Susan Lynch, PhD
Background.
The human superorganism represents a coalition of man and microbes, with the greatest diversity and burden of these species concentrated in the lower gastrointestinal (GI) tract. Recent studies in this emerging field have demonstrated relationships between the composition of these communities and diverse aspects of host physiology, including immunological and metabolic function. Our research focuses on microbial communities associated with chronic inflammatory diseases of the gastrointestinal and respiratory tracts. Using clinical samples to inform studies using murine models, we examine interactions between the microbial community and specific species within these consortia with the host mucosal surface and immune response, in an effort to better understand microbial-host interplay in the context of chronic inflammatory disease.
Major goals. Research in the Lynch laboratory addresses key questions about the human microbiome:
1. What are the changes in microbial composition and function that underlie chronic inflammatory diseases such as inflammatory bowel disease and asthma?
2. What is the impact of environmental microbial exposure on initial gastrointestinal colonization events and development of the neonatal immune response?
3. How does microbiome perturbation affect the composition and behavior of microbial populations and influence host immune response?
4. Can manipulation of microbial assemblages provide alternative therapeutic strategies for management of patients with chronic disease?
On-going research.
Inflammatory Bowel Disease. We are currently examining the impact of host genetics and diet on the gastrointestinal microbiome of patients with ulcerative colitis. Using a murine model of colitis, we also are performing studies of microbiome manipulation with bacterial species to identify microbial functions that abrogate established disease.
Cystic fibrosis (CF). Long-term lung function decline in CF patients is punctuated by acute pulmonary infections. We are currently examining airway community dynamics that occur during such respiratory infection events. In separate studies we are examining the impact of cystic fibrosis transmembrane regulator mutation on gastrointestinal community composition. We are also engaged in a clinical trial examining the impact of probiotic supplementation on the gastrointestinal and respiratory microbiota of pediatric CF patients.
Asthma. Current research efforts are focused on examining the influence of house dust microbial exposures on the development of the gastrointestinal microbiome and it’s link to immune maturation and asthma outcomes in pediatric populations. We are also engaged in studies examining the potential for early life probiotic supplementation to impact gastrointestinal microbial community structure and function and assess the impact of such changes on childhood atopy and asthma development. Other studies include examination of the airway microbiome of severe asthmatic patients and the impact of corticosteroid use on airway and gastrointestinal microbiota of asthmatic populations. Murine studies are currently in progress to identify species and mechanisms of microbial protection against allergen and viral airway infection.
Sinusitus. Upper airway infections, particularly chronic sinus