Publications by authors named "Shirin Moossavi"

37 Publications

Repeatability and reproducibility assessment in a large-scale population-based microbiota study: case study on human milk microbiota.

Microbiome 2021 02 10;9(1):41. Epub 2021 Feb 10.

Children's Hospital Research Institute of Manitoba, Winnipeg, MB, Canada.

Background: Quality control including assessment of batch variabilities and confirmation of repeatability and reproducibility are integral component of high throughput omics studies including microbiome research. Batch effects can mask true biological results and/or result in irreproducible conclusions and interpretations. Low biomass samples in microbiome research are prone to reagent contamination; yet, quality control procedures for low biomass samples in large-scale microbiome studies are not well established.

Results: In this study, we have proposed a framework for an in-depth step-by-step approach to address this gap. The framework consists of three independent stages: (1) verification of sequencing accuracy by assessing technical repeatability and reproducibility of the results using mock communities and biological controls; (2) contaminant removal and batch variability correction by applying a two-tier strategy using statistical algorithms (e.g. decontam) followed by comparison of the data structure between batches; and (3) corroborating the repeatability and reproducibility of microbiome composition and downstream statistical analysis. Using this approach on the milk microbiota data from the CHILD Cohort generated in two batches (extracted and sequenced in 2016 and 2019), we were able to identify potential reagent contaminants that were missed with standard algorithms and substantially reduce contaminant-induced batch variability. Additionally, we confirmed the repeatability and reproducibility of our results in each batch before merging them for downstream analysis.

Conclusion: This study provides important insight to advance quality control efforts in low biomass microbiome research. Within-study quality control that takes advantage of the data structure (i.e. differential prevalence of contaminants between batches) would enhance the overall reliability and reproducibility of research in this field. Video abstract.
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http://dx.doi.org/10.1186/s40168-020-00998-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877029PMC
February 2021

Capturing the diversity of the human milk microbiota through culture-enriched molecular profiling: a feasibility study.

FEMS Microbiol Lett 2021 Feb;368(3)

Manitoba Interdisciplinary Lactation Centre (MILC), Children's Hospital Research Institute of Manitoba, Winnipeg, MB R3E 3P4, Canada.

Previous human milk studies have confirmed the existence of a highly diverse bacterial community using culture-independent and targeted culture-dependent techniques. However, culture-enriched molecular profiling of milk microbiota has not been done. Additionally, the impact of storage conditions and milk fractionation on microbiota composition is not understood. In this feasibility study, we optimized and applied culture-enriched molecular profiling to study culturable milk microbiota in eight milk samples collected from mothers of infants admitted to a neonatal intensive care unit. Fresh samples were immediately plated or stored at -80°C for 2 weeks (short-term frozen). Long-term samples were stored at -20°C for >6 months. Samples were cultured using 10 different culture media and incubated both aerobically and anaerobically. We successfully isolated major milk bacteria, including Streptococcus, Staphylococcus and Bifidobacterium, from fresh milk samples, but were unable to culture any bacteria from the long-term frozen samples. Short-term freezing shifted the composition of viable milk bacteria from the original composition in fresh samples. Nevertheless, the inter-individual variability of milk microbiota composition was observed even after short-term storage. There was no major difference in the overall milk microbiota composition between milk fractions in this feasibility study. This is among the first studies on culture-enriched molecular profiling of the milk microbiota demonstrating the effect of storage and fractionation on milk microbiota composition.
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http://dx.doi.org/10.1093/femsle/fnab001DOI Listing
February 2021

Biological observations in microbiota analysis are robust to the choice of 16S rRNA gene sequencing processing algorithm: case study on human milk microbiota.

BMC Microbiol 2020 09 18;20(1):290. Epub 2020 Sep 18.

Department of Animal Science, University of Manitoba, Winnipeg, MB, Canada.

Background: In recent years, the microbiome field has undergone a shift from clustering-based methods of operational taxonomic unit (OTU) designation based on sequence similarity to denoising algorithms that identify exact amplicon sequence variants (ASVs), and methods to identify contaminating bacterial DNA sequences from low biomass samples have been developed. Although these methods improve accuracy when analyzing mock communities, their impact on real samples and downstream analysis of biological associations is less clear.

Results: Here, we re-processed our recently published milk microbiota data using Qiime1 to identify OTUs, and Qiime2 to identify ASVs, with or without contaminant removal using decontam. Qiime2 resolved the mock community more accurately, primarily because Qiime1 failed to detect Lactobacillus. Qiime2 also considerably reduced the average number of ASVs detected in human milk samples (364 ± 145 OTUs vs. 170 ± 73 ASVs, p < 0.001). Compared to the richness, the estimated diversity measures had a similar range using both methods albeit statistically different (inverse Simpson index: 14.3 ± 8.5 vs. 15.6 ± 8.7, p = 0.031) and there was strong consistency and agreement for the relative abundances of the most abundant bacterial taxa, including Staphylococcaceae and Streptococcaceae. One notable exception was Oxalobacteriaceae, which was overrepresented using Qiime1 regardless of contaminant removal. Downstream statistical analyses were not impacted by the choice of algorithm in terms of the direction, strength, and significance of associations of host factors with bacterial diversity and overall community composition.

