Publications by authors named "Zamir Halpern"

120 Publications

Impaired COMMD10-Mediated Regulation of Ly6C Monocyte-Driven Inflammation Disrupts Gut Barrier Function.

Front Immunol 2018 14;9:2623. Epub 2018 Nov 14.

The Research Center for Digestive Tract and Liver Diseases, Tel-Aviv Sourasky Medical Center and Sackler School of Medicine, Tel-Aviv University, Tel Aviv, Israel.

Ly6C monocyte tissue infiltrates play important roles in mediating local inflammation, bacterial elimination and resolution during sepsis and inflammatory bowel disease (IBD). Yet, the immunoregulatory pathways dictating their activity remain poorly understood. COMMD family proteins are emerging as key regulators of signaling and protein trafficking events during inflammation, but the specific role of COMMD10 in governing Ly6C monocyte-driven inflammation is unknown. Here we report that COMMD10 curbs canonical and non-canonical inflammasome activity in Ly6C monocytes in a model of LPS-induced systemic inflammation. Accordingly, its deficiency in myeloid cells, but not in tissue resident macrophages, resulted in increased Ly6C monocyte liver and colonic infiltrates, elevated systemic cytokine storm, increased activation of caspase-1 and-11 in the liver and colon, and augmented IL-1β production systemically and specifically in LPS-challenged circulating Ly6C monocytes. These inflammatory manifestations were accompanied by impaired intestinal barrier function with ensuing bacterial dissemination to the mesenteric lymph nodes and liver leading to increased mortality. The increased inflammasome activity and intestinal barrier leakage were ameliorated by the inducible ablation of COMMD10-deficient Ly6C monocytes. In consistence with these results, COMMD10-deficiency in Ly6C monocytes, but not in intestinal-resident lamina propria macrophages, led to increased IL-1β production and aggravated colonic inflammation in a model of DSS-induced colitis. Finally, COMMD10 expression was reduced in Ly6C monocytes and their corresponding human CD14 monocytes sorted from mice subjected to DSS-induced colitis or from IBD patients, respectively. Collectively, these results highlight COMMD10 as a negative regulator of Ly6C monocyte inflammasome activity during systemic inflammation and IBD.
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http://dx.doi.org/10.3389/fimmu.2018.02623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6246736PMC
October 2019

Post-Antibiotic Gut Mucosal Microbiome Reconstitution Is Impaired by Probiotics and Improved by Autologous FMT.

Cell 2018 09;174(6):1406-1423.e16

Immunology Department, Weizmann Institute of Science, 7610001 Rehovot, Israel. Electronic address:

Probiotics are widely prescribed for prevention of antibiotics-associated dysbiosis and related adverse effects. However, probiotic impact on post-antibiotic reconstitution of the gut mucosal host-microbiome niche remains elusive. We invasively examined the effects of multi-strain probiotics or autologous fecal microbiome transplantation (aFMT) on post-antibiotic reconstitution of the murine and human mucosal microbiome niche. Contrary to homeostasis, antibiotic perturbation enhanced probiotics colonization in the human mucosa but only mildly improved colonization in mice. Compared to spontaneous post-antibiotic recovery, probiotics induced a markedly delayed and persistently incomplete indigenous stool/mucosal microbiome reconstitution and host transcriptome recovery toward homeostatic configuration, while aFMT induced a rapid and near-complete recovery within days of administration. In vitro, Lactobacillus-secreted soluble factors contributed to probiotics-induced microbiome inhibition. Collectively, potential post-antibiotic probiotic benefits may be offset by a compromised gut mucosal recovery, highlighting a need of developing aFMT or personalized probiotic approaches achieving mucosal protection without compromising microbiome recolonization in the antibiotics-perturbed host.
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http://dx.doi.org/10.1016/j.cell.2018.08.047DOI Listing
September 2018

Personalized Gut Mucosal Colonization Resistance to Empiric Probiotics Is Associated with Unique Host and Microbiome Features.

Cell 2018 09;174(6):1388-1405.e21

Immunology Department, Weizmann Institute of Science, Rehovot, 7610001, Israel. Electronic address:

Empiric probiotics are commonly consumed by healthy individuals as means of life quality improvement and disease prevention. However, evidence of probiotic gut mucosal colonization efficacy remains sparse and controversial. We metagenomically characterized the murine and human mucosal-associated gastrointestinal microbiome and found it to only partially correlate with stool microbiome. A sequential invasive multi-omics measurement at baseline and during consumption of an 11-strain probiotic combination or placebo demonstrated that probiotics remain viable upon gastrointestinal passage. In colonized, but not germ-free mice, probiotics encountered a marked mucosal colonization resistance. In contrast, humans featured person-, region- and strain-specific mucosal colonization patterns, hallmarked by predictive baseline host and microbiome features, but indistinguishable by probiotics presence in stool. Consequently, probiotics induced a transient, individualized impact on mucosal community structure and gut transcriptome. Collectively, empiric probiotics supplementation may be limited in universally and persistently impacting the gut mucosa, meriting development of new personalized probiotic approaches.
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http://dx.doi.org/10.1016/j.cell.2018.08.041DOI Listing
September 2018

The Critical Role of Chemokine (C-C Motif) Receptor 2-Positive Monocytes in Autoimmune Cholangitis.

Front Immunol 2018 15;9:1852. Epub 2018 Aug 15.

The Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.

The therapy of primary biliary cholangitis (PBC) has lagged behind other autoimmune diseases despite significant improvements in our understanding of both immunological and molecular events that lead to loss of tolerance to the E2 component of pyruvate dehydrogenase, the immunodominant autoepitope of PBC. It is well known that Ly6C monocytes are innate immune cells infiltrating inflammatory sites that are dependent on the expression of C-C motif chemokine receptor 2 (CCR2) for emigration from bone marrow. Importantly, humans with PBC have a circulating monocyte pro-inflammatory phenotype with macrophage accumulation in portal tracts. We have taken advantage of an inducible chemical xenobiotic model of PBC and recapitulated the massive infiltration of monocytes to portal areas. To determine the clinical significance, we immunized both CCR2-deficient mice and controls with 2OA-BSA and noted that CCR2 deficiency is protective for the development of autoimmune cholangitis. Importantly, because of the therapeutic potential, we focused on inhibiting monocyte infiltration through the use of cenicriviroc (CVC), a dual chemokine receptor CCR2/CCR5 antagonist shown to be safe in human trials. Importantly, treatment with CVC resulted in amelioration of all aspects of disease severity including serum total bile acids, histological severity score, and fibrosis stage. In conclusion, our results indicate a major role for Ly6C monocytes and for CCR2 in PBC pathogenesis and suggest that inhibition of this axis by CVC should be explored in humans through the use of clinical trials.
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http://dx.doi.org/10.3389/fimmu.2018.01852DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6104446PMC
September 2019

fecal toxin level is associated with disease severity and prognosis.

