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ROBERT ALLEN BRITTON

TitleProfessor
InstitutionBaylor College of Medicine
DepartmentDepartment of Molecular Virology & Microbiology
DivisionMolecular Virology & Microbiology
AddressOne Baylor Plaza
Houston TX 77030
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    Collapse Biography 
    Collapse awards and honors
    2007 - 2013NSF CAREER Award
    2010College of Natural Science Teacher Scholar Award, Michigan State University

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    Areas of Interest

    The role of intestinal bacteria in health and disease
    Recombineering in lactic acid bacteria
    GTPase control of ribosome assembly

    Research Summary

    1. The role of intestinal bacteria in health and disease.

    Recent work into the role of intestinal bacteria in a variety of disease states including inflammatory bowel disease, obesity, and diabetes has established a clear link between these bacteria and our health. The Britton laboratory is focused on two areas of research in this area: the role of probiotic bacteria in treating disease and the role of the intestinal microbiota in preventing pathogen invasion.

    Probiotic Lactobacillus reuteri

    Much of our work focuses on characterizing how different strains of Lactobacillus reuteri impact various aspects of the host response including inflammation, bone health, pathogen invasion and intestinal function. We use a variety of in vitro and animal models to explore how L. reuteri impacts health. Our overall goals are to identify novel probiotic strains that can be used to prevent or ameliorate disease and to develop a platform for the delivery of biotherapeutics.

    Microbiota and prevention of pathogen invasion.

    We are interested in understanding how the intestinal microbiota provides a barrier to incoming pathogens and how perturbations of the microbiota result in an established infection. We have focused most of our attention on the pathogen Clostridium difficile, which is the most common cause of antibiotic associated diarrhea and is quickly becoming the most common cause of nosocomial infections. We have developed mini-bioreactors and mice colonized with a human intestinal microbiota to address which members of the community are responsible for inhibiting C. difficile invasion. Our ultimate goal is to develop a probiotic cocktail derived from the human intestinal microbiota that will suppress C. difficile invasion.

    This project is funded by the NIH Enteric Research Investigative Network (ERIN). The Michigan State University ERIN is directed by Linda Mansfield with myself and Shannon Manning as project leaders.

    Collaborators: Much of the work we do is interdisciplinary and thus we engage in a number of collaborative projects. Our collaborators include Laura McCabe (Michigan State University), Nara Parameswaran (Michigan State University), Vincent Young (University of Michigan), James Versalovic (Baylor College of Medicine), Stefan Roos (Swedish University of Agricultural Sciences), Eamonn Connolly (Biogaia AB), Linda Mansfield (Michigan State University), Shannon Manning (Michigan State University), Kathryn Eaton (University of Michigan).


    2. Recombineering in lactic acid bacteria.

    Recombineering technology allows for the precise genetic manipulation of bacterial chromosomes. Using single-stranded DNA (ssDNA) recombineering technology point mutations, small deletions, and small insertions can be recovered without the need for selection. Previous to our recent work, non-selected ssDNA recombineering could only be performed in Escherichia coli. We have now established non-selected recombineering in two lactic acid bacteria strains, Lactobacillus reuteri and Lactococcus lactis. We also have shown that recombineering can function in other Gram-positive bacteria as well. We can achieve average recombineering efficiencies of ~15% in L. lactis, which will now enable directed evolution of multiple chromosomal sites to be achieved simultaneously. Finally, we have also developed an efficient method for inserting genes stably into the chromosome of L. reuteri, which will enable the use of this human-derived organism to be used in the intestinal delivery of biotherapeutics and vaccines.L. reuteri.

    Collaborators: James Ferrara (Mt. Sinai School of Medicine), Jeff Tabor (Rice University), Jan Peter van Pijkeren (University of Wisconsin-Madison).


    3. GTPase control of ribosome assembly. GTPases play an important role in the assembly of ribosomes in all three kingdoms of life. The molecular mechanisms by which they function are largely unknown. We are studying the ribosome assembly GTPase RbgA in Bacillus subtilis in an attempt to understand how these proteins act in the maturation of the large ribosomal subunit using a combination of biochemical, structural and genetic approaches. Interestingly, mutation or depletion of RbgA results in the accumulation of a ribosome assembly intermediate that is arrested at a very late stage of development. Work on eukaryotic homologs of RbgA suggests that these proteins are involved in a late assembly step of the large ribosomal subunit. The results from this bacterial work will have important implications for the formation of cytoplasmic, mitochondrial, and chloroplast ribosomes.