Conclusion: Overall, the biological observations and conclusions were robust to the choice of the sequencing processing methods and contaminant removal.
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http://dx.doi.org/10.1186/s12866-020-01949-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7501722PMC
September 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

Breastmilk Feeding Practices Are Associated with the Co-Occurrence of Bacteria in Mothers' Milk and the Infant Gut: the CHILD Cohort Study.

Cell Host Microbe 2020 08 10;28(2):285-297.e4. Epub 2020 Jul 10.

Children's Hospital Research Institute of Manitoba and Developmental Origins of Chronic Diseases in Children Network (DEVOTION), Winnipeg, MB, Canada; Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB, Canada. Electronic address:

Gut microbiota play a critical role in infant health. It is now accepted that breastmilk contains live bacteria from endogenous and exogenous sources, but it remains unclear whether these bacteria transfer to the infant gut and whether this process is influenced by breastmilk feeding practices. Here, we show that certain bacteria, including Streptococcus spp. and Veillonella dispar, co-occur in mothers' milk and their infants' stool, and co-occurrence is reduced when infants receive pumped breastmilk. The relative abundances of commonly shared species are positively correlated between breastmilk and stool. Overall, gut microbiota composition is strongly associated with breastfeeding exclusivity and duration but not breastmilk feeding mode (nursing versus pumping). Moreover, breastmilk bacteria contributed to overall gut microbiota variation to a similar extent as other modifiers of the infant microbiome, such as birth mode. These results provide evidence that breastmilk may transfer bacteria to the infant gut and influence microbiota development.
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http://dx.doi.org/10.1016/j.chom.2020.06.009DOI Listing
August 2020

Human milk fungi: environmental determinants and inter-kingdom associations with milk bacteria in the CHILD Cohort Study.

BMC Microbiol 2020 06 5;20(1):146. Epub 2020 Jun 5.

Children's Hospital Research Institute of Manitoba, Developmental Origins of Chronic Diseases in Children Network (DEVOTION), Winnipeg, MB, Canada.

Background: Fungi constitute an important yet frequently neglected component of the human microbiota with a possible role in health and disease. Fungi and bacteria colonise the infant gastrointestinal tract in parallel, yet most infant microbiome studies have ignored fungi. Milk is a source of diverse and viable bacteria, but few studies have assessed the diversity of fungi in human milk.

Results: Here we profiled mycobiota in milk from 271 mothers in the CHILD birth cohort and detected fungi in 58 (21.4%). Samples containing detectable fungi were dominated by Candida, Alternaria, and Rhodotorula, and had lower concentrations of two human milk oligosaccharides (disialyllacto-N-tetraose and lacto-N-hexaose). The presence of milk fungi was associated with multiple outdoor environmental features (city, population density, and season), maternal atopy, and early-life antibiotic exposure. In addition, despite a strong positive correlation between bacterial and fungal richness, there was a co-exclusion pattern between the most abundant fungus (Candida) and most of the core bacterial genera.

Conclusion: We profiled human milk mycobiota in a well-characterised cohort of mother-infant dyads and provide evidence of possible host-environment interactions in fungal inoculation. Further research is required to establish the role of breastfeeding in delivering fungi to the developing infant, and to assess the health impact of the milk microbiota in its entirety, including both bacterial and fungal components.
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http://dx.doi.org/10.1186/s12866-020-01829-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7275434PMC
June 2020

Origins of human milk microbiota: new evidence and arising questions.

Gut Microbes 2020 11 4;12(1):1667722. Epub 2019 Nov 4.

Children's Hospital Research Institute of Manitoba , Winnipeg, MB, Canada.

Human milk contains a diverse community of bacteria. The growing appreciation of commensal microbes and increasing availability of high-throughput technology has set the stage for a theory-driven approach to the study of milk microbiota, and translation of this knowledge to improve maternal and child health. We recently profiled the milk microbiota of healthy Canadian mothers and applied theory-driven causal modeling, finding that mode of breast milk feeding (nursing directly at the breast vs. pumping and feeding breast milk from a bottle) was significantly associated with milk microbiota composition. This observation could reflect an increased exposure to pumps and/or a decreased exposure to the infant mouth. Either way, it provides evidence for the retrograde mechanism of milk inoculation. Here, we discuss the implications of this research and related controversies, and raise new questions about the origins and function of milk bacteria.
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http://dx.doi.org/10.1080/19490976.2019.1667722DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524145PMC
November 2020

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

Integrated Analysis of Human Milk Microbiota With Oligosaccharides and Fatty Acids in the CHILD Cohort.

Front Nutr 2019 16;6:58. Epub 2019 May 16.

Children's Hospital Research Institute of Manitoba, Winnipeg, MB, Canada.

