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Donda K, Torres BA, Maheshwari A. Non-coding RNAs in Neonatal Necrotizing Enterocolitis. NEWBORN 2022; 1:120-130. [PMID: 35754997 PMCID: PMC9219563 DOI: 10.5005/jp-journals-11002-0012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Affiliation(s)
- Keyur Donda
- Department of Pediatrics, University of South Florida Health Morsani College of Medicine, Tampa, Florida, United States of America
| | - Benjamin A Torres
- Department of Pediatrics, University of South Florida Health Morsani College of Medicine, Tampa, Florida, United States of America
| | - Akhil Maheshwari
- Global Newborn Society, Clarksville, Maryland, United States of America
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2
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Nair J, Maheshwari A. Non-coding RNAs in Necrotizing Enterocolitis- A New Frontier? Curr Pediatr Rev 2022; 18:25-32. [PMID: 34727861 DOI: 10.2174/1573396317666211102093646] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 06/30/2021] [Accepted: 09/01/2021] [Indexed: 11/22/2022]
Abstract
With the recognition that only 2% of the human genome encodes for a protein, a large part of the "non-coding" portion is now being evaluated for a regulatory role in cellular processes. These non-coding RNAs (ncRNAs) are subdivided based on the size of the nucleotide transcript into microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), but most of our attention has been focused on the role of microRNAs (miRNAs) in human health and disease. Necrotizing enterocolitis (NEC), an inflammatory bowel necrosis affecting preterm infants, has a multifactorial, unclear etiopathogenesis, and we have no specific biomarkers for diagnosis or the impact of directed therapies. The information on ncRNAs, in general, and particularly in NEC, is limited. Increasing information from other inflammatory bowel disorders suggests that these transcripts may play an important role in intestinal inflammation. Here, we review ncRNAs for definitions, classifications, and possible roles in prematurity and NEC using some preliminary information from our studies and from an extensive literature search in multiple databases including PubMed, EMBASE, and Science Direct. miRNAs will be described in another manuscript in this series, hence in this manuscript we mainly focus on lncRNAs.
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Affiliation(s)
- Jayasree Nair
- Department of Pediatrics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA
| | - Akhil Maheshwari
- Department of Pediatrics, Johns Hopkins University, Baltimore, MD, USA
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3
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Bervoets L, Ippel JH, Smolinska A, van Best N, Savelkoul PHM, Mommers MAH, Penders J. Practical and Robust NMR-Based Metabolic Phenotyping of Gut Health in Early Life. J Proteome Res 2021; 20:5079-5087. [PMID: 34587745 PMCID: PMC8576838 DOI: 10.1021/acs.jproteome.1c00617] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
While substantial efforts have been made to optimize and standardize fecal metabolomics for studies in adults, the development of a standard protocol to analyze infant feces is, however, still lagging behind. Here, we present the development of a hands-on and robust protocol for proton 1H NMR spectroscopy of infant feces. The influence of extraction solvent, dilution ratio, homogenization method, filtration, and duration of centrifugation on the biochemical composition of infant feces was carefully evaluated using visual inspection of 1H NMR spectra in combination with multivariate statistical modeling. The optimal metabolomics protocol was subsequently applied on feces from seven infants collected at 8 weeks, 4, and 9 months of age. Interindividual variation was exceeding the variation induced by different fecal sample preparation methods, except for filtration. We recommend extracting fecal samples using water with a dilution ratio of 1:5 feces-to-water to homogenize using bead beating and to remove particulates using centrifugation. Samples collected from infants aged 8 weeks and 4 months showed elevated concentrations of milk oligosaccharide derivatives and lactic acid, whereas short-chain fatty acids (SCFAs) and branched-chain amino acids (BCAAs) were higher in the 9 month samples. The established protocol enables hands-on and robust analyses of the infant gut metabolome. The wide-ranging application of this protocol will facilitate interlaboratory comparison of infants' metabolic profiles and finally aid in a better understanding of infant gut health.
