecting a polyp trap to suction onto the instrument channel port. Fragmentation was defined as multiple pieces of the specimen in formalin, as grossly described by the pathologist. Alternative approaches (methods II, III, and IV) were all compared with the conventional method (method I).

Results: The method I fragmentation rate of polyps was 60.3% (123/204). Method II extraction reduced fragmentation to 43.0% (52/121, P = .003), proving that fragmentation occurs with passage through the suction valve channel. Method III had a lower fragmentation rate of 23.1% (6/26, P < .001). Method IV likewise showed a reduced fragmentation rate of 18.5% (5/27, P < .001).

Conclusions: Polyp fragmentation is reduced by removal of the suction valve button. There is also a decrease in fragmentation rates in removing the polyp by connecting the polyp trap to the instrument port. Our study suggests that decreasing polyp fragmentation and improving pathology margin interpretability is possible through methods that extract polyps through the instrument port with currently available devices.
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http://dx.doi.org/10.1016/j.gie.2018.05.015DOI Listing
September 2018

KRAS mutation and epithelial-macrophage interplay in pancreatic neoplastic transformation.

Int J Cancer 2018 10 9;143(8):1994-2007. Epub 2018 Aug 9.

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

Pancreatic ductal adenocarcinoma (PDA) is characterized by epithelial mutations in KRAS and prominent tumor-associated inflammation, including macrophage infiltration. But knowledge of early interactions between neoplastic epithelium and macrophages in PDA carcinogenesis is limited. Using a pancreatic organoid model, we found that the expression of mutant KRAS in organoids increased (i) ductal to acinar gene expression ratios, (ii) epithelial cells proliferation and (iii) colony formation capacity in vitro, and endowed pancreatic cells with the ability to generate neoplastic tumors in vivo. KRAS mutations induced a protumorigenic phenotype in macrophages. Altered macrophages decreased epithelial pigment epithelial derived factor (PEDF) expression and induced a cancerous phenotype. We validated our findings using annotated patient samples from The Cancer Genome Atlas (TCGA) and in our human PDA specimens. Epithelium-macrophage cross-talk occurs early in pancreatic carcinogenesis where KRAS directly induces cancer-related phenotypes in epithelium, and also promotes a protumorigenic phenotype in macrophages, in turn augmenting neoplastic growth.
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http://dx.doi.org/10.1002/ijc.31592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6128758PMC
October 2018

Feasibility of Colon Cancer Screening by Fecal Immunochemical Test in Iran.

Arch Iran Med 2017 Dec 1;20(12):726-733. Epub 2017 Dec 1.

Digestive Oncology Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.

Background: Colorectal cancer (CRC) is the third most common cancer in Iran, where there is no mass screening for the disease yet. We aimed to measure the feasibility of a pilot CRC screening program based on fecal immunochemical test (FIT) in Iranian population and the implications for scaling-up at the national level.

Methods: A single quantitative FIT was offered by health navigators to individuals aged between 45 and 75 years in primary health centers in rural and urban areas in Tehran. Participants who had a positive FIT were referred for colonoscopy.

Results: A total of 1044 asymptomatic average-risk individuals were enrolled. The mean age (SD) was 54.1 ± 7.0 years and nearly 63.0% (n = 657) were female. Only a small fraction of the participants had a prior screening practice (2.2%) and were aware of colon cancer (13.7%). In sum, 1002 returned the FIT kit, of whom the stool sample was unsatisfactory for testing in six participants (0.6%). The FIT uptake was 96.0%, positivity rate was 9.1% and the detection rates were 11.9% for adenomas and 7.1% for advanced adenomas. No cancer was detected. The positive predictive value (PPV) of the FIT was about 17% for any colonic neoplasms.

Conclusion: This is the first study that reports minimal quality metrics within a CRC screening process. FIT modality as a test of choice for colon cancer screening in average-risk people is a safe and highly acceptable method of screening in Iranian people. The results of the current study may not be limited to Iranians, and could have implications to other developing countries with similar trends of CRC epidemic.
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December 2017

Dietary Fiber Treatment Corrects the Composition of Gut Microbiota, Promotes SCFA Production, and Suppresses Colon Carcinogenesis.

Genes (Basel) 2018 Feb 16;9(2). Epub 2018 Feb 16.