Human milk contains many bioactive components that are typically studied in isolation, including bacteria. We performed an integrated analysis of human milk oligosaccharides and fatty acids to explore their associations with milk microbiota. We studied a sub-sample of 393 mothers in the CHILD birth cohort. Milk was collected at 3-4 months postpartum. Microbiota was analyzed by 16S rRNA gene V4 sequencing. Oligosaccharides and fatty acids were analyzed by rapid high-throughput high performance and gas liquid chromatography, respectively. Dimension reduction was performed with principal component analysis for oligosaccharides and fatty acids. Center log-ratio transformation was applied to all three components. Associations between components were assessed using Spearman rank correlation, network visualization, multivariable linear regression, redundancy analysis, and structural equation modeling. -values were adjusted for multiple comparisons. Key covariates were considered, including fucosyltransferase-2 (FUT2) secretor status of mother and infant, method of feeding (direct breastfeeding or pumped breast milk), and maternal fish oil supplement use. Overall, correlations were strongest between milk components of the same type. For example, FUT2-dependent HMOs were positively correlated with each other, and was negatively correlated with other core taxa. Some associations were also observed between components of different types. Using redundancy analysis and structural equation modeling, the overall milk fatty acid profile was significantly associated with milk microbiota composition. In addition, some individual fatty acids [22:6n3 (docosahexaenoic acid), 22:5n3, 20:5n3, 17:0, 18:0] and oligosaccharides (fucosyl-lacto-N-hexaose, lacto-N-hexaose, lacto-N-fucopentaose I) were associated with microbiota α diversity, while others (C18:0, 3'-sialyllactose, disialyl-lacto-N-tetraose) were associated with overall microbiota composition. Only a few significant associations between individual HMOs and microbiota were observed; notably, among mothers using breast pumps prevalence was associated with lower abundances of disialyl-lacto-N-hexaose. Additionally, among non-secretor mothers, was positively correlated with sialylated HMOs. Using multiple approaches to integrate and analyse milk microbiota, oligosaccharides, and fatty acids, we observed several associations between different milk components and microbiota, some of which were modified by secretor status and/or breastfeeding practices. Additional research is needed to further validate and mechanistically characterize these associations and determine their relevance to infant gut and respiratory microbiota development and health.
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http://dx.doi.org/10.3389/fnut.2019.00058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6532658PMC
May 2019

Normal Microbiota: Let us Change our Perspective.

Authors:
Shirin Moossavi

Arch Iran Med 2019 04 1;22(4):220. Epub 2019 Apr 1.

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

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April 2019

Composition and Variation of the Human Milk Microbiota Are Influenced by Maternal and Early-Life Factors.

Cell Host Microbe 2019 02;25(2):324-335.e4

Children's Hospital Research Institute of Manitoba, Pediatrics and Child Health, Winnipeg, MB, Canada; Developmental Origins of Chronic Diseases in Children Network (DEVOTION), Winnipeg, MB, Canada. Electronic address:

Breastmilk contains a complex community of bacteria that may help seed the infant gut microbiota. The composition and determinants of milk microbiota are poorly understood. Among 393 mother-infant dyads from the CHILD cohort, we found that milk microbiota at 3-4 months postpartum was dominated by inversely correlated Proteobacteria and Firmicutes, and exhibited discrete compositional patterns. Milk microbiota composition and diversity were associated with maternal factors (BMI, parity, and mode of delivery), breastfeeding practices, and other milk components in a sex-specific manner. Causal modeling identified mode of breastfeeding as a key determinant of milk microbiota composition. Specifically, providing pumped breastmilk was consistently associated with multiple microbiota parameters including enrichment of potential pathogens and depletion of bifidobacteria. Further, these data support the retrograde inoculation hypothesis, whereby the infant oral cavity impacts the milk microbiota. Collectively, these results identify features and determinants of human milk microbiota composition, with potential implications for infant health and development.
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http://dx.doi.org/10.1016/j.chom.2019.01.011DOI Listing
February 2019

Quantifying and Interpreting the Association between Early-Life Gut Microbiota Composition and Childhood Obesity.

mBio 2019 02 12;10(1). Epub 2019 Feb 12.

Children's Hospital Research Institute of Manitoba, Pediatrics and Child Health, Winnipeg, Manitoba, Canada.

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http://dx.doi.org/10.1128/mBio.02787-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372801PMC
February 2019

The Prebiotic and Probiotic Properties of Human Milk: Implications for Infant Immune Development and Pediatric Asthma.

Front Pediatr 2018 24;6:197. Epub 2018 Jul 24.

Children's Hospital Research Institute of Manitoba, Winnipeg, MB, Canada.

The incidence of pediatric asthma has increased substantially in recent decades, reaching a worldwide prevalence of 14%. This rapid increase may be attributed to the loss of "Old Friend" microbes from the human microbiota resulting in a less diverse and "dysbiotic" gut microbiota, which fails to optimally stimulate immune development during infancy. This hypothesis is supported by observations that the gut microbiota is different in infants who develop asthma later in life compared to those who remain healthy. Thus, early life exposures that influence gut microbiota play a crucial role in asthma development. Breastfeeding is one such exposure; it is generally considered protective against pediatric asthma, although conflicting results have been reported, potentially due to variations in milk composition between individuals and across populations. Human milk oligosaccharides (HMOs) and milk microbiota are two major milk components that influence the infant gut microbiota and hence, development of the immune system. Among their many immunomodulatory functions, HMOs exert a selective pressure within the infant gut microbial niche, preferentially promoting the proliferation of specific bacteria including . Milk is also a source of viable bacteria originating from the maternal gut and infant oral cavity. As such, breastmilk has prebiotic and probiotic properties that can modulate two of the main forces controlling the gut microbial community assembly, i.e., dispersal and selection. Here, we review the latest evidence, mechanisms and hypotheses for the synergistic and/or additive effects of milk microbiota and HMOs in protecting against pediatric asthma.
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http://dx.doi.org/10.3389/fped.2018.00197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6095009PMC
July 2018

Association of T Helper 1 Cytokine Gene Single Nucleotide Polymorphisms with Ulcerative Colitis and Crohn's Disease.