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Affiliation(s)
- Liene Bervoets
- Department of Medical Microbiology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, 6229 HX Maastricht, The Netherlands
| | - Johannes H Ippel
- Department of Biochemistry, CARIM Cardiovascular Research Institute Maastricht, Maastricht University, 6229 HX Maastricht, The Netherlands
| | - Agnieszka Smolinska
- Department of Pharmacology and Toxicology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, 6229 HX Maastricht, The Netherlands
| | - Niels van Best
- Department of Medical Microbiology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, 6229 HX Maastricht, The Netherlands.,Institute of Medical Microbiology, RWTH University Hospital Aachen, 52074 Aachen, Germany
| | - Paul H M Savelkoul
- Department of Medical Microbiology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, 6229 HX Maastricht, The Netherlands.,Department of Medical Microbiology & Infection Control, VUMC, 1081 HV Amsterdam, The Netherlands
| | - Monique A H Mommers
- Department of Epidemiology, Maastricht University, 6229 HX Maastricht, The Netherlands
| | - John Penders
- Department of Medical Microbiology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, 6229 HX Maastricht, The Netherlands
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Abstract
Integrative analysis of high-quality metagenomics and metabolomics data from fecal samples provides novel clues for the mechanism underpinning gut microbe-human interactions. However, data regarding the influence of fecal collection methods on both metagenomics and metabolomics are sparse. Six fecal collection methods (the gold standard [GS] [i.e., immediate freezing at −80°C with no solution], 95% ethanol, RNAlater, OMNIgene Gut, fecal occult blood test [FOBT] cards, and Microlution) were used to collect 88 fecal samples from eight healthy volunteers for whole-genome shotgun sequencing (WGSS) and untargeted metabolomic profiling. Metrics assessed included the abundances of predominant phyla and α- and β-diversity at the species, gene, and pathway levels. Intraclass correlation coefficients (ICCs) were calculated for microbes and metabolites to estimate (i) stability (day 4 versus day 0 within each method), (ii) concordance (day 0 for each method versus the GS), and (iii) reliability (day 4 for each method versus the GS). For the top 4 phyla and microbial diversity metrics at the species, gene, and pathway levels, generally high stability and reliability were observed for most methods except for 95% ethanol; similar concordances were seen for different methods. For metabolomics data, 95% ethanol showed the highest stability, concordance, and reliability (median ICCs = 0.71, 0.71, and 0.65, respectively). Taken together, OMNIgene Gut, FOBT cards, RNAlater, and Microlution, but not 95% ethanol, were reliable collection methods for gut metagenomic studies. However, 95% ethanol was the best for preserving fecal metabolite profiles. We recommend using separate collecting methods for gut metagenomic sequencing and fecal metabolomic profiling in large population studies. IMPORTANCE The choice of fecal collection method is essential for studying gut microbe-human interactions in large-scale population-based research. In this study, we examined the effects of fecal collection methods and storage time at ambient temperature on variations in the gut microbiome community composition; microbial diversity metrics at the species, gene, and pathway levels; antibiotic resistance genes; and metabolome profiling. Our findings suggest using different fecal sample collection methods for different data generation purposes. OMNIgene Gut, FOBT cards, RNAlater, and Microlution, but not 95% ethanol, were reliable collection methods for gut metagenomic studies. However, 95% ethanol was the best for preserving fecal metabolite profiles.
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5
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Zhou Y, He Y, Liu L, Zhou W, Wang P, Hu H, Nie Y, Chen Y. Alterations in Gut Microbial Communities Across Anatomical Locations in Inflammatory Bowel Diseases. Front Nutr 2021; 8:615064. [PMID: 33718417 PMCID: PMC7952524 DOI: 10.3389/fnut.2021.615064] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 02/05/2021] [Indexed: 12/19/2022] Open
Abstract
We previously discovered that gut microbiota can serve as universal microbial biomarkers for diagnosis, disease activity assessment, and predicting the response to infliximab treatment for inflammatory bowel diseases (IBD). Much still remains unknown about the relationship between alterations in gut microbiota and IBD affected bowel region, in particular in the case of ulcerative colitis (UC) and colonic Crohn's disease (cCD) without endoscopic and biopsy data. In the current study gut microbiota from a population in China was found to be distinct from that of the Western world [Human Microbiome Project (HMP) data]. Furthermore, both gut microbiota greatly differed from microbiota of other anatomical locations (oral, skin, airway, and vagina), with higher alpha-diversity (Chinese gut > HMP gut > oral microbiome > airway microbiome > skin microbiome > vaginal microbiome), and marked differences in microbiome composition. In patients with IBD in China, UC was characterized by the presence of Gardnerella, while cCD was characterized by the presence of Fusobacterium. Moreover, gut microbiota, such as Gardnerella and Fusobacterium, may be potential biomarkers for identifying UC from cCD. Together, this study revealed crucial differences in microbial communities across anatomical locations, and demonstrated that there was an important association between IBD affected bowel region and gut microbiota.