    Collaborators: Joaquin Ortega (McMaster University), James Williamson (Scripps Institute).

    Funding

    We are grateful to the following funding agencies for current and past support of our research: NIH, NSF, DARPA, Michigan State University Foundation, Gerber Foundation, Michigan State University Vice President for Research Office, Biogaia AB, Christian Hansen, Novozymes, Procter and Gamble, Michigan State University Department of Microbiology and Molecular Genetics.

    Collapse keywords
    Microbiome, microbiota, probiotics, ribosome, bacterial genetics, precision genome editing, recombineering, Clostridium difficile, biotherapeutics


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    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.
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    1. Wang C, Zaheer M, Bian F, Quach D, Swennes AG, Britton RA, Pflugfelder SC, de Paiva CS. Sjögren-Like Lacrimal Keratoconjunctivitis in Germ-Free Mice. Int J Mol Sci. 2018 Feb 13; 19(2). PMID: 29438346.
      View in: PubMed
    2. Quach D, Collins F, Parameswaran N, McCabe L, Britton RA. Microbiota Reconstitution Does Not Cause Bone Loss in Germ-Free Mice. mSphere. 2018 Jan-Feb; 3(1). PMID: 29299532.
      View in: PubMed
    3. Spinler JK, Auchtung J, Brown A, Boonma P, Oezguen N, Ross CL, Luna RA, Runge J, Versalovic J, Peniche A, Dann SM, Britton RA, Haag A, Savidge TC. Next-Generation Probiotics Targeting Clostridium difficile through Precursor-Directed Antimicrobial Biosynthesis. Infect Immun. 2017 10; 85(10). PMID: 28760934.
      View in: PubMed
    4. Ortiz-Velez L, Britton R. Genetic Tools for the Enhancement of Probiotic Properties. Microbiol Spectr. 2017 Sep; 5(5). PMID: 28936946.
      View in: PubMed
    5. Roth C, Chan S, Offen WA, Hemsworth GR, Willems LI, King DT, Varghese V, Britton R, Vocadlo DJ, Davies GJ. Structural and functional insight into human O-GlcNAcase. Nat Chem Biol. 2017 Jun; 13(6):610-612. PMID: 28346405.
      View in: PubMed
    6. Razi A, Britton RA, Ortega J. The impact of recent improvements in cryo-electron microscopy technology on the understanding of bacterial ribosome assembly. Nucleic Acids Res. 2017 Feb 17; 45(3):1027-1040. PMID: 28180306.
      View in: PubMed
    7. Quach D, Britton RA. Gut Microbiota and Bone Health. Adv Exp Med Biol. 2017; 1033:47-58. PMID: 29101651.
      View in: PubMed
    8. Velly H, Britton RA, Preidis GA. Mechanisms of cross-talk between the diet, the intestinal microbiome, and the undernourished host. Gut Microbes. 2016 Dec 05; 1-15. PMID: 27918230.
      View in: PubMed
    9. Ni X, Davis JH, Jain N, Razi A, Benlekbir S, McArthur AG, Rubinstein JL, Britton RA, Williamson JR, Ortega J. YphC and YsxC GTPases assist the maturation of the central protuberance, GTPase associated region and functional core of the 50S ribosomal subunit. Nucleic Acids Res. 2016 Sep 30; 44(17):8442-55. PMID: 27484475.
      View in: PubMed
    10. Collins FL, Irwin R, Bierhalter H, Schepper J, Britton RA, Parameswaran N, McCabe LR. Lactobacillus reuteri 6475 Increases Bone Density in Intact Females Only under an Inflammatory Setting. PLoS One. 2016; 11(4):e0153180. PMID: 27058036; PMCID: PMC4825993.
    11. Auchtung JM, Robinson CD, Farrell K, Britton RA. MiniBioReactor Arrays (MBRAs) as a Tool for Studying C. difficile Physiology in the Presence of a Complex Community. Methods Mol Biol. 2016; 1476:235-58. PMID: 27507346.
      View in: PubMed
    12. McCabe L, Britton RA, Parameswaran N. Prebiotic and Probiotic Regulation of Bone Health: Role of the Intestine and its Microbiome. Curr Osteoporos Rep. 2015 Dec; 13(6):363-71. PMID: 26419466.