United European Gastroenterol J 2018 Jun 21;6(5):773-780. Epub 2017 Dec 21.

Department of Gastroenterology and Liver Diseases, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.

Background: Antibiotic-associated colitis caused by () is the most common cause of hospital-acquired diarrhea. The pathogenesis of colitis is mediated by bacterial toxins. infection (CDI) severity may be determined by the fecal level of these toxins.

Objective: The objective of this article is to determine whether fecal toxin (CDT) levels are associated with disease severity and prognosis.

Methods: A cross-sectional study of patients admitted with CDI in a tertiary center between 2011 and 2015 was conducted. Fecal CDT levels were determined by quantitative ELISA. Severe CDI was defined as a leukocyte count of > 15 × 10 cells/μl, creatinine levels that deteriorated by > 1.5 times the baseline level, or albumin levels < 3 g/dl.

Results: Seventy-three patients were recruited for this study. Patients with severe CDI ( = 47) had significantly higher toxin levels compared to patients with mild to moderate CDI ( = 26) (651 ng/ml (IQR 138-3200) versus 164 ng/ml (IQR 55.2-400.1), respectively;  = 0.001). A high toxin level (>2500 ng/ml) was associated with an increased mortality rate (odds ratio 11.8; 95% confidence interval 2.5-56).

Conclusions: The fecal CDT level is associated with disease severity and mortality rate. Measuring CDT levels may be an objective and accurate way to define the severity of CDI.
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http://dx.doi.org/10.1177/2050640617750809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6068787PMC
June 2018

Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection.

Science 2018 03 8;359(6382):1376-1383. Epub 2018 Mar 8.

Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.

Obesity, diabetes, and related manifestations are associated with an enhanced, but poorly understood, risk for mucosal infection and systemic inflammation. Here, we show in mouse models of obesity and diabetes that hyperglycemia drives intestinal barrier permeability, through GLUT2-dependent transcriptional reprogramming of intestinal epithelial cells and alteration of tight and adherence junction integrity. Consequently, hyperglycemia-mediated barrier disruption leads to systemic influx of microbial products and enhanced dissemination of enteric infection. Treatment of hyperglycemia, intestinal epithelial-specific GLUT2 deletion, or inhibition of glucose metabolism restores barrier function and bacterial containment. In humans, systemic influx of intestinal microbiome products correlates with individualized glycemic control, indicated by glycated hemoglobin levels. Together, our results mechanistically link hyperglycemia and intestinal barrier function with systemic infectious and inflammatory consequences of obesity and diabetes.
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http://dx.doi.org/10.1126/science.aar3318DOI Listing
March 2018

Environment dominates over host genetics in shaping human gut microbiota.

Nature 2018 03 28;555(7695):210-215. Epub 2018 Feb 28.

Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 7610001, Israel.

Human gut microbiome composition is shaped by multiple factors but the relative contribution of host genetics remains elusive. Here we examine genotype and microbiome data from 1,046 healthy individuals with several distinct ancestral origins who share a relatively common environment, and demonstrate that the gut microbiome is not significantly associated with genetic ancestry, and that host genetics have a minor role in determining microbiome composition. We show that, by contrast, there are significant similarities in the compositions of the microbiomes of genetically unrelated individuals who share a household, and that over 20% of the inter-person microbiome variability is associated with factors related to diet, drugs and anthropometric measurements. We further demonstrate that microbiome data significantly improve the prediction accuracy for many human traits, such as glucose and obesity measures, compared to models that use only host genetic and environmental data. These results suggest that microbiome alterations aimed at improving clinical outcomes may be carried out across diverse genetic backgrounds.
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http://dx.doi.org/10.1038/nature25973DOI Listing
March 2018

Smoking Habits are Strongly Associated With Colorectal Polyps in a Population-based Case-control Study.

J Clin Gastroenterol 2018 10;52(9):805-811

Department of Gastroenterology, Tel Aviv Sourasky Medical Center.

Goals: The goal of this study is to test the association between lifetime smoking habits and colorectal polyps of different classifications.

Background: Smoking is an established risk factor for several cancers, including colorectal cancer. However, the association between lifetime smoking habits including intensity, duration, and cessation, and premalignant colorectal polyps is yet to be established.

Study: A case-control study among 828 consecutive subjects aged 40 to 70 years, undergoing screening or diagnostic colonoscopy. Exclusion criteria were: medically treated diabetes, colectomy, and belonging to colorectal cancer high risk group. Polyps were stratified according to histology (serrated or adenomatous polyp) and location. All participants underwent anthropometric measurements and a structured medical and lifestyle interview.

Results: Current-smoking was more strongly associated with increased odds for distal rather than proximal polyps [odds ratio (OR), 4.00; 95% confidence interval (CI), 2.40-6.68 and OR, 2.52; 95% CI, 1.46-4.36, respectively], with serrated-polyps rather than adenomas (OR, 6.36; 95% CI, 2.77-14.57 and OR, 3.01; 1.90-4.74, respectively). All levels of smoking intensity (daily cigarettes) were associated with colorectal polyps. A dose-response association was seen between smoking duration and colorectal polyps. Smoking duration of ≥20 years was strongly associated with distal polyps (OR, 4.01; 95% CI, 1.62-9.84), independently of potential confounders, smoking intensity and years since smoking cessation. All associations were stronger for distal serrated polyps.

Conclusions: Smoking duration is associated with colorectal plyps, independently of other potential confounders, smoking intensity, and cessation. The association is stronger with distal rather than proximal polyps, and with serrated polyps rather than adenomas.
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http://dx.doi.org/10.1097/MCG.0000000000000935DOI Listing
October 2018

Distinct Metabolic Profiles are Associated with Colorectal Adenomas and Serrated Polyps.

Obesity (Silver Spring) 2017 11;25 Suppl 2:S72-S80

Department of Gastroenterology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.