Dig Dis 2019 22;37(1):21-32. Epub 2018 Aug 22.

Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran,

Background: Inflammatory bowel disease (IBD) mostly comprised of Crohn's disease (CD) and ulcerative colitis (UC) is a condition arising from the combined effects of genetic, environmental, and immunological factors. IBD is associated with inflammation and altered cytokine profile.

Objective: This study was aimed at assessing the association between T helper type 1 (Th1) cytokine polymorphisms (interferon gamma [IFN-γ] +874 A/T, interleukin-12 [IL-12] -1188 A/C, IL-2 -330 G/T, IL-2 +166 G/T) and susceptibility to and clinical features of IBD.

Methods: The study population was composed of 75 IBD patients (40 CD patients and 35 UC patients) and 140 healthy controls. Genotyping was performed using polymerase chain reaction with sequence-specific primers.

Results: The A allele of IFN-γ +874 polymorphism was overrepresented in the whole population of patients with IBD (OR 1.63; 95% CI 1.08-2.47; p = 0.020) and as well in the subpopulation of patients with CD (OR 2.14; 95% CI 1.26-3.63; p = 0.004), but not in UC. Multiple pairwise comparisons indicated that genotypes of single nucleotide polymorphisms (SNPs) within the IL-2 and IFN-γ genes are correlated with IBD, CD, and UC, while neither allele nor genotype frequency of th1 IL-12 -1188 polymorphism was associated with IBD, CD, or UC. Haplotype analysis also revealed that the presence of IL-2 -330/+166 TG haplotype versus the remaining haplotypes (GG, TT, and GT) is a protective factor against IBD (OR 0.62; p = 0.046).

Conclusions: The present study reports (for the first time) significant associations between SNPs within the IFN-γ and IL-2 genes and IBD.
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http://dx.doi.org/10.1159/000492027DOI Listing
December 2018

Opium Use and Risk of Pancreatic Cancer: A Prospective Cohort Study.

Cancer Epidemiol Biomarkers Prev 2018 03 20;27(3):268-273. Epub 2017 Dec 20.

Liver and Pancreatobiliary Diseases Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran.

We examined the association between opium consumption and pancreatic cancer incidence in a large-scale prospective cohort of the general population in northeastern Iran. A total of 50,045 adults were systematically followed up (median of 7.4 years), and incident cases of pancreatic cancer were identified. Self-reported data on opium consumption was collected at baseline. Cumulative use (-year) was defined as number of nokhods (a local unit, approximately 0.2 g) of opium consumed per day multiplied by number of years consuming. Adjusted HRs and 95% confidence intervals (CIs) for the association between opium consumption and pancreatic cancer were calculated using Cox proportional hazards regression models. Overall, 54 confirmed cases of pancreatic cancer were identified. Opium use of more than 81 nokhod-years (high cumulative use), compared with never use, was strongly associated with pancreatic cancer even after adjustments for multiple potential confounding factors [HR = 3.01; 95% CI, 1.25-7.26]. High cumulative consumption of opium was significantly associated with risk of pancreatic cancer after adjusting for cumulative dose of cigarette smoking [HR = 3.56; 95% CI, 1.49-8.50]. In a sensitivity analysis, we excluded participants (including 2 pancreatic cancer cases) who were recruited within the first 5 years of starting opium consumption; high cumulative use of opium was still associated with pancreatic cancer risk [HR = 2.75; 95% CI, 1.14-6.64]. Our results showed a positive association between opium consumption and pancreatic cancer. This is the first prospective large-scale study to show the association of opium consumption with pancreatic cancer as a risk factor. .
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http://dx.doi.org/10.1158/1055-9965.EPI-17-0592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5835180PMC
March 2018

Interleukin-4 and Interleukin-10 Gene Polymorphisms in Patients with Inflammatory Bowel Disease.

Immunol Invest 2017 Oct;46(7):714-729

g Research Center for Immunodeficiencies, Children's Medical Center , Tehran University of Medical Sciences , Tehran , Iran.

Background: Changes in cytokine expression have been frequently found in patients with inflammatory bowel disease (IBD). Cytokine values outside the normal range may be somewhat related to common polymorphisms within cytokine genes.

Objective: The present study was designed to investigate the possible association between polymorphisms within Interleukin IL-4 and IL-10 genes and susceptibility to and clinical features of IBD.

Methods: The study population was composed of 140 healthy controls and 75 patients with IBD (40 patients with Crohn's disease (CD) and 35 patients with ulcerative colitis (UC)). Genotyping was performed using polymerase chain reaction with sequence-specific primers.