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

Epidemiological studies propose a protective role for dietary fiber in colon cancer (CRC). One possible mechanism of fiber is its fermentation property in the gut and ability to change microbiota composition and function. Here, we investigate the role of a dietary fiber mixture in polyposis and elucidate potential mechanisms using TS4Cre×cAPC° mice. Stool microbiota profiling was performed, while functional prediction was done using PICRUSt. Stool short-chain fatty acid (SCFA) metabolites were measured. Histone acetylation and expression of SCFA butyrate receptor were assessed. We found that SCFA-producing bacteria were lower in the polyposis mice, suggesting a decline in the fermentation product of dietary fibers with polyposis. Next, a high fiber diet was given to polyposis mice, which significantly increased SCFA-producing bacteria as well as SCFA levels. This was associated with an increase in SCFA butyrate receptor and a significant decrease in polyposis. In conclusion, we found polyposis to be associated with dysbiotic microbiota characterized by a decline in SCFA-producing bacteria, which was targetable by high fiber treatment, leading to an increase in SCFA levels and amelioration of polyposis. The prebiotic activity of fiber, promoting beneficial bacteria, could be the key mechanism for the protective effects of fiber on colon carcinogenesis. SCFA-promoting fermentable fibers are a promising dietary intervention to prevent CRC.
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http://dx.doi.org/10.3390/genes9020102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5852598PMC
February 2018

Colorectal Cancer and Alcohol Consumption-Populations to Molecules.

Cancers (Basel) 2018 Jan 30;10(2). Epub 2018 Jan 30.

Division of Digestive Diseases, Hepatology, and Nutrition, Department of Internal Medicine, Rush University Medical Center, Chicago, IL 60612, USA.

Colorectal cancer (CRC) is a major cause of morbidity and mortality, being the third most common cancer diagnosed in both men and women in the world. Several environmental and habitual factors have been associated with the CRC risk. Alcohol intake, a common and rising habit of modern society, is one of the major risk factors for development of CRC. Here, we will summarize the evidence linking alcohol with colon carcinogenesis and possible underlying mechanisms. Some epidemiologic studies suggest that even moderate drinking increases the CRC risk. Metabolism of alcohol involves ethanol conversion to its metabolites that could exert carcinogenic effects in the colon. Production of ethanol metabolites can be affected by the colon microbiota, another recently recognized mediating factor to colon carcinogenesis. The generation of acetaldehyde and alcohol's other metabolites leads to activation of cancer promoting cascades, such as DNA-adduct formation, oxidative stress and lipid peroxidation, epigenetic alterations, epithelial barrier dysfunction, and immune modulatory effects. Not only does alcohol induce its toxic effect through carcinogenic metabolites, but alcoholics themselves are predisposed to a poor diet, low in folate and fiber, and circadian disruption, which could further augment alcohol-induced colon carcinogenesis.
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http://dx.doi.org/10.3390/cancers10020038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5836070PMC
January 2018

Alcohol Feeding in Mice Promotes Colonic Hyperpermeability and Changes in Colonic Organoid Stem Cell Fate.

Alcohol Clin Exp Res 2017 Dec 7;41(12):2100-2113. Epub 2017 Nov 7.

Department of Pharmacology, Rush University, Chicago, Illinois.

Background: Alcohol increases intestinal permeability to proinflammatory microbial products that promote liver disease, even after a period of sobriety. We sought to test the hypothesis that alcohol affects intestinal stem cells using an in vivo model and ex vivo organoids generated from jejunum and colon from mice fed chronic alcohol.

Methods: Mice were fed a control or an alcohol diet. Intestinal permeability, liver steatosis-inflammation, and stool short-chain fatty acids (SCFAs) were measured. Jejunum and colonic organoids and tissue were stained for stem cell, cell lineage, and apical junction markers with assessment of mRNA by PCR and RNA-seq. ChIP-PCR analysis was carried out for Notch1 using an antibody specific for acetylated histone 3.

Results: Alcohol-fed mice exhibited colonic (but not small intestinal) hyperpermeability, steatohepatitis, and decreased butyrate/total SCFA ratio in stool. Stem cell, cell lineage, and apical junction marker staining in tissue or organoids from jejunum tissue were not impacted by alcohol. Only chromogranin A (Chga) was increased in jejunum organoids by qPCR. However, colonic tissue and organoid staining exhibited an alcohol-induced significant decrease in cytokeratin 20+  (Krt20+) absorptive lineage enterocytes, a decrease in occludin and E-cadherin apical junction proteins, an increase in Chga, and an increase in the Lgr5 stem cell marker. qPCR revealed an alcohol-induced decrease in colonic organoid and tissue Notch1, Hes1, and Krt20 and increased Chga, supporting an alteration in stem cell fate due to decreased Notch1 expression. Colonic tissue ChIP-PCR revealed alcohol feeding suppressed Notch1 mRNA expression (via deacetylation of histone H3) and decreased Notch1 tissue staining.