      View in: PubMed
    13. Auchtung JM, Robinson CD, Britton RA. Cultivation of stable, reproducible microbial communities from different fecal donors using minibioreactor arrays (MBRAs). Microbiome. 2015; 3:42. PMID: 26419531.
      View in: PubMed
    14. Singh P, Teal TK, Marsh TL, Tiedje JM, Mosci R, Jernigan K, Zell A, Newton DW, Salimnia H, Lephart P, Sundin D, Khalife W, Britton RA, Rudrik JT, Manning SD. Intestinal microbial communities associated with acute enteric infections and disease recovery. Microbiome. 2015; 3:45. PMID: 26395244.
      View in: PubMed
    15. Collins J, Auchtung JM, Schaefer L, Eaton KA, Britton RA. Humanized microbiota mice as a model of recurrent Clostridium difficile disease. Microbiome. 2015; 3:35. PMID: 26289776.
      View in: PubMed
    16. Zhang J, Motyl KJ, Irwin R, MacDougald OA, Britton RA, McCabe LR. Loss of Bone and Wnt10b Expression in Male Type 1 Diabetic Mice Is Blocked by the Probiotic Lactobacillus reuteri. Endocrinology. 2015 Sep; 156(9):3169-82. PMID: 26135835.
      View in: PubMed
    17. Britton RA, Irwin R, Quach D, Schaefer L, Zhang J, Lee T, Parameswaran N, McCabe LR. Probiotic L. reuteri treatment prevents bone loss in a menopausal ovariectomized mouse model. J Cell Physiol. 2014 Nov; 229(11):1822-30. PMID: 24677054; PMCID: PMC4129456.
    18. Gulati M, Jain N, Davis JH, Williamson JR, Britton RA. Functional interaction between ribosomal protein L6 and RbgA during ribosome assembly. PLoS Genet. 2014 Oct; 10(10):e1004694. PMID: 25330043; PMCID: PMC4199504.
    19. van Pijkeren JP, Britton RA. Precision genome engineering in lactic acid bacteria. Microb Cell Fact. 2014 Aug 29; 13 Suppl 1:S10. PMID: 25185700; PMCID: PMC4155826.
    20. Dishisha T, Pereyra LP, Pyo SH, Britton RA, Hatti-Kaul R. Flux analysis of the Lactobacillus reuteri propanediol-utilization pathway for production of 3-hydroxypropionaldehyde, 3-hydroxypropionic acid and 1,3-propanediol from glycerol. Microb Cell Fact. 2014; 13:76. PMID: 24886501; PMCID: PMC4045878.
    21. Robinson CD, Auchtung JM, Collins J, Britton RA. Epidemic Clostridium difficile strains demonstrate increased competitive fitness compared to nonepidemic isolates. Infect Immun. 2014 Jul; 82(7):2815-25. PMID: 24733099; PMCID: PMC4097623.
    22. Britton RA, Young VB. Role of the intestinal microbiota in resistance to colonization by Clostridium difficile. Gastroenterology. 2014 May; 146(6):1547-53. PMID: 24503131; PMCID: PMC3995857.
    23. Jensen H, Roos S, Jonsson H, Rud I, Grimmer S, van Pijkeren JP, Britton RA, Axelsson L. Role of Lactobacillus reuteri cell and mucus-binding protein A (CmbA) in adhesion to intestinal epithelial cells and mucus in vitro. Microbiology. 2014 Apr; 160(Pt 4):671-81. PMID: 24473252.
      View in: PubMed
    24. Jomaa A, Jain N, Davis JH, Williamson JR, Britton RA, Ortega J. Functional domains of the 50S subunit mature late in the assembly process. Nucleic Acids Res. 2014 Mar; 42(5):3419-35. PMID: 24335279; PMCID: PMC3950693.
    25. McCabe LR, Irwin R, Schaefer L, Britton RA. Probiotic use decreases intestinal inflammation and increases bone density in healthy male but not female mice. J Cell Physiol. 2013 Aug; 228(8):1793-8. PMID: 23389860; PMCID: PMC4091780.
    26. Sharma D, Malik A, Lee E, Britton RA, Parameswaran N. Gene dosage-dependent negative regulatory role of ?-arrestin-2 in polymicrobial infection-induced inflammation. Infect Immun. 2013 Aug; 81(8):3035-44. PMID: 23753627; PMCID: PMC3719563.