Results: Higher frequencies for the C allele of IL-4-590 polymorphism (P < 0.0001; odds ratio [OR], 5.68; 95% confidence interval [95% CI], 3.28-9.83) and for the T allele of IL-4-1098 polymorphism (P = 0.016; OR, 1.83; 95% CI, 1.11-3.02) were observed in the whole group of IBD patients. The IL-4-590 C allele was also significantly overrepresented when IBD patients were subdivided into CD and UC (P < 0.0001; OR, 5.2-6.28). While the IL-4-1098 T allele was present at higher frequencies in patients with UC (P = 0.05; OR, 1.95), but not in CD (P = 0.09). Multiple pairwise comparisons indicated that genotypes of all polymorphisms investigated within IL-4 gene are correlated with IBD, CD, and UC. Haplotype analysis showed that the IL-4-1098/-590 TC haplotype might predispose individuals to IBD, CD, and UC whereas the IL-4-1098/-590 TT and GC haplotypes have a protective effect. On the contrary, neither allele nor genotype frequencies of IL-10 polymorphisms (IL-10-1082 A > G, IL-10-592 A > C, and IL-10-819 T > C) were associated with IBD, CD, or UC.

Conclusions: The present study suggests that IL-4 polymorphisms might play a role in susceptibility to IBD and its major subtypes in the Iranian population.
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http://dx.doi.org/10.1080/08820139.2017.1360343DOI Listing
October 2017

Early-Life Antibiotic Exposure, Gut Microbiota Development, and Predisposition to Obesity.

Nestle Nutr Inst Workshop Ser 2017 27;88:67-79. Epub 2017 Mar 27.

Antibiotics are often prescribed inappropriately to infants and young children, with potentially adverse effects on the developing gut microbiota and related metabolic processes. We review evidence from 17 epidemiologic studies suggesting that antibiotic exposure during critical periods of early development may influence weight gain and the development of obesity. Complementary research in both humans and rodents indicates that gut microbiota play a key role in this process, although further research is needed to confirm and characterize the causal mechanisms involved. Obesity is a complex and multifactorial condition; thus, a multipronged prevention strategy will be required to curb the current obesity epidemic. Evidence to date suggests this strategy should include the judicious use of antibiotics, especially in early life when the developing gut microbiota is particularly susceptible to perturbations with long-lasting implications for metabolic programming and obesity risk.
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http://dx.doi.org/10.1159/000455216DOI Listing
November 2017

Inverse Association of Plasma Level of Glutathione Peroxidase with Liver Fibrosis in Chronic Hepatitis B: Potential Role of Iron.

Middle East J Dig Dis 2016 Apr;8(2):122-30

Liver and Pancreatobiliary Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran.

BACKGROUND Oxidative stress has a major pathogenic role for liver damage following chronic hepatitis B. Glutathione peroxidase (Gpx) is necessary in oxidative state mechanism that is generally down-regulated by Hepatitis B virus (HBV) infection. On the other hand, disorders of iron homeostasis have been found out in HBV infected patients. Therefore, the objective of this study was to assess the interplay of Gpx and serum iron on clinical and virological features of patients with chronic HBV infection. METHODS One hundred and fifty adult, treatment-naïve, patients with chronic hepatitis B were randomly designated from an ongoing cohort of patients with HBV. Plasma Gpx1 concentration and HBV DNA quantity were measured. Liver stiffness was measured by transient elastography. RESULTS Serum iron had a positive association with HBV DNA count in the total population. Serum iron was not associated with liver stiffness. However, HBV DNA was significantly associated with liver stiffness only in male patients. Serum Gpx was inversely associated with liver stiffness. Serum iron and Gpx had indirect effects on liver stiffness via HBV DNA count. We observed dissimilar effects of serum iron on HBV DNA and Gpx on liver stiffness in male and female patients. CONCLUSION We identified interplay of serum iron and Gpx1 in relation to level of liver fibrosis in patients with chronic hepatitis B. Our results propose that oxidative stress and serum iron are differentially implicated in the progression of chronic hepatitis B in male and female patients.
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http://dx.doi.org/10.15171/mejdd.2016.17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4885611PMC
April 2016

Repeated Intraportal Injection of Mesenchymal Stem Cells in Combination with Pioglitazone in Patients with Compensated Cirrhosis: A Clinical Report of Two Cases.

Arch Iran Med 2016 Feb;19(2):131-6

Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.

Background: Transplantation of mesenchymal stem cells (MSCs) in combination with pioglitazone, an agonist of peroxisome proliferator-activated receptor-γ (PPAR-γ), can reduce liver fibrosis in models of liver injury. In this study, we conducted a pilot study of intraportal infusion of autologous MSCs in combination with pioglitazone to assess safety, feasibility, and effectiveness in patients with compensated cirrhosis.

Methods: Two patients with compensated cirrhosis were enrolled in this study. Intraportal autologous bone marrow-derived MSCs were transplanted twice (6 months interval) to the patients. Meanwhile, 30 mg/day pioglitazone was prescribed for 12 months.  Patients were assessed at baseline and months 1, 3, 6, and 12 post-infusion.