Objective: Prevention of colorectal cancer (CRC) by colonoscopy is recommended according to age and personal/familial history. Metabolic alterations are associated with colorectal adenomas, but data are scarce regarding serrated polyps and advanced polyps. The aim of this study was to evaluate the association between metabolic alterations and colorectal polyp type and advanced polyps.

Methods: A case-control study was conducted among consecutive subjects, 40 to 70 years old, who underwent screening/diagnostic colonoscopy from 2010 to 2015. Subjects who were treated for diabetes, who had a family/personal history of CRC, and who were at high risk for CRC were excluded. Participants underwent anthropometric, laboratory, and ultrasonographic evaluations and a medical and lifestyle interview. Polyps were histologically classified as adenomatous or serrated polyps and divided into advanced and non-advanced categories.

Results: The study included 828 participants (58.4 ± 6.6 years, 50.4% men). Abdominal obesity (odds ratio [OR] = 1.67, 95% CI: 1.20-2.30), hypertension (OR = 1.47, 95% CI: 1.03-2.09), and a high glycosylated hemoglobin percentage (HbA1c%) (OR = 1.57, 95% CI: 1.06-2.34) were independently associated with colorectal adenomas, whereas a high triglyceride to high-density lipoprotein cholesterol (TG/HDL) ratio was independently associated with serrated polyps (OR = 2.31, 95% CI: 1.32-4.03). A combination of three metabolic alterations was strongly associated with colorectal polyps.

Conclusions: Abdominal obesity, hypertension, and a high HbA1c% are independently associated with adenomas, whereas a high TG/HDL ratio is associated with serrated polyps. These parameters are easily accessible in clinical practice and may help define high-risk groups for CRC.
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http://dx.doi.org/10.1002/oby.22001DOI Listing
November 2017

A Retrospective Comparison of Fecal Microbial Transplantation Methods for Recurrent Clostridium Difficile Infection.

Isr Med Assoc J 2016 Oct;18(10):594-599

Departments of Gastroenterology and Liver Diseases.

Background: Antibiotic treatment of Clostridium difficile infection (CDI) has a high failure rate. Fecal microbiota transplantation (FMT) has proven very effective in treating these recurrences.

Objectives: To determine which method of fecal microbiota transplantation (upper or lower gastrointestinal) and which type of donor (a relative or unrelated) is superior.

Methods: This is a retrospective analysis of treatment protocols and outcomes in 22 patients with refractory or recurrent CDI who underwent FMT at two Israeli facilities. Each center used a different donor type, stool preparation and method of delivery. The Tel Aviv Sourasky Medical Center used unrelated fecal donors and frozen stool samples and delivered them primarily (92%) via the lower gastrointestinal (GI) tract. Shaare Zedek Medical Center used fresh donor stool of relatives and delivered them primarily (90%) via the upper GI tract.

Results: FMT had an overall 2 month cure rate of 89%. Patients treated with FMT that was executed through the lower GI tract recovered faster from the infection (1.6 ± 1.08 vs. 2.4 ± 1 days for the upper tract, P = 0.03). The results also showed that patients who received lower GI tract FMTs were more likely to be cured of CDI (100% vs. 75% for upper tract FMTs, P = 0.16). Five patients (22%) died of CDI/FMT-unrelated causes and two (10%) died of CDI/FMT-related causes during the study period.

Conclusions: Lower GI tract FMT is a safe and effective treatment for refractory and recurrent CDI, and yields quicker results than upper GI tract FMT.
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October 2016

Protective role of soluble receptor for advanced glycation end-products in patients with non-alcoholic fatty liver disease.

Dig Liver Dis 2017 May 19;49(5):523-529. Epub 2017 Jan 19.

Liver Unit, Department of Gastroenterology, Tel-Aviv Medical Center, Tel-Aviv, Israel; The Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

Background: Soluble receptor for advanced glycation end-products (sRAGE) exerts protective metabolic effects.

Aims: To identify if sRAGE plays a protective role in NAFLD.

Methods: sRAGE (n=55) and Nε-(Carboxymethyl) lysine (CML) (n=36) serum levels were measured in NAFLD patients. Liver steatosis and fibrosis were non-invasively quantified by the hepatorenal index and the NAFLD fibrosis score (NFS).

Results: sRAGE levels were lower in NAFLD patients compared to controls (1207±439 vs. 1596±562ng/l, P<0.001) and were lower among subjects with moderate-severe steatosis compared with mild (1043±287 vs. 1378±506, P=0.005). Higher sRAGE was associated with lower steatosis with adjustment for age, gender, BMI and fasting insulin (OR=0.998, 0.996-0.999 95%CI, P=0.018). CML was not correlated with liver steatosis (r=0.07, P=0.683), but was positively correlated with AST (r=0.34, P=0.04), GGT (r=0.38, P=0.023) and HbA1C (r=0.37, P=0.027). sRAGE tended to be higher in subjects with NFS<-1.455 compared with NFS>-1.455 (1287±450 n=36 vs. 1051±364 n=13, P=0.08). While sRAGE was positively correlated with vegetables consumption (r=0.268, P=0.05), CML levels were not associated with sRAGE or dietary intake. sRAGE increased following a 3 month-lifestyle intervention (1194±446 vs. 1367±440 n=31, P<0.001) and change in sRAGE levels was negatively correlated with change in ALT levels (r=-0.37, P=0.041).

Conclusion: sRAGE plays a protective role in NAFLD and it is influenced by lifestyle.
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http://dx.doi.org/10.1016/j.dld.2017.01.148DOI Listing
May 2017

Microbiota Diurnal Rhythmicity Programs Host Transcriptome Oscillations.

Cell 2016 Dec;167(6):1495-1510.e12

Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel. Electronic address:

The intestinal microbiota undergoes diurnal compositional and functional oscillations that affect metabolic homeostasis, but the mechanisms by which the rhythmic microbiota influences host circadian activity remain elusive. Using integrated multi-omics and imaging approaches, we demonstrate that the gut microbiota features oscillating biogeographical localization and metabolome patterns that determine the rhythmic exposure of the intestinal epithelium to different bacterial species and their metabolites over the course of a day. This diurnal microbial behavior drives, in turn, the global programming of the host circadian transcriptional, epigenetic, and metabolite oscillations. Surprisingly, disruption of homeostatic microbiome rhythmicity not only abrogates normal chromatin and transcriptional oscillations of the host, but also incites genome-wide de novo oscillations in both intestine and liver, thereby impacting diurnal fluctuations of host physiology and disease susceptibility. As such, the rhythmic biogeography and metabolome of the intestinal microbiota regulates the temporal organization and functional outcome of host transcriptional and epigenetic programs.
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http://dx.doi.org/10.1016/j.cell.2016.11.003DOI Listing
December 2016

Persistent microbiome alterations modulate the rate of post-dieting weight regain.