    27. Gulati M, Jain N, Anand B, Prakash B, Britton RA. Mutational analysis of the ribosome assembly GTPase RbgA provides insight into ribosome interaction and ribosome-stimulated GTPase activation. Nucleic Acids Res. 2013 Mar 1; 41(5):3217-27. PMID: 23325847; PMCID: PMC3597669.
    28. Stockdale SR, Mahony J, Courtin P, Chapot-Chartier MP, van Pijkeren JP, Britton RA, Neve H, Heller KJ, Aideh B, Vogensen FK, van Sinderen D. The lactococcal phages Tuc2009 and TP901-1 incorporate two alternate forms of their tail fiber into their virions for infection specialization. J Biol Chem. 2013 Feb 22; 288(8):5581-90. PMID: 23300085; PMCID: PMC3581408.
    29. Van Pijkeren JP, Neoh KM, Sirias D, Findley AS, Britton RA. Exploring optimization parameters to increase ssDNA recombineering in Lactococcus lactis and Lactobacillus reuteri. Bioengineered. 2012 Jul-Aug; 3(4):209-17. PMID: 22750793; PMCID: PMC3476877.
    30. De Weirdt R, Crabbé A, Roos S, Vollenweider S, Lacroix C, van Pijkeren JP, Britton RA, Sarker S, Van de Wiele T, Nickerson CA. Glycerol supplementation enhances L. reuteri's protective effect against S. Typhimurium colonization in a 3-D model of colonic epithelium. PLoS One. 2012; 7(5):e37116. PMID: 22693569; PMCID: PMC3365044.
    31. Britton RA, Young VB. Interaction between the intestinal microbiota and host in Clostridium difficile colonization resistance. Trends Microbiol. 2012 Jul; 20(7):313-9. PMID: 22595318; PMCID: PMC3408078.
    32. Thomas CM, Hong T, van Pijkeren JP, Hemarajata P, Trinh DV, Hu W, Britton RA, Kalkum M, Versalovic J. Histamine derived from probiotic Lactobacillus reuteri suppresses TNF via modulation of PKA and ERK signaling. PLoS One. 2012; 7(2):e31951. PMID: 22384111; PMCID: PMC3285189.
    33. van Pijkeren JP, Britton RA. High efficiency recombineering in lactic acid bacteria. Nucleic Acids Res. 2012 May; 40(10):e76. PMID: 22328729; PMCID: PMC3378904.
    34. Achila D, Gulati M, Jain N, Britton RA. Biochemical characterization of ribosome assembly GTPase RbgA in Bacillus subtilis. J Biol Chem. 2012 Mar 9; 287(11):8417-23. PMID: 22267738; PMCID: PMC3318688.
    35. Jones SE, Whitehead K, Saulnier D, Thomas CM, Versalovic J, Britton RA. Cyclopropane fatty acid synthase mutants of probiotic human-derived Lactobacillus reuteri are defective in TNF inhibition. Gut Microbes. 2011 Mar-Apr; 2(2):69-79. PMID: 21637024; PMCID: PMC3225771.
    36. Eaton KA, Honkala A, Auchtung TA, Britton RA. Probiotic Lactobacillus reuteri ameliorates disease due to enterohemorrhagic Escherichia coli in germfree mice. Infect Immun. 2011 Jan; 79(1):185-91. PMID: 20974822; PMCID: PMC3019869.
    37. Ditty JL, Kvaal CA, Goodner B, Freyermuth SK, Bailey C, Britton RA, Gordon SG, Heinhorst S, Reed K, Xu Z, Sanders-Lorenz ER, Axen S, Kim E, Johns M, Scott K, Kerfeld CA. Incorporating genomics and bioinformatics across the life sciences curriculum. PLoS Biol. 2010; 8(8):e1000448. PMID: 20711478; PMCID: PMC2919421.
    38. Walter J, Britton RA, Roos S. Host-microbial symbiosis in the vertebrate gastrointestinal tract and the Lactobacillus reuteri paradigm. Proc Natl Acad Sci U S A. 2011 Mar 15; 108 Suppl 1:4645-52. PMID: 20615995; PMCID: PMC3063604.
    39. Schaefer L, Auchtung TA, Hermans KE, Whitehead D, Borhan B, Britton RA. The antimicrobial compound reuterin (3-hydroxypropionaldehyde) induces oxidative stress via interaction with thiol groups. Microbiology. 2010 Jun; 156(Pt 6):1589-99. PMID: 20150236.
      View in: PubMed
    40. Young VB, Britton RA, Schmidt TM. The human microbiome and infectious diseases: beyond koch. Interdiscip Perspect Infect Dis. 2008; 2008:296873. PMID: 19343181; PMCID: PMC2662322.