Results: Procedural complications or any major adverse effects did not occur in this pilot study.  The patients' clinical conditions remained stable with no evidence of deterioration during the course of the study. A transient improvement in the Model for End-Stage Liver Disease (MELD) score was observed at month 3 post-infusion in one patient, which eventually returned to baseline at month 12.

Conclusion: The combination of pioglitazone with MSCs is safe and feasible. The data justify further study of the combination therapy in cirrhotic patients.
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http://dx.doi.org/0161902/AIM.0011DOI Listing
February 2016

Intraportal Infusion of Bone Marrow Mononuclear or CD133+ Cells in Patients With Decompensated Cirrhosis: A Double-Blind Randomized Controlled Trial.

Stem Cells Transl Med 2016 Jan 10;5(1):87-94. Epub 2015 Dec 10.

Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, Academic Center for Education, Culture and Research, Tehran, Iran

Unlabelled: The present study assessed the effects of intraportal infusions of autologous bone marrow-derived mononuclear cells (MNCs) and/or CD133+ cells on liver function in patients with decompensated cirrhosis. We randomly assigned 27 eligible patients to a placebo, MNCs, and/or CD133+ cells. Cell infusions were performed at baseline and month 3. We considered the absolute changes in the Model for End-Stage Liver Disease (MELD) scores at months 3 and 6 after infusion as the primary outcome. The participants and those who assessed the outcomes were unaware of the treatment intervention assignments. After 6 months, 9 patients were excluded because of liver transplantation (n=3), hepatocellular carcinoma (n=1), loss to follow-up (n=3), and death (n=2). The final analysis included 4 patients from the CD133+ group, 8 from the MNC group, and 6 from the placebo group. No improvement was seen in the MELD score at month 6 using either CD133+ cells or MNC infusions compared with placebo. However, at month 3 after infusion, a trend was seen toward a higher mean absolute change in the MELD score in patients who had received CD133+ cells compared with placebo (-2.00±1.87 vs. -0.13±1.46; p=.08). No significant adverse events occurred in the present study. A transient improvement in the MELD score was observed in subjects treated with CD133+ cells but not in the MNC or placebo group. Although the study was not powered to make definitive conclusions, the data justify further study of CD133+ therapy in cirrhotic patients.

Significance: Cell therapy is a new approach in liver disease. Several clinical experiments have been reported on the safety of bone marrow-derived stem cells to treat liver disorders. However, the effectiveness of these approaches in the long-term follow-ups of patients initiated controversial discussions among the scientific community. A double-blind randomized controlled trial was designed to address this concern scientifically. A transient improvement in the patients' signs occurred; however, for a sustainable result, more work is needed. The results of multiple administrations of cells reported in the present study can be compared with the results from other single-injection studies.
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http://dx.doi.org/10.5966/sctm.2015-0004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4704869PMC
January 2016

Mean Polyp per Patient Is an Accurate and Readily Obtainable Surrogate for Adenoma Detection Rate: Results from an Opportunistic Screening Colonoscopy Program.

Middle East J Dig Dis 2015 Oct;7(4):214-9

Digestive Oncology Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran ; Sasan Alborz Biomedical Research Center, Masoud Gastroenterology and Hepatology Clinic, Tehran, Iran.

BACKGROUND The incidence of colorectal cancer is rising in several developing countries. In the absence of integrated endoscopy and pathology databases, adenoma detection rate (ADR), as a validated quality indicator of screening colonoscopy, is generally difficult to obtain in practice. We aimed to measure the correlation of polyp-related indicators with ADR in order to identify the most accurate surrogate(s) of ADR in routine practice. METHODS We retrospectively reviewed the endoscopic and histopathological findings of patients who underwent colonoscopy at a tertiary gastrointestinal clinic. The overall ADR and advanced-ADR were calculated using patient-level data. The Pearson's correlation coefficient (r) was applied to measure the strength of the correlation between the quality metrics obtained by endoscopists. RESULTS A total of 713 asymptomatic adults aged 50 and older who underwent their first-time screening colonoscopy were included in this study. The ADR and advanced-ADR were 33.00% (95% CI: 29.52-36.54) and 13.18% (95% CI: 10.79-15.90), respectively. We observed good correlations between polyp detection rate (PDR) and ADR (r=0.93), and mean number of polyp per patient (MPP) and ADR (r=0.88) throughout the colon. There was a positive, yet insignificant correlation between advanced ADRs and non-advanced ADRs (r=0.42, p=0.35). CONCLUSION MPP is strongly correlated with ADR, and can be considered as a reliable and readily obtainable proxy for ADR in opportunistic screening colonoscopy programs.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4655841PMC
October 2015

Minimum Requirements for Reporting Fecal Microbiota Transplant Trial.

Middle East J Dig Dis 2015 Jul;7:177-80

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

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4560633PMC
July 2015

Physicians' Knowledge and Attitude Towards Fecal Microbiota Transplant in Iran.