Nature 2016 Dec 24;540(7634):544-551. Epub 2016 Nov 24.

Immunology Department, Weizmann Institute of Science, 76100 Rehovot, Israel.

In tackling the obesity pandemic, considerable efforts are devoted to the development of effective weight reduction strategies, yet many dieting individuals fail to maintain a long-term weight reduction, and instead undergo excessive weight regain cycles. The mechanisms driving recurrent post-dieting obesity remain largely elusive. Here we identify an intestinal microbiome signature that persists after successful dieting of obese mice and contributes to faster weight regain and metabolic aberrations upon re-exposure to obesity-promoting conditions. Faecal transfer experiments show that the accelerated weight regain phenotype can be transmitted to germ-free mice. We develop a machine-learning algorithm that enables personalized microbiome-based prediction of the extent of post-dieting weight regain. Additionally, we find that the microbiome contributes to diminished post-dieting flavonoid levels and reduced energy expenditure, and demonstrate that flavonoid-based 'post-biotic' intervention ameliorates excessive secondary weight gain. Together, our data highlight a possible microbiome contribution to accelerated post-dieting weight regain, and suggest that microbiome-targeting approaches may help to diagnose and treat this common disorder.
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http://dx.doi.org/10.1038/nature20796DOI Listing
December 2016

Serum levels of endocannabinoids are independently associated with nonalcoholic fatty liver disease.

Obesity (Silver Spring) 2017 01 15;25(1):94-101. Epub 2016 Nov 15.

Obesity and Metabolism Laboratory, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.

Objective: To evaluate the association between circulating levels of endocannabinoids (eCBs) and non-alcoholic fatty liver disease (NAFLD).

Methods: The serum levels of the main eCBs, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their endogenous precursor and breakdown product, arachidonic acid (AA), were analyzed by liquid chromatography/tandem mass spectrometry in 105 volunteers screened for NAFLD. Hepatic ultrasound, fasting blood tests, and anthropometrics were assessed. Liver fat was quantified by the hepato-renal-ultrasound index representing the ratio between the brightness level of the liver and the kidney.

Results: Patients with NAFLD had higher levels (pmol/mL) of AA (2,721 ± 1,112 vs. 2,248 ± 977, P = 0.022) and 2-AG (46.5 ± 25.8 vs. 33.5 ± 13.6, P = 0.003), but not AEA. The trend for higher levels of AA and 2-AG in the presence of NAFLD was observed in both genders and within subgroups of overweight and obesity. The association of AA and 2-AG with NAFLD was maintained with adjustment for age, gender, and BMI (OR = 1.001, 1.000-1.001 95% CI, P = 0.008 and OR = 1.05, 1.01-1.09, P = 0.006, respectively) or waist circumference.

Conclusions: This study is the first to show high circulating levels of 2-AG and AA in NAFLD patients compared with controls, independent of obesity. The findings may suggest an independent role of eCBs in the pathogenesis of NAFLD.
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http://dx.doi.org/10.1002/oby.21687DOI Listing
January 2017

Tumor macrophages are pivotal constructors of tumor collagenous matrix.

J Exp Med 2016 10 3;213(11):2315-2331. Epub 2016 Oct 3.

Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel

Tumor-associated macrophages (TAMs) promote tumor development, invasion, and dissemination by various mechanisms. In this study, using an orthotopic colorectal cancer (CRC) model, we found that monocyte-derived TAMs advance tumor development by the remodeling of its extracellular matrix (ECM) composition and structure. Unbiased transcriptomic and proteomic analyses of (a) TAM-abundant and -deficient tumor tissues and (b) sorted tumor-associated and -resident colonic macrophage subpopulations defined a distinct TAM-induced ECM molecular signature composed of an ensemble of matricellular proteins and remodeling enzymes they provide to the tumor microenvironment. Remarkably, many of these ECM proteins are specifically increased in human CRC versus healthy colon. Specifically, we demonstrate that although differentiating into TAMs, monocytes up-regulate matrix-remodeling programs associated with the synthesis and assembly of collagenous ECM, specifically collagen types I, VI, and XIV. This finding was further established by advanced imaging showing that TAMs instruct the deposition, cross-linking, and linearization of collagen fibers during tumor development, especially at areas of tumor invasiveness. Finally, we show that cancer-associated fibroblasts are significantly outnumbered by TAMs in this model and that their expression of collagen XIV and I is reduced by TAM deficiency. Here, we outline a novel TAM protumoral function associated with building of the collagenous ECM niche.
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http://dx.doi.org/10.1084/jem.20151193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5068227PMC
October 2016

Regulation of glucose dynamics by noninvasive peripheral electrical stimulation in normal and insulin-resistant rats.

Metabolism 2016 06 17;65(6):863-73. Epub 2016 Mar 17.

School of Physics and Astronomy, Raymond & Beverly Sackler Faculty of Exact Sciences, Tel Aviv University, Israel; Center for Theoretical Biological Physics, Rice University, Houston, TX, USA.

Background: The epidemic nature of type 2 diabetes mellitus (T2DM), along with the downsides of current treatments, has raised the need for therapeutic alternatives.

Methods: We studied normo-glycemic and high-fat diet (HFD), induced insulin-resistant Wistar Han rats for 2 to 3weeks. Rats received peripheral electrical stimulation (PES) treatment (2Hz/16Hz bursts, 10mA) in their hind limbs for 3min, 3 times per week. Glucose tolerance was evaluated by using a glucose tolerance test at the beginning and again at the end of the study. The effect of an acute PES treatment on metabolic rates of glucose appearance and turnover was measured by using the hyperinsulinemic-euglycemic clamp (HEGC) test.

Results: Repeated PES treatment significantly inhibited the progression of glucose intolerance in normal and insulin-resistant rats and prevented HFD-induced gains in body weight and fat mass. Acute treatment induced a prolonged effect on glucose turnover, as evaluated by the HEGC test. Increased hepatic glucose output was observed during the basal state (P<0.005). Under hyperinsulinemic conditions, PES improved tissue sensitivity to insulin (41.1%, P<0.01), improved suppression of hepatic glucose production (58.9±4.4% vs. 87.1±4.4%, P<0.02) and significantly elevated the rate of glycogenesis (P<0.01), compared with controls.