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Affiliation(s)
- Youlian Zhou
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Yan He
- State Key Laboratory of Organ Failure Research, Division of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Le Liu
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Wanyan Zhou
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Pu Wang
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Han Hu
- Shenzhen Xbiome Biotech Co. Ltd., Shenzhen, China
| | - Yuqiang Nie
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Ye Chen
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
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6
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Zhou Y, Xu ZZ, He Y, Yang Y, Liu L, Lin Q, Nie Y, Li M, Zhi F, Liu S, Amir A, González A, Tripathi A, Chen M, Wu GD, Knight R, Zhou H, Chen Y. Gut Microbiota Offers Universal Biomarkers across Ethnicity in Inflammatory Bowel Disease Diagnosis and Infliximab Response Prediction. mSystems 2018; 3:e00188-17. [PMID: 29404425 PMCID: PMC5790872 DOI: 10.1128/msystems.00188-17] [Citation(s) in RCA: 226] [Impact Index Per Article: 32.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2017] [Accepted: 12/05/2017] [Indexed: 12/14/2022] Open
Abstract
Gut microbiota dysbiosis contributes to the onset and perpetuation of inflammatory bowel disease (IBD). Given that gut microbiotas vary across geography and ethnicity, it remains obscure whether any universal microbial signatures for IBD diagnosis and prognosis evaluation exist irrespective of populations. Here we profiled the fecal microbiota of a series of Chinese IBD patients and combined them with two Western IBD cohorts, PRISM and RISK, for meta-analyses. We found that the gut microbial alteration patterns in IBD are similar among Chinese and Westerners. Our prediction model based on gut microbiome for IBD diagnosis is robust across the cohorts, which showed 87.5% and 79.1% prediction accuracy in Crohn's disease (CD) and ulcerative colitis (UC) patients, respectively. A relative increase in the levels of Actinobacteria and Proteobacteria (Enterobacteriaceae) and a relative decrease in the levels of Firmicutes (Clostridiales) were strongly correlated with IBD severity (P < 0.05). Additionally, restoration of gut microbiota diversity and a significant increase in Clostridiales relative abundance were found in patients responding to infliximab (IFX [Remicade]) treatment compared to those in relapse. Moreover, certain microbes, mainly Clostridiales, predicted the treatment effectiveness with 86.5% accuracy alone and 93.8% accuracy in combination with calprotectin levels and Crohn's disease activity index (CDAI). Taking the results together, we conclude that gut microbiota can offer a set of universal biomarkers for diagnosis, disease activity evaluation, and infliximab treatment response prediction in IBD. IMPORTANCE In the present report, we show that the human fecal microbiota contains promising and universal biomarkers for the noninvasive evaluation of inflammatory bowel disease severity and IFX treatment efficacy, emphasizing the potential ability to mine the gut microbiota as a modality to stratify IBD patients and apply personalized therapy for optimal outcomes.