Middle East J Dig Dis 2015 Jul;7:155-60

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

BACKGROUND Fecal microbiota transplant (FMT) is employed to replace the 'unhealthy' microbiota of the patient with the 'healthy' microbiota of a pre-screened healthy donor. Given the growing importance of gut microbiota dysbiosis in the pathogenesis of intestinal or extraintestinal diseases; it is conceivable that FMT becomes integrated in the routine clinical practice. Our objective was to assess the knowledge and attitude of the Iranian physicians towards FMT. METHODS We surveyed the participants of Iranian gastroenterology and hepatology 2014 conference. RESULTS Overall, 146 (68.5%) were familiar with FMT; of whom 132 (94.28%) were willing to accept FMT if scientifically and ethically approved and 115 (88.46%) were willing to refer their patients for FMT if indicated. In total, 42 (30.7%) had identified stool preparation as the most unappealing aspect of FMT, while 17 (11.6%) reported the therapeutic use of fecal material as the most unappealing and 39 (28.5%) indicated that both are equally unappealing. The doctors who had an overall positive opinion toward FMT reported less negative feelings towards FMT. CONCLUSION Iranian physicians are willing to accept FMT as a therapeutic option if it is scientifically justified and ethically approved. Nevertheless, physicians prefer to skip the stool preparation phase; as they are more in favour of synthetic microbiota as opposed to fecal microbiota.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4560629PMC
July 2015

The possible impact of sortilin in reducing HBsAg expression in chronic hepatitis B.

J Med Virol 2016 Apr 8;88(4):647-52. Epub 2015 Sep 8.

Liver and Pancreatobiliary Diseases Research Center, Digestive Disease Research Institute, Tehran University of Medical Sciences, Tehran, Iran.

Hepatitis B virus (HBV) infection is a major global health problem. Chronically infected people are at risk for progressive hepatic fibrosis and consequent cirrhosis. Hepatitis B surface antigen (HBsAg) level in serum is a complementary marker for intrahepatic HBV DNA and covalently closed circular DNA (cccDNA). Sortilin-1 (SORT1) has been reported to be involved in the post-Golgi vesicle trafficking of Apo lipoproteins degradation pathways. This study was designed to evaluate the hepatic and serum expression of HBsAg and its association with hepatic SORT1 gene expression in patients with chronic HBV. Thirty chronic hepatitis B patients with histological examination results were enrolled in this study. Liver biopsies were analyzed for hepatic HBsAg and SORT1 gene expression by immunohistochemistry and quantitative real time PCR (qRT-PCR), respectively. Twenty seven out of 30 (90%) liver biopsies had positive staining for HBsAg and showed a significant inverse association with hepatic SORT1 fold change gene expression (β = -0.5, P = 0.042). There was significant association between HBV DNA levels and HBsAg expression in hepatocyte or serum titer of HBsAg (r = 0.39, P = 0.029; r = 0.39, P = 0.032 respectively). Serum ALT was also correlated with hepatic activity index (HAI) score (β = 0.6, P = 0.001). Inverse association between hepatic SORT1 gene expression and hepatic HBsAg expression indicates the possible role of sortilin in HBsAg particle formation.
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http://dx.doi.org/10.1002/jmv.24367DOI Listing
April 2016

Distinctive expression pattern of interleukin-17 cytokine family members in colorectal cancer.

Tumour Biol 2016 Feb 25;37(2):1609-15. Epub 2015 Aug 25.

Division of Digestive Diseases, Rush University Medical Center, Chicago, IL, USA.

Colorectal cancer (CRC) is one of the most common cancers in both genders. Even though interleukin (IL)-17A was shown to play an important role in intestinal tumourigenesis and CRC, other IL-17 family members were not studied well. We therefore studied the expression of IL-17 cytokine family members in CRC. Ten healthy colons and ten CRC mucosa were immunostained for IL-17B, IL-17C, IL-17E, and IL-17F, and their receptors IL-17RA, IL-17RB, and IL-17RC. Double immunofluorescence staining of the CRC mucosa was done for IL-17B with markers of neutrophils, endothelial cells, macrophages, T cells, mast cells, or fibroblasts. While IL-17B was increased in CRC with a strong presence both in the epithelial and stromal compartments, IL-17C showed different expression depending on the grade of differentiation and IL-17E remained unchanged. In contrast, IL-17F was decreased in CRC compared to healthy control. Colon epithelial cells stained positive for IL-17RA, IL-17RB, and IL-17RC in both healthy control and CRC. Neutrophils were the main source of IL-17B in the stroma. IL-17 family members demonstrated distinct expression patterns in CRC, suggesting a differential role exerted by each member in colon carcinogenesis.
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http://dx.doi.org/10.1007/s13277-015-3941-xDOI Listing
February 2016

Heterogeneity of the level of activity of lgr5+ intestinal stem cells.

Authors:
Shirin Moossavi

Int J Mol Cell Med 2014 ;3(4):216-24

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

Intestinal stem cells (ISCs) are a group of rare cells located in the intestinal crypts which are responsible for the maintenance of the intestinal epithelial homeostasis and regeneration following injury or inflammation. Lineage tracing experiments in mice have proven that ISCs can repopulate the entire intestinal crypt. It is noteworthy that in such experiments, only a subset of intestinal crypts is marked by the specific marker. This is suggestive of different levels of activity of stem cells in different crypts i.e. intracryptal variation. Niche succession i.e. dominating the entire crypt by the progenies of one stem cell is also suggestive of the intercryptal stem cell heterogeneity. Regional differences in crypt size, proliferative index, and distribution of proliferative cells along the crypt axis have been reported. It is conceivable that ISCs are heterogeneous in terms of their levels of activity. Appreciation of such heterogeneity will significantly challenge the way in which ISCs are investigated. A better understanding of ISC biology will in turn improve our mechanistic understanding of major intestinal disease including inflammatory bowel disease and colorectal cancer.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4293609PMC
January 2015

Significance of IL-1RA Polymorphism in Iranian Patients with Inflammatory Bowel Disease.