Conclusions: The present study indicates that a noninvasive PES treatment of very short duration is sufficiently potent to stimulate glucose utilization and improve hepatic insulin sensitivity in rats. Repeated PES treatment may have a beneficial effect on HFD-induced adiposity and control of body weight.
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http://dx.doi.org/10.1016/j.metabol.2016.03.004DOI Listing
June 2016

Non-alcoholic fatty liver disease is not associated with a lower health perception.

World J Gastroenterol 2016 May;22(17):4362-72

Liat Mlynarsky, Roni Lotan, Muriel Webb, Zamir Halpern, Erwin Santo, Oren Shibolet, Shira Zelber-Sagi, Department of Gastroenterology, Tel Aviv Medical Center, Tel-Aviv 6423906, Israel.

Aim: To examine the association between non-alcoholic fatty liver disease (NAFLD) and general health perception.

Methods: This cross sectional and prospective follow-up study was performed on a cohort of a sub-sample of the first Israeli national health and nutrition examination survey, with no secondary liver disease or history of alcohol abuse. On the first survey, in 2003-2004, 349 participants were included. In 2009-2010 participants from the baseline survey were invited to participate in a follow-up survey. On both baseline and follow-up surveys the data collected included: self-reported general health perception, physical activity habits, frequency of physician's visits, fatigue impact scale and abdominal ultrasound. Fatty liver was diagnosed by abdominal ultrasonography using standardized criteria and the ratio between the median brightness level of the liver and the right kidney was calculated to determine the Hepato-Renal Index.

Results: Out of 349 eligible participants in the first survey, 213 volunteers participated in the follow-up cohort and were included in the current analysis, NAFLD was diagnosed in 70/213 (32.9%). The prevalence of "very good" self-reported health perception was lower among participants diagnosed with NAFLD compared to those without NAFLD. However, adjustment for BMI attenuated the association (OR = 0.73, 95%CI: 0.36-1.50, P = 0.392). Similar results were observed for the hepato-renal index; it was inversely associated with "very good" health perception but adjustment for BMI attenuated the association. In a full model of multivariate analysis, that included all potential predictors for health perception, NAFLD was not associated with the self-reported general health perception (OR = 0.86, 95%CI: 0.40-1.86, P = 0.704). The odds for "very good" self-reported general health perception (compared to "else") increased among men (OR = 2.42, 95%CI: 1.26-4.66, P = 0.008) and those with higher performance of leisure time physical activity (OR = 1.01, 95%CI: 1.00-1.01, P < 0.001, per every minute/week) and decreased with increasing level of BMI (OR = 0.91, 95%CI: 0.84-0.99, P = 0.028, per every kg/m(2)) and older age (OR = 0.96, 95%CI: 0.93-0.99, P = 0.033, per one year). Current smoking was not associated with health perception (OR = 1.31, 95%CI: 0.54-3.16, P = 0.552). Newly diagnosed (naive) and previously diagnosed (at the first survey, not naive) NAFLD patients did not differ in their self-health perception. The presence of NAFLD at the first survey as compared to normal liver did not predict health perception deterioration at the 7 years follow-up. In terms of health-services utilization, subjects diagnosed with NAFLD had a similar number of physician's visits (general physicians and specialty consultants) as in the normal liver group. Parameters in the fatigue impact scale were equivalent between the NAFLD and the normal liver groups.

Conclusion: Fatty liver without clinically significant liver disease does not have independent impact on self-health perception.
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http://dx.doi.org/10.3748/wjg.v22.i17.4362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4853694PMC
May 2016

A novel colonoscope with panoramic visualization detected more simulated polyps than conventional colonoscopy in a live swine model.

Endosc Int Open 2015 Dec 6;3(6):E642-5. Epub 2015 Oct 6.

Tel Aviv Medical Center, Tel-Aviv, Israel.- ; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.

Background And Study Aims: The Aer-O-Scope™ Colonoscope System (AOS) combines panoramic 360° view with standard forward view. We assessed the AOS's ability to identify lesions implanted in live swine, compared to conventional colonoscopy (CC).

Patients And Methods: Twelve swine colons were surgically ligated and beads sewn within. Five procedures (3 AOS and 2 CC) were performed on each swine and findings reported. Physicians were blinded to number, size, and color of beads. The sequence of procedures and physicians was randomized. Pigs, physicians, and colonoscopes were randomly alternated between examination rooms, maintaining physician blindness. Two independent blinded physicians interpreted procedure videos offline.

Results: A total of 259 /273 (94.9 %) of lesions were visualized by AOS compared to 158 /182 with CC (86.8 %) (P = 0.002). Miss rates of lesions ≥ 6 mm were 2.6 % and 10.5 %, respectively (P = 0.022), and 6.9 % and 15.1 %, respectively, for lesions < 6 mm (P = 0.031). Mean agreement between AOS and CC for lesion detection was 88.3 %. The benefit of AOS was maintained in offline video review.

Conclusions: AOS, featuring panoramic 360° view, demonstrated high detection rates for simulated colonic lesions in a live swine model.
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http://dx.doi.org/10.1055/s-0034-1393080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4683140PMC
December 2015

Microbiota-Modulated Metabolites Shape the Intestinal Microenvironment by Regulating NLRP6 Inflammasome Signaling.

Cell 2015 Dec;163(6):1428-43

Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address:

Host-microbiome co-evolution drives homeostasis and disease susceptibility, yet regulatory principles governing the integrated intestinal host-commensal microenvironment remain obscure. While inflammasome signaling participates in these interactions, its activators and microbiome-modulating mechanisms are unknown. Here, we demonstrate that the microbiota-associated metabolites taurine, histamine, and spermine shape the host-microbiome interface by co-modulating NLRP6 inflammasome signaling, epithelial IL-18 secretion, and downstream anti-microbial peptide (AMP) profiles. Distortion of this balanced AMP landscape by inflammasome deficiency drives dysbiosis development. Upon fecal transfer, colitis-inducing microbiota hijacks this microenvironment-orchestrating machinery through metabolite-mediated inflammasome suppression, leading to distorted AMP balance favoring its preferential colonization. Restoration of the metabolite-inflammasome-AMP axis reinstates a normal microbiota and ameliorates colitis. Together, we identify microbial modulators of the NLRP6 inflammasome and highlight mechanisms by which microbiome-host interactions cooperatively drive microbial community stability through metabolite-mediated innate immune modulation. Therefore, targeted "postbiotic" metabolomic intervention may restore a normal microenvironment as treatment or prevention of dysbiosis-driven diseases.
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http://dx.doi.org/10.1016/j.cell.2015.10.048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5665753PMC
December 2015

Personalized Nutrition by Prediction of Glycemic Responses.