    41. Britton RA, Versalovic J. Probiotics and gastrointestinal infections. Interdiscip Perspect Infect Dis. 2008; 2008:290769. PMID: 19277100; PMCID: PMC2648624.
    42. Britton RA. Role of GTPases in bacterial ribosome assembly. Annu Rev Microbiol. 2009; 63:155-76. PMID: 19575570.
      View in: PubMed
    43. Hüfner E, Britton RA, Roos S, Jonsson H, Hertel C. Global transcriptional response of Lactobacillus reuteri to the sourdough environment. Syst Appl Microbiol. 2008 Oct; 31(5):323-38. PMID: 18762399.
      View in: PubMed
    44. Cadieux P, Wind A, Sommer P, Schaefer L, Crowley K, Britton RA, Reid G. Evaluation of reuterin production in urogenital probiotic Lactobacillus reuteri RC-14. Appl Environ Microbiol. 2008 Aug; 74(15):4645-9. PMID: 18539802; PMCID: PMC2519358.
    45. Whitehead K, Versalovic J, Roos S, Britton RA. Genomic and genetic characterization of the bile stress response of probiotic Lactobacillus reuteri ATCC 55730. Appl Environ Microbiol. 2008 Mar; 74(6):1812-9. PMID: 18245259; PMCID: PMC2268311.
    46. Wicker-Planquart C, Foucher AE, Louwagie M, Britton RA, Jault JM. Interactions of an essential Bacillus subtilis GTPase, YsxC, with ribosomes. J Bacteriol. 2008 Jan; 190(2):681-90. PMID: 17981968; PMCID: PMC2223697.
    47. Wall T, Båth K, Britton RA, Jonsson H, Versalovic J, Roos S. The early response to acid shock in Lactobacillus reuteri involves the ClpL chaperone and a putative cell wall-altering esterase. Appl Environ Microbiol. 2007 Jun; 73(12):3924-35. PMID: 17449683; PMCID: PMC1932720.
    48. Uicker WC, Schaefer L, Koenigsknecht M, Britton RA. The essential GTPase YqeH is required for proper ribosome assembly in Bacillus subtilis. J Bacteriol. 2007 Apr; 189(7):2926-9. PMID: 17237168; PMCID: PMC1855813.
    49. Britton RA, Wen T, Schaefer L, Pellegrini O, Uicker WC, Mathy N, Tobin C, Daou R, Szyk J, Condon C. Maturation of the 5' end of Bacillus subtilis 16S rRNA by the essential ribonuclease YkqC/RNase J1. Mol Microbiol. 2007 Jan; 63(1):127-38. PMID: 17229210.
      View in: PubMed
    50. Schaefer L, Uicker WC, Wicker-Planquart C, Foucher AE, Jault JM, Britton RA. Multiple GTPases participate in the assembly of the large ribosomal subunit in Bacillus subtilis. J Bacteriol. 2006 Dec; 188(23):8252-8. PMID: 16997968; PMCID: PMC1698177.
    51. Uicker WC, Schaefer L, Britton RA. The essential GTPase RbgA (YlqF) is required for 50S ribosome assembly in Bacillus subtilis. Mol Microbiol. 2006 Jan; 59(2):528-40. PMID: 16390447.
      View in: PubMed
    52. Jiang X, Zhao B, Britton R, Lim LY, Leong D, Sanghera JS, Zhou BB, Piers E, Andersen RJ, Roberge M. Inhibition of Chk1 by the G2 DNA damage checkpoint inhibitor isogranulatimide. Mol Cancer Ther. 2004 Oct; 3(10):1221-7. PMID: 15486189.
      View in: PubMed
    53. Stanley NR, Britton RA, Grossman AD, Lazazzera BA. Identification of catabolite repression as a physiological regulator of biofilm formation by Bacillus subtilis by use of DNA microarrays. J Bacteriol. 2003 Mar; 185(6):1951-7. PMID: 12618459; PMCID: PMC150146.
    54. Britton RA. DNA microarrays and bacterial gene expression. Methods Enzymol. 2003; 370:264-78. PMID: 14712651.
      View in: PubMed
    55. Britton RA, Eichenberger P, Gonzalez-Pastor JE, Fawcett P, Monson R, Losick R, Grossman AD. Genome-wide analysis of the stationary-phase sigma factor (sigma-H) regulon of Bacillus subtilis. J Bacteriol. 2002 Sep; 184(17):4881-90. PMID: 12169614; PMCID: PMC135291.
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