Dig Dis Sci 2015 May 3;60(5):1389-95. Epub 2014 Dec 3.

Department of Gastroenterology and Hepatology, Tehran University of Medical Sciences, Tehran, Iran.

Background And Aim: Interleukin (IL)-1 family members play an important role in the pathogenesis of inflammatory bowel disease (IBD). There are conflicting results regarding the association of IL-1 gene cluster single nucleotide polymorphisms (SNPs) with IBD and its clinical features. The aim of this study was to examine IL-1α -889 C/T, IL-1β -511 C/T, IL-1β +3962 C/T, IL-1R Pst-I1970 C/T, and IL-1RA Mspa-I11100 C/T SNPs in Iranian patients.

Methods: In this study, SNPs of IL-1 family members were investigated in 75 patients with IBD (40 CD and 35 UC), using polymerase chain reaction with sequence-specific primers method.

Results: IL-1β -511 CC genotype was significantly less present in UC compared to controls, while IL-1RA Mspa-I11100 CC was significantly associated with both Crohn's disease (CD) and ulcerative colitis (UC). IL-1α -889 TT genotype was more frequently associated with extraintestinal manifestations. A significant association was observed between IL-1β +3962 TT genotype and the disease activity in IBD. IL-1RA Mspa-I11100 CC was significantly less frequent in CD patients who need immunosuppressive therapy. IL-1RA Mspa-I11100 CT was associated with earlier age of onset in IBD, while TT genotype was associated with higher age of onset in IBD.

Conclusions: IL-1 SNPs seem to be associated with IBD and could affect the disease severity as well.
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http://dx.doi.org/10.1007/s10620-014-3457-zDOI Listing
May 2015

Cohort profile: golestan hepatitis B cohort study- a prospective long term study in northern iran ​.

Middle East J Dig Dis 2014 Oct;6(4):186-94

Liver and Pancreatobiliary Diseases Research Center, Digestive Disease Research Institute, Shariati Hospital, Tehran university of Medical Sciences, Tehran, Iran.

Hepatitis B virus (HBV) infection is the most common cause of end stage liver disease in Iran and in Golestan province. Large-scale population-based prospective cohort studies with long term follow-up are the method of choice to accurately understand the natural course of HBV infection. To date, several studies of HBV epidemiology, natural history, progression to cirrhosis and association with HCC have been reported from other countries. However, few of these are prospective and fewer still are population-based. Moreover, the underlying molecular mechanisms and immunogenetic determinants of the outcome of HBV infection especially in low and middle income countries remains largely unknown. Therefore, the hepatitis B cohort study (HBCS), nested as part of the Golestan Cohort Study (GCS), Golestan, Iran was established in 2008 with the objective to prospectively investigate the natural course of chronic hepatitis B with reference to its epidemiology, viral/host genetic interactions, clinical features and outcome in the Middle East where genotype D HBV accounts for >90% of infections. In 2008, a baseline measurement of HBV surface antigen (HBsAg) was performed on stored serum samples of all GCS participants. A sub-cohort of 3,505 individuals were found to be HBsAg positive and were enrolled in the Golestan HBCS. In 2011, all first degree relatives of HBsAg positive subjects including their children and spouses were invited for HBV serology screening and those who were positive for HBsAg were also included in the Golestan HBCS.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4208926PMC
October 2014

The necessity for an Iranian gut microbiome initiative.

Authors:
Shirin Moossavi

Middle East J Dig Dis 2014 Apr;6(2):109-10

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

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4034665PMC
April 2014

Location-specific effect of microbiota and MyD88-dependent signaling on Wnt/β-catenin pathway and intestinal stem cells.

Authors:
Shirin Moossavi

Gut Microbes 2014 Jan-Feb;5(1):11-4. Epub 2013 Dec 16.

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

Intestinal homeostasis depends on the proper activity of the intestinal stem cells (ISCs) and an appropriate host response to the normal resident microbiota. The question on the effect of microbiota on ISCs behavior has not been addressed yet. Canonical Wnt pathway and ISC gene expression signature was compared in germfree vs. conventional and MyD88(-/-) vs. Myd88(+/+) mice based on publicly available gene expression data sets. Microbiota and MyD88-dependent signaling have distinct effects on the Wnt pathway and ISC at gene expression level. In addition, the effect of microbiota and MyD88-dependent signaling on Wnt pathway and ISCs show regional variation. The net effect of microbiota on Wnt pathway and ISCs cannot be inferred from the available data. Nonetheless, the data are suggestive of a potential regulatory mechanism of the Wnt pathway by the microbiota and plausibly by any alteration in the microbiota composition.
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http://dx.doi.org/10.4161/gmic.27291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4049928PMC
January 2015