Cell 2015 Nov;163(5):1079-1094

Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 7610001, Israel; Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel. Electronic address:

Elevated postprandial blood glucose levels constitute a global epidemic and a major risk factor for prediabetes and type II diabetes, but existing dietary methods for controlling them have limited efficacy. Here, we continuously monitored week-long glucose levels in an 800-person cohort, measured responses to 46,898 meals, and found high variability in the response to identical meals, suggesting that universal dietary recommendations may have limited utility. We devised a machine-learning algorithm that integrates blood parameters, dietary habits, anthropometrics, physical activity, and gut microbiota measured in this cohort and showed that it accurately predicts personalized postprandial glycemic response to real-life meals. We validated these predictions in an independent 100-person cohort. Finally, a blinded randomized controlled dietary intervention based on this algorithm resulted in significantly lower postprandial responses and consistent alterations to gut microbiota configuration. Together, our results suggest that personalized diets may successfully modify elevated postprandial blood glucose and its metabolic consequences. VIDEO ABSTRACT.
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http://dx.doi.org/10.1016/j.cell.2015.11.001DOI Listing
November 2015

Fecal Microbiota Transplantation for Clostridium difficile-Associated Diarrhea.

Isr Med Assoc J 2015 Aug;17(8):510-4

Clostridium difficile-associated diarrhea is a problem most hospital-based physicians will face in their career. This review aims to refresh current knowledge with regard to Clostridium difficile infection and bring physicians up to date with the latest developments in the growing field of fecal microbiota transplantation, the benefits it offers, and the promise this and other developments hold for the future.
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August 2015

A novel self-propelled disposable colonoscope is effective for colonoscopy in humans (with video).

Gastrointest Endosc 2016 May 21;83(5):998-1004.e1. Epub 2015 Sep 21.

Tel Aviv Medical Center, Tel Aviv, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Background And Aims: The self-propelled disposable colonoscope (SPDC) with a 360° view is designed to enhance visualization, minimize risks of perforation and infection transmission, and shorten operator training time associated with conventional colonoscopy (CC). We evaluated SPDC efficacy for cecal intubation and safety.

Methods: Prospective patients presenting for colorectal cancer screening underwent SPDC immediately followed by CC. Initial patients necessary for SPDC operators to achieve proficiency comprised the training cohort. Subsequent enrolled patients comprised the study cohort. SPDC colonoscopy was performed up to the cecum, where anatomic landmarks were photographed and mucosal suction marks were placed. During SPDC withdrawal, polyps were recorded and similarly marked. On the second pass (by using CC), any potential mucosal damage and suction marks from the SPDC as well as polyps were recorded. Main endpoints included SPDC cecal intubation rates, confirmed by anatomic landmarks and residual marks seen on subsequent CC, and frequency and severity of adverse events and mucosal damage with SPDC. The secondary endpoint was subjective procedure proficiency, evaluated by the operator based on the training cohort. The tertiary endpoint was documenting pathologies visualized with SPDC.

Results: Fifty-six of 58 enrolled subjects completed the study. Proficiency with SPDC was attained after 8 to 10 procedures. Cecal intubation was successful in 98.2% (55/56 subjects; 95% confidence interval [CI], 90.4%-99.9%), including 100% (95% CI, 90.7%-100%) of the study cohort and 94.4% (95% CI, 72.7%-99.9%) of the training cohort. No mucosal damage or adverse events were reported. SPDC detected 87.5% of polyps seen in tandem CC, including all polyps larger than 5 mm.

Conclusions: SPDC was highly successful, simple to use, and safe in achieving complete colonoscopy (cecal intubation). (

Clinical Trial Registration Number: 0692-12-TLV.).
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http://dx.doi.org/10.1016/j.gie.2015.08.083DOI Listing
May 2016

Assessment of Liver and Spleen Stiffness in Patients With Myelofibrosis Using FibroScan and Shear Wave Elastography.

Ultrasound Q 2015 Sep;31(3):166-9

*Department of Gastroenterology, Tel Aviv Medical Center; †Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv; ‡Hematology Laboratory, Sheba Medical Center, Tel Hashomer; §Department of Statistics and Operations Research, Faculty of Exact Sciences, Tel Aviv University, Tel Aviv; and ∥Institute of Thrombosis and Hemostasis, Sheba Medical Center, Tel Hashomer, Israel.

Liver stiffness and spleen stiffness in patients with myelofibrosis have traditionally been assessed through manual palpation and thus influenced by interobserver variability. In this article, for the first time, liver stiffness and spleen stiffness of patients with myelofibrosis were evaluated through FibroScan and shear wave elastography (SWE). Nine patients with myelofibrosis comprised the study group. They were compared with 11 patients with liver cirrhosis and 8 healthy volunteers. Before the FibroScan study, all patients underwent ultrasound study to delineate the left intercostal space for validated measurements. In patients with myelofibrosis, the mean stiffness of the spleen was 41.3 and 32.9 kilopascals (kPa) through FibroScan and SWE, respectively. The mean stiffness of the liver was 7.8 kPa through FibroScan and 10.4 kPa through SWE. The stiffness of the spleen in patients with cirrhosis was even higher, reaching a mean of 58.5 kPa through FibroScan and 40.5 kPa through SWE. The means were considerably lower among the healthy controls (13.5 and 18.1 kPa, respectively). The correlation between spleen stiffness among the patients with cirrhosis is negative and opposite in direction (r = -0.35) in comparison with the patients with myelofibrosis (r = 0.78). Among the patients with liver cirrhosis and myelofibrosis, spleen size was weakly related to spleen stiffness as assessed through SWE (r = 0.49) but had almost no relation to the FibroScan measure (r = 0.13). The FibroScan and SWE of the spleen have little ability to distinguish between the patients with myelofibrosis and cirrhosis, but they do differentiate both patient groups from the healthy controls. The stiffness of spleen and liver as measured through FibroScan and SWE was not correlated to the longevity of myelofibrosis.
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http://dx.doi.org/10.1097/RUQ.0000000000000139DOI Listing
September 2015

Deep enteroscopy with a conventional colonoscope: initial multicenter study by using a through-the-scope balloon catheter system.