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Affiliation(s)
- Youlian Zhou
- Department of Gastroenterology, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, China
| | - Zhenjiang Zech Xu
- Department of Pediatrics, University of California, San Diego, La Jolla, California, USA
- School of Food and Technology, Nanchang University, Nanchang, China
- State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, China
| | - Yan He
- Department of Environmental Health, School of Public Health and Tropical Medicine, State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China
- State Key Laboratory of Organ Failure Research, Division of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Yunsheng Yang
- Institute of Digestive Diseases, Chinese PLA General Hospital, Beijing, China
| | - Le Liu
- Department of Gastroenterology, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Qianyun Lin
- Department of Gastroenterology, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yuqiang Nie
- Department of Gastroenterology, Guangzhou Digestive Disease Center, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, China
| | - Mingsong Li
- Department of Gastroenterology, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Fachao Zhi
- Department of Gastroenterology, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Side Liu
- Department of Gastroenterology, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Amnon Amir
- Department of Pediatrics, University of California, San Diego, La Jolla, California, USA
| | - Antonio González
- Department of Pediatrics, University of California, San Diego, La Jolla, California, USA
| | - Anupriya Tripathi
- Department of Pediatrics, University of California, San Diego, La Jolla, California, USA
| | - Minhu Chen
- Department of Gastroenterology, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Gary D. Wu
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Rob Knight
- Department of Pediatrics, University of California, San Diego, La Jolla, California, USA
- Department of Computer Science and Engineering, University of California, San Diego, La Jolla, California, USA
- Center for Microbiome Innovation, University of California, San Diego, La Jolla, California, USA
| | - Hongwei Zhou
- State Key Laboratory of Organ Failure Research, Division of Laboratory Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Ye Chen
- Department of Gastroenterology, State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China
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7
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Xiong M, Bao Y, Xu X, Wang H, Han Z, Wang Z, Liu Y, Huang S, Song Z, Chen J, Peek RM, Yin L, Chen LF, Cheng J. Selective killing of Helicobacter pylori with pH-responsive helix-coil conformation transitionable antimicrobial polypeptides. Proc Natl Acad Sci U S A 2017; 114:12675-12680. [PMID: 29133389 PMCID: PMC5715757 DOI: 10.1073/pnas.1710408114] [Citation(s) in RCA: 113] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Current clinical treatment of Helicobacter pylori infection, the main etiological factor in the development of gastritis, gastric ulcers, and gastric carcinoma, requires a combination of at least two antibiotics and one proton pump inhibitor. However, such triple therapy suffers from progressively decreased therapeutic efficacy due to the drug resistance and undesired killing of the commensal bacteria due to poor selectivity. Here, we report the development of antimicrobial polypeptide-based monotherapy, which can specifically kill H. pylori under acidic pH in the stomach while inducing minimal toxicity to commensal bacteria under physiological pH. Specifically, we designed a class of pH-sensitive, helix-coil conformation transitionable antimicrobial polypeptides (HCT-AMPs) (PGA)m-r-(PHLG-MHH)n, bearing randomly distributed negatively charged glutamic acid and positively charged poly(γ-6-N-(methyldihexylammonium)hexyl-l-glutamate) (PHLG-MHH) residues. The HCT-AMPs showed unappreciable toxicity at physiological pH when they adopted random coiled conformation. Under acidic condition in the stomach, they transformed to the helical structure and exhibited potent antibacterial activity against H. pylori, including clinically isolated drug-resistant strains. After oral gavage, the HCT-AMPs afforded comparable H. pylori killing efficacy to the triple-therapy approach while inducing minimal toxicity against normal tissues and commensal bacteria, in comparison with the remarkable killing of commensal bacteria by 65% and 86% in the ileal contents and feces, respectively, following triple therapy. This strategy renders an effective approach to specifically target and kill H. pylori in the stomach while not harming the commensal bacteria/normal tissues.