Conclusions: Data support a model for alcohol-induced colonic hyperpermeability via epigenetic effects on Notch1, and thus Hes1, suppression through a mechanism involving histone H3 deacetylation at the Notch1 locus. This decreased enterocyte and increased enteroendocrine cell colonic stem cell fate and decreased apical junctional proteins leading to hyperpermeability.
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http://dx.doi.org/10.1111/acer.13519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5711563PMC
December 2017

Alcohol and Gut-Derived Inflammation.

Alcohol Res 2017 ;38(2):163-171

Faraz Bishehsari, M.D., Ph.D., is an Assistant Professor; Garth Swanson, M.D., is an Assistant Professor; Vishal Desai, M.D., is a Physician; Robin M. Voigt, Ph.D., is an Assistant Professor; Christopher B. Forsyth, Ph.D., is an Associate Professor; and Ali Keshavarzian, M.D., is a Professor, all in the Department of Internal Medicine, Division of Gastroenterology, Rush University Medical Center, Chicago, Illinois. Emmeline Magno, M.D., is an Internist in the Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois.

In large amounts, alcohol and its metabolites can overwhelm the gastrointestinal tract (GI) and liver and lead to damage both within the GI and in other organs. Specifically, alcohol and its metabolites promote intestinal inflammation through multiple pathways. That inflammatory response, in turn, exacerbates alcohol-induced organ damage, creating a vicious cycle and leading to additional deleterious effects of alcohol both locally and systemically. This review summarizes the mechanisms by which chronic alcohol intake leads to intestinal inflammation, including altering intestinal microbiota composition and function, increasing the permeability of the intestinal lining, and affecting the intestinal immune homeostasis. Understanding the mechanisms of alcohol-induced intestinal inflammation can aid in the discovery of therapeutic approaches to mitigate alcohol-induced organ dysfunctions.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5513683PMC
May 2018

Erratum to: LINE-1 is preferentially hypomethylated within adenomatous polyps in the presence of synchronous colorectal cancer.

Clin Epigenetics 2017;9:76. Epub 2017 Jul 27.

Department of Internal Medicine, Rush University Medical Center, 1717 W Congress Parkway, 10 Kellogg, Chicago, IL 60612 USA.

[This corrects the article DOI: 10.1186/s13148-017-0325-7.].
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http://dx.doi.org/10.1186/s13148-017-0375-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5530521PMC
July 2017

Screening for Lynch Syndrome in Cases with Colorectal Carcinoma from Mashhad.

Arch Iran Med 2017 Jun;20(6):332-337

Anatomical and Clinical Pathologist, Moayyed Medical Laboratory, Mashhad, Iran.

Introduction: Lynch Syndrome (LS) is a genetically inherited autosomal disorder that increases the risk of many types of cancer, especially colorectal cancer (CRC). Identifying these subjects improves morbidity and mortality. We aimed to assess the prevalence of LS with both clinical criteria and universal strategy in Mashhad, Iran.

Methods: In this retrospective study, we screened 322 patients with CRC between 2013 and 2016 in Mashhad, Iran. CRCs were screened based on Amsterdam II criteria, revised Bethesda guideline, and universal strategy. Information regarding the clinical criteria was obtained by interviewing the patients or, their families. Tumors were screened by pathologists with IHC staining of four Mismatch repair (MMR) proteins (MLH1, MSH2, MSH6, and PMS2). Tumors with absent IHC staining of MLH1 were tested for BRAF mutations to exclude sporadic CRCs.

Results: Of 322 CRCs, 33 cases were found to be deficient-MMR; 22 of these had concurrent loss of MLH1 and PMS2, followed by concurrent loss of MSH2 and MSH6 in 8 CRCs. Twenty-two cases with a loss of MLH1 underwent testing for the BRAF mutation, 4 of which were recognized as a positive BRAF mutation. Finally, 29 CRCs were found as being positive screen for LS. Poor sensitivity (21.74%) was found for the Amsterdam II criteria and a poor positive predictive value (15.39%) for the revised Bethesda.

Conclusion: Application of clinical criteria may not be effective enough to identify LS and at least 2-antibody panel (PMS2, MSH6) should be conducted for newly diagnosed CRCs.
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http://dx.doi.org/0172006/AIM.003DOI Listing
June 2017