Gastrointest Endosc 2015 Nov 16;82(5):855-60. Epub 2015 Jun 16.

New York University School of Medicine, New York, New York, USA. Electronic address:

Background And Aims: The advent of capsule endoscopy has revolutionized evaluation of the small bowel. Capsule endoscopy has become the criterion standard as the initial examination to diagnose small-bowel abnormalities, but does not allow for tissue sampling or therapeutic intervention. Deep enteroscopy can be performed by using a balloon-assisted device or a spiral overtube for both diagnostic and therapeutic interventions of the small bowel. Deep enteroscopy is time-consuming and requires special endoscopes and accessories to perform the examination. We studied a novel through-the-scope balloon catheter system used for deep enteroscopy that uses a conventional colonoscope and standard accessories.

Methods: We performed a 9-center, retrospective study using a novel TTS balloon system for small-bowel evaluation. The new through-the-scope device is an on-demand balloon catheter that is inserted through the instrument channel of a standard colonoscope and enables deep advancement into the small bowel in either the anterograde or retrograde approach. It consists of a balloon inflation/deflation system and a single-use balloon catheter designed for anchoring in the small bowel. The balloon is inflated to an anchoring pressure in the small intestine, and a repetitive push-pull technique is performed, with the endoscope sliding over the guiding catheter to the inflated balloon. The catheter may be removed and reinserted to allow for therapeutic intervention while maintaining the endoscope position.

Results: A total of 98 patients were included; 52% were male, and the mean age was 55 years old (range 15-94 years). Indications included abdominal pain, iron-deficiency anemia, occult GI bleeding, diarrhea, abnormal capsule endoscopy, weight loss, protein losing enteropathy, retained foreign body, altered anatomy ERCP, and small-bowel strictures. Anterograde enteroscopy was performed in 65 patients. The average depth of insertion was 158 cm (range 50-350 cm) from the pylorus. Retrograde enteroscopy was performed in 33 cases. The average depth of insertion was 89 cm (range 20-150 cm) beyond the ileocecal valve. Overall, diagnostic yield was 44%. The average advancement time for the anterograde and retrograde enteroscopy cases was 15.5 minutes. There were no procedural adverse outcomes reported in the 98 cases.

Conclusions: The TTS advancing balloon is a safe and effective way to perform deep enteroscopy by using a conventional colonoscope without the need for an overtube. Procedure time is shorter than that of other forms of deep enteroscopy. Diagnostic yield and depth of insertion are on par with other forms of deep enteroscopy. This is the largest reported study using this novel technology to diagnose and treat small-bowel disease.
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http://dx.doi.org/10.1016/j.gie.2015.04.037DOI Listing
November 2015

Increased risk for colorectal adenomas and cancer in mono-allelic MUTYH mutation carriers: results from a cohort of North-African Jews.

Fam Cancer 2015 Sep;14(3):427-36

Departmant of Gastroenterology, Tel-Aviv Sourasky Medical Center, 6 Weizmann St., 64239, Tel Aviv, Israel,

Bi-allelic MUTYH gene mutations are associated with a clinical phenotype of multiple colorectal adenomas and an increased risk for colorectal cancer (CRC). It is unclear whether mono-allelic MUTYH gene carriers (heterozygotes) are also at increased risk for even few adenomas or cancer. In order to clarify an association between MUTYH heterozygotes and adenomas, we evaluated the frequency and types of MUTYH mutations and variants in 72 North-African Jews having few (≥3) colorectal adenomas with or without early onset (<50 years) CRC compared to 29 healthy controls. Germ-line DNA was analyzed for a panel of 6 MUTYH mutations and variants, and Sanger sequencing of the entire MUTYH gene was performed for mono-allelic MUTYH mutation carriers. APC gene mutations and Lynch syndrome were excluded in the relevant cases according to accepted clinical criteria. Twenty-two of the 72 adenoma subjects (30.5%) had MUTYH mutations or variants. Nine were homozygotes or compound heterozygotes: all had >10 adenomas and one had CRC. Thirteen others were mono-allelic carriers (heterozygotes) of a single MUTYH mutation: six had more than ten adenomas and seven had less than ten adenomas; of these 13 mono-allelic carriers, six had a neoplasm: three CRCs and three extra-intestinal tumors. Eleven of the thirteen mono-allelic carriers with adenomas had a family history of cancer in first or second degree relatives. A multivariable model showed positive correlation between G396D, Y179C and 1186 ins GG mutations and number of adenomas (OR 8.6, 10.2 and 14.4, respectively). The Q324H variant was negatively associated with the number of adenomatous polyps (OR -5.23). In conclusion, MUTYH mutations are prevalent among Jews of North-African origin with colorectal adenomas with or without early onset CRC. Mono-allelic MUTYH carriers with a family history of cancer had a clinical phenotype that varied from having only few adenomas to multiple (>10) adenomas. These findings support MUTYH testing in patients with even few adenomas and suggest the consideration of increased surveillance in mono-allelic carriers with a family history of cancer.
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http://dx.doi.org/10.1007/s10689-015-9799-7DOI Listing
September 2015

Comparison of adenoma detection and miss rates between a novel balloon colonoscope and standard colonoscopy: a randomized tandem study.

Endoscopy 2015 Mar 17;47(3):238-44. Epub 2015 Feb 17.

Department of Internal Medicine and Gastroenterology, St. Marienkrankenhaus Frankfurt, Frankfurt, Germany.

Background And Study Aims: Although colonoscopy is the "gold standard" for colorectal cancer screening, a significant number of adenomas are still missed during standard colonoscopy, often because they are hidden behind colonic folds and flexures. The aim of this study was to assess the ability of a novel balloon colonoscope (G-EYE endoscope; Smart Medical Systems, Ra'anana, Israel) to increase adenoma detection and reduce the miss rate compared with standard colonoscopy.

Patients And Methods: This was a multicenter, randomized, prospective, controlled study in patients (age ≥ 40 years) undergoing colonoscopy for screening or diagnostic work-up (including surveillance). Patients underwent same-day, back-to-back tandem colonoscopy. Patients in Group A underwent standard colonoscopy followed by balloon colonoscopy, and patients in Group B underwent balloon colonoscopy followed by the standard technique. The adenoma detection and miss rates were compared between the two colonoscopy procedures.