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Affiliation(s)
- Menghua Xiong
- Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801
| | - Yan Bao
- Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801
| | - Xin Xu
- Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Institute of Functional Nano & Soft Materials, Collaborative Innovation Center of Suzhou Nano Science & Technology, Soochow University, Jiangsu, China 215123
| | - Hua Wang
- Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801
| | - Zhiyuan Han
- Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801
| | - Zhiyu Wang
- Frederick Seitz Materials Research Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL 61801
| | - Yeqing Liu
- Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangdong, China 510120
| | - Songyin Huang
- Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangdong, China 510120
| | - Ziyuan Song
- Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801
| | - Jinjing Chen
- Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801
| | - Richard M Peek
- Division of Gastroenterology, Department of Medicine and Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232
| | - Lichen Yin
- Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Institute of Functional Nano & Soft Materials, Collaborative Innovation Center of Suzhou Nano Science & Technology, Soochow University, Jiangsu, China 215123;
| | - Lin-Feng Chen
- Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801;
| | - Jianjun Cheng
- Department of Materials Science and Engineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801;
- Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Institute of Functional Nano & Soft Materials, Collaborative Innovation Center of Suzhou Nano Science & Technology, Soochow University, Jiangsu, China 215123
- Frederick Seitz Materials Research Laboratory, University of Illinois at Urbana-Champaign, Urbana, IL 61801
- Department of Bioengineering, University of Illinois at Urbana-Champaign, Urbana, IL 61801
- Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL 61801
- Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801
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8
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Li D, Achkar JP, Haritunians T, Jacobs JP, Hui KY, D'Amato M, Brand S, Radford-Smith G, Halfvarson J, Niess JH, Kugathasan S, Büning C, Schumm LP, Klei L, Ananthakrishnan A, Aumais G, Baidoo L, Dubinsky M, Fiocchi C, Glas J, Milgrom R, Proctor DD, Regueiro M, Simms LA, Stempak JM, Targan SR, Törkvist L, Sharma Y, Devlin B, Borneman J, Hakonarson H, Xavier RJ, Daly M, Brant SR, Rioux JD, Silverberg MS, Cho JH, Braun J, McGovern DPB, Duerr RH. A Pleiotropic Missense Variant in SLC39A8 Is Associated With Crohn's Disease and Human Gut Microbiome Composition. Gastroenterology 2016; 151:724-32. [PMID: 27492617 PMCID: PMC5037008 DOI: 10.1053/j.gastro.2016.06.051] [Citation(s) in RCA: 102] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2016] [Revised: 06/30/2016] [Accepted: 06/30/2016] [Indexed: 01/07/2023]
Abstract
BACKGROUND & AIMS Genome-wide association studies have identified 200 inflammatory bowel disease (IBD) loci, but the genetic architecture of Crohn's disease (CD) and ulcerative colitis remain incompletely defined. Here, we aimed to identify novel associations between IBD and functional genetic variants using the Illumina ExomeChip (San Diego, CA). METHODS Genotyping was performed in 10,523 IBD cases and 5726 non-IBD controls. There were 91,713 functional single-nucleotide polymorphism loci in coding regions analyzed. A novel identified association was replicated further in 2 independent cohorts. We further examined the association of the identified single-nucleotide polymorphism with microbiota from 338 mucosal lavage samples in the Mucosal Luminal Interface cohort measured using 16S sequencing. RESULTS We identified an association between CD and a missense variant encoding alanine or threonine at position 391 in the zinc transporter solute carrier family 39, member 8 protein (SLC39A8 alanine 391 threonine, rs13107325) and replicated the association with CD in 2 replication cohorts (combined meta-analysis P = 5.55 × 10(-13)). This variant has been associated previously with distinct phenotypes including obesity, lipid levels, blood pressure, and schizophrenia. We subsequently determined that the CD risk allele was associated with altered colonic mucosal microbiome composition in both healthy controls (P = .009) and CD cases (P = .0009). Moreover, microbes depleted in healthy carriers strongly overlap with those reduced in CD patients (P = 9.24 × 10(-16)) and overweight individuals (P = 6.73 × 10(-16)). CONCLUSIONS Our results suggest that an SLC39A8-dependent shift in the gut microbiome could explain its pleiotropic effects on multiple complex diseases including CD.
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Affiliation(s)
- Dalin Li
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Jean-Paul Achkar
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, Ohio
| | - Talin Haritunians
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Jonathan P Jacobs
- Division of Digestive Diseases, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Ken Y Hui
- Division of Gastroenterology, Department of Medicine, Yale University, New Haven, Connecticut
| | - Mauro D'Amato
- Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden; Biocruces Health Research Institute, Barakaldo, Bizkaia, Spain
| | - Stephan Brand
- Department of Medicine II, University Hospital Munich-Grosshadern, Munich, Germany
| | - Graham Radford-Smith
- Inflammatory Bowel Diseases, Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia; Department of Gastroenterology, Royal Brisbane and Women's Hospital, Brisbane, Australia; School of Medicine, University of Queensland, Brisbane, Australia
| | - Jonas Halfvarson
- Department of Gastroenterology, Faculty of Medicine and Health, Örebro University, Orebro, Sweden
| | - Jan-Hendrik Niess
- Department of Internal Medicine I, University of Ulm, Ulm, Germany; Division of Visceral Surgery and Medicine, Department of Gastroenterology, Inselspital Bern, Bern, Switzerland; Gastroenterology and Hepatology, University Hospital Basel, Basel, Switzerland
| | - Subra Kugathasan
- Department of Pediatrics, Emory University School of Medicine and Children's Health Care of Atlanta, Atlanta, Georgia
| | - Carsten Büning
- Internal Medicine, Krankenhaus Waldfriede, Berlin, Germany
| | - L Philip Schumm
- Department of Public Health Sciences, Biostatistical Laboratory, University of Chicago, Chicago, Illinois
| | - Lambertus Klei
- Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Ashwin Ananthakrishnan
- Gastroenterology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Guy Aumais
- Université de Montréal, Montréal, Québec, Canada; Hopital Maisonneuve Rosemont, Montréal, Québec, Canada
| | - Leonard Baidoo
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Marla Dubinsky
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York
| | | | - Jürgen Glas
- Department of Preventive Dentistry and Periodontology, Ludwig-Maximilians-University, Munich, Germany
| | - Raquel Milgrom
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Deborah D Proctor
- Division of Gastroenterology, Department of Medicine, Yale University, New Haven, Connecticut
| | - Miguel Regueiro
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Lisa A Simms
- Inflammatory Bowel Diseases, Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Joanne M Stempak
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Stephan R Targan
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Leif Törkvist
- Department of Clinical Science Intervention and Technology, Karolinska Institutet, Stockholm, Sweden; Center for Digestive Disease, IBD-unit, Karolinska University Hospital, Stockholm, Sweden
| | - Yashoda Sharma
- Department of Genetic & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Bernie Devlin
- Department of Psychiatry, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - James Borneman
- Department of Plant Pathology and Microbiology, University of California, Riverside, Riverside, California
| | - Hakon Hakonarson
- Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Ramnik J Xavier
- Gastroenterology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Mark Daly
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Steven R Brant
- Division of Gastroenterology and Hepatology, School of Medicine, Johns Hopkins University, Baltimore, Maryland; Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland
| | - John D Rioux
- Université de Montréal, Montréal, Québec, Canada; Montreal Heart Institute, Montréal, Québec, Canada
| | - Mark S Silverberg
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Judy H Cho
- Department of Genetic & Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York; Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Jonathan Braun
- Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California
| | - Dermot P B McGovern
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Richard H Duerr
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania.
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Wang W, Xu S, Ren Z, Jiang J, Zheng S. Gut microbiota and allogeneic transplantation. J Transl Med 2015; 13:275. [PMID: 26298517 PMCID: PMC4546814 DOI: 10.1186/s12967-015-0640-8] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2015] [Accepted: 08/14/2015] [Indexed: 02/06/2023] Open
Abstract
The latest high-throughput sequencing technologies show that there are more than 1000 types of microbiota in the human gut. These microbes are not only important to maintain human health, but also closely related to the occurrence and development of various diseases. With the development of transplantation technologies, allogeneic transplantation has become an effective therapy for a variety of end-stage diseases. However, complications after transplantation still restrict its further development. Post-transplantation complications are closely associated with a host's immune system. There is also an interaction between a person's gut microbiota and immune system. Recently, animal and human studies have shown that gut microbial populations and diversity are altered after allogeneic transplantations, such as liver transplantation (LT), small bowel transplantation (SBT), kidney transplantation (KT) and hematopoietic stem cell transplantation (HTCT). Moreover, when complications, such as infection, rejection and graft versus host disease (GVHD) occur, gut microbial populations and diversity present a significant dysbiosis. Several animal and clinical studies have demonstrated that taking probiotics and prebiotics can effectively regulate gut microbiota and reduce the incidence of complications after transplantation. However, the role of intestinal decontamination in allogeneic transplantation is controversial. This paper reviews gut microbial status after transplantation and its relationship with complications. The role of intervention methods, including antibiotics, probiotics and prebiotics, in complications after transplantation are also discussed. Further research in this new field needs to determine the definite relationship between gut microbial dysbiosis and complications after transplantation. Additionally, further research examining gut microbial intervention methods to ameliorate complications after transplantation is warranted. A better understanding of the relationship between gut microbiota and complications after allogeneic transplantation may make gut microbiota as a therapeutic target in the future.
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Affiliation(s)
- Weilin Wang
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China.
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China.
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China.
| | - Shaoyan Xu
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China.
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China.
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China.
| | - Zhigang Ren
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China.
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China.
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China.
| | - Jianwen Jiang
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China.
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China.
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China.
| | - Shusen Zheng
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China.
- Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China.
- Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, Zhejiang, China.
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Liang L, Ai L, Qian J, Fang JY, Xu J. Long noncoding RNA expression profiles in gut tissues constitute molecular signatures that reflect the types of microbes. Sci Rep 2015; 5:11763. [PMID: 26123364 PMCID: PMC4485256 DOI: 10.1038/srep11763] [Citation(s) in RCA: 74] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Accepted: 06/03/2015] [Indexed: 12/26/2022] Open
Abstract
The gut microbiota is commonly referred to as a hidden organ due to its pivotal effects on host physiology, metabolism, nutrition and immunity. The gut microbes may be shaped by environmental and host genetic factors, and previous studies have focused on the roles of protein-coding genes. Here we show a link between long non-coding RNA (lncRNA) expression and gut microbes. By repurposing exon microarrays and comparing the lncRNA expression profiles between germ-free, conventional and different gnotobiotic mice, we revealed subgroups of lncRNAs that were specifically enriched in each condition. A nearest shrunken centroid methodology was applied to obtain lncRNA-based signatures to identify mice in different conditions. The lncRNA-based prediction model successfully identified different gnotobiotic mice from conventional and germ-free mice, and also discriminated mice harboring transplanted microbes from fecal samples of mice or zebra fishes. To achieve optimal prediction accuracy, fewer lncRNAs were required in the prediction model than protein-coding genes. Taken together, our study demonstrated the effecacy of lncRNA expression profiles in discriminating the types of microbes in the gut. These results also provide a resource of gut microbe-associated lncRNAs for the development of lncRNA biomarkers and the identification of functional lncRNAs in host-microbes interactions.
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Affiliation(s)
- Lunxi Liang
- State Key Laboratory for Oncogenes and Related Genes; Key Laboratory of Gastroenterology & Hepatology, Ministry of Health; Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China
- Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, 145 Middle Shandong Rd, Shanghai 200001, China
| | - Luoyan Ai
- State Key Laboratory for Oncogenes and Related Genes; Key Laboratory of Gastroenterology & Hepatology, Ministry of Health; Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China
- Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, 145 Middle Shandong Rd, Shanghai 200001, China
| | - Jin Qian
- State Key Laboratory for Oncogenes and Related Genes; Key Laboratory of Gastroenterology & Hepatology, Ministry of Health; Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China
- Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, 145 Middle Shandong Rd, Shanghai 200001, China
| | - Jing-Yuan Fang
- State Key Laboratory for Oncogenes and Related Genes; Key Laboratory of Gastroenterology & Hepatology, Ministry of Health; Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China
- Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, 145 Middle Shandong Rd, Shanghai 200001, China
| | - Jie Xu
- State Key Laboratory for Oncogenes and Related Genes; Key Laboratory of Gastroenterology & Hepatology, Ministry of Health; Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200001, China
- Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, 145 Middle Shandong Rd, Shanghai 200001, China
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Wang WL, Xu SY, Ren ZG, Tao L, Jiang JW, Zheng SS. Application of metagenomics in the human gut microbiome. World J Gastroenterol 2015; 21:803-814. [PMID: 25624713 PMCID: PMC4299332 DOI: 10.3748/wjg.v21.i3.803] [Citation(s) in RCA: 233] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Revised: 09/30/2014] [Accepted: 11/07/2014] [Indexed: 02/06/2023] Open
Abstract
There are more than 1000 microbial species living in the complex human intestine. The gut microbial community plays an important role in protecting the host against pathogenic microbes, modulating immunity, regulating metabolic processes, and is even regarded as an endocrine organ. However, traditional culture methods are very limited for identifying microbes. With the application of molecular biologic technology in the field of the intestinal microbiome, especially metagenomic sequencing of the next-generation sequencing technology, progress has been made in the study of the human intestinal microbiome. Metagenomics can be used to study intestinal microbiome diversity and dysbiosis, as well as its relationship to health and disease. Moreover, functional metagenomics can identify novel functional genes, microbial pathways, antibiotic resistance genes, functional dysbiosis of the intestinal microbiome, and determine interactions and co-evolution between microbiota and host, though there are still some limitations. Metatranscriptomics, metaproteomics and metabolomics represent enormous complements to the understanding of the human gut microbiome. This review aims to demonstrate that metagenomics can be a powerful tool in studying the human gut microbiome with encouraging prospects. The limitations of metagenomics to be overcome are also discussed. Metatranscriptomics, metaproteomics and metabolomics in relation to the study of the human gut microbiome are also briefly discussed.
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Walters SS, Quiros A, Rolston M, Grishina I, Li J, Fenton A, DeSantis TZ, Thai A, Andersen GL, Papathakis P, Nieves R, Prindiville T, Dandekar S. Analysis of Gut Microbiome and Diet Modification in Patients with Crohn's Disease. SOJ MICROBIOLOGY & INFECTIOUS DISEASES 2014; 2:1-13. [PMID: 29756026 PMCID: PMC5944867 DOI: 10.15226/sojmid/2/3/00122] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE The human intestine harbors trillions of commensal microbes that live in homeostasis with the host immune system. Changes in the composition and complexity of gut microbial communities are seen in inflammatory bowel disease (IBD), indicating disruption in host-microbe interactions. Multiple factors including diet and inflammatory conditions alter the microbial complexity. The goal of this study was to develop an optimized methodology for fecal sample processing and to detect changes in the gut microbiota of patients with Crohn's disease receiving specialized diets. DESIGN Fecal samples were obtained from patients with Crohn's disease in a pilot diet crossover trial comparing the effects of a specific carbohydrate diet (SCD) versus a low residue diet (LRD) on the composition and complexity of the gut microbiota and resolution of IBD symptoms. The gut microbiota composition was assessed using a high-density DNA microarray PhyloChip. RESULTS DNA extraction from fecal samples using a column based method provided consistent results. The complexity of the gut microbiome was lower in IBD patients compared to healthy controls. An increased abundance of Bacteroides fragilis (B. fragilis) was observed in fecal samples from IBD positive patients. The temporal response of gut microbiome to the SCD resulted in an increased microbial diversity while the LRD diet was associated with reduced diversity of the microbial communities. CONCLUSION Changes in the composition and complexity of the gut microbiome were identified in response to specialized carbohydrate diet. The SCD was associated with restructuring of the gut microbial communities.
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Affiliation(s)
| | - Antonio Quiros
- Department of Internal Medicine, University of CA Davis, Sacramento, USA
- Division of Pediatric Gastroenterology MUSC Children’s Hospital, Charleston, SC
| | - Matthew Rolston
- Department of Medical Microbiology and Immunology, University of CA Davis, USA
| | - Irina Grishina
- Department of Medical Microbiology and Immunology, University of CA Davis, USA
| | - Jay Li
- Department of Medical Microbiology and Immunology, University of CA Davis, USA
| | - Anne Fenton
- Department of Medical Microbiology and Immunology, University of CA Davis, USA
| | - Todd Z. DeSantis
- Department of Bioinformatics, Second Genome, San Bruno, CA 94066
| | - Anne Thai
- Department of Internal Medicine, University of CA Davis, Sacramento, USA
| | - Gary L Andersen
- Ecology Department, Lawrence Berkeley National Laboratory, Berkeley, CA 94720
| | - Peggy Papathakis
- Department of Nutrition, California Polytechnic State University, San Luis Obispo, CA, USA
| | - Raquel Nieves
- Department of Pediatrics, David Grant Medical Center, Travis Air Force Base, California, 94535
| | - Thomas Prindiville
- Department of Internal Medicine, University of CA Davis, Sacramento, USA
| | - Satya Dandekar
- Department of Medical Microbiology and Immunology, University of CA Davis, USA
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