Results: A total of 126 patients were enrolled and randomized into Group A (n = 60) or Group B (n = 66). The adenoma miss rate of balloon colonoscopy was significantly lower than that of standard colonoscopy (7.5 % vs. 44.7 %; P = 0.0002). The detection of additional adenomas by balloon colonoscopy was significant (81.0 %; P = 0.0002), in particular, the relative amount of adenomas detected in the ascending colon by balloon colonoscopy was 41 % versus 14 % for standard colonoscopy.

Conclusions: A novel balloon colonoscopy technique detected significantly more adenomas than standard colonoscopy, and missed fewer adenomas. Balloon colonoscopy has the potential to increase the effectiveness of colorectal cancer screening and surveillance colonoscopy.
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http://dx.doi.org/10.1055/s-0034-1391437DOI Listing
March 2015

Coffee consumption and nonalcoholic fatty liver onset: a prospective study in the general population.

Transl Res 2015 Mar 17;165(3):428-36. Epub 2014 Oct 17.

Liver Unit, Department of Gastroenterology, Tel Aviv Medical Center, Tel Aviv, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Retrospective studies suggest that coffee consumption may exert beneficial effects in patients with nonalcoholic fatty liver; however, prospective data supporting a protective role on liver steatosis development are lacking. In this study, we aimed to evaluate the association between coffee consumption and fatty liver onset in the general population. The analysis was performed both in a cross-sectional cohort (n = 347) and, prospectively, in a subcohort of patients without fatty liver at baseline and followed-up for 7 years (n = 147). Fatty liver was diagnosed with abdominal ultrasound and liver steatosis was quantified noninvasively by hepatorenal index (HRI) and SteatoTest, whereas FibroTest was used to assess fibrosis degree. A structured questionnaire on coffee consumption was administrated during a face-to-face interview. Neither the incidence nor the prevalence of fatty liver according to ultrasonography, SteatoTest, and the HRI was associated with coffee consumption. In the cross-sectional study, high coffee consumption was associated with a lower proportion of clinically significant fibrosis ≥ F2 (8.8% vs 16.3%; P = 0.038); consistently, in multivariate logistic regression analysis, high coffee consumption was associated with lower odds for significant fibrosis (odds ratio = 0.49, 95% confidence interval, 0.25-0.97; P = 0.041) and was the strongest predictor for significant fibrosis. No association was demonstrated between coffee consumption and the new onset of nonalcoholic fatty liver, but coffee intake may exert beneficial effects on fibrosis progression.
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http://dx.doi.org/10.1016/j.trsl.2014.10.008DOI Listing
March 2015

Transkingdom control of microbiota diurnal oscillations promotes metabolic homeostasis.

Cell 2014 Oct 16;159(3):514-29. Epub 2014 Oct 16.

Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel. Electronic address:

All domains of life feature diverse molecular clock machineries that synchronize physiological processes to diurnal environmental fluctuations. However, no mechanisms are known to cross-regulate prokaryotic and eukaryotic circadian rhythms in multikingdom ecosystems. Here, we show that the intestinal microbiota, in both mice and humans, exhibits diurnal oscillations that are influenced by feeding rhythms, leading to time-specific compositional and functional profiles over the course of a day. Ablation of host molecular clock components or induction of jet lag leads to aberrant microbiota diurnal fluctuations and dysbiosis, driven by impaired feeding rhythmicity. Consequently, jet-lag-induced dysbiosis in both mice and humans promotes glucose intolerance and obesity that are transferrable to germ-free mice upon fecal transplantation. Together, these findings provide evidence of coordinated metaorganism diurnal rhythmicity and offer a microbiome-dependent mechanism for common metabolic disturbances in humans with aberrant circadian rhythms, such as those documented in shift workers and frequent flyers.
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http://dx.doi.org/10.1016/j.cell.2014.09.048DOI Listing
October 2014

Genetic and electrophysiological characteristics of recurrent acute pancreatitis.

J Pediatr Gastroenterol Nutr 2015 May;60(5):675-9

*Medical College of Wisconsin, Milwaukee †Hadassah Hebrew University Medical Center, Jerusalem ‡Meir Medical Center, Kfar-Saba §Souraski Medical Center, Tel-Aviv ||Soroka Medical Center, Ben Gurion University of the Negev, Beer-Sheva ¶Assaf Harofe Medical Center, Tzrifin #Schneider Children's Medical Center, Petach-Tikva **Meyer Children's Medical Center, Haifa, Israel ††Beaujon Hospital, Clichy ‡‡CHU de Brest, Brest, France.

Objectives: The aim was to present the workup of patients with acute recurrent pancreatitis (ARP) for genetic analysis and electrophysiological testing.

Methods: Patients with ARP with unknown etiology were referred for genetic testing and evaluation of cystic fibrosis transmembrane conductor regulator (CFTR) function by nasal potential difference (NPD) testing.

Results: A total of 67 patients were evaluated. The mean age was 23 ± 17 years (median 17.0 years, range 1.5-72 years); 90% were Jewish and 10% Arab. Ten (15%) patients carried PRSS1 gene mutation (K23R(7), R122H(2), and D21A(1)). One patient had K172E/- (chymotrypsin C [CTRC]) mutation, 1 had I42M (serine protease inhibitor Kazal type 1 [SPINK1])/V235I (CTRC) together with ΔF508/5T, 1 patient had R67H (SPINK1)/V235I (CTRC), and 1 patient had V235I (CTRC)/-. Ten of 67 (15%) patients submitted for CFTR gene testing carried mutations (ΔF508/L997F, ΔF508/5T(11TG), W1282/5T(12TG), W1282X/Y1014C, ΔF508/R31C, R117H/-, R117H/Y1014C, D1152H/-, 5T(11TG)/-, and L997F/-). Fifty-four (80%) patients underwent sweat testing. Of these, 5 had sweat chloride ≥60 mEq/L, and 22 patients had sweat chloride from 40 to 60 mEq/L. Of the 56 (83%) patients had nasal potential difference testing, 4 (6%) with abnormal results.

Conclusions: One-third (34%) of patients with ARP carry mutations for hereditary pancreatitis including rare mutations (K23R), and 12.5% have evidence of cftr mutations and 10% had CFTR dysfunction underscoring the importance of genetic and functional workup of these patients.
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http://dx.doi.org/10.1097/MPG.0000000000000623DOI Listing
May 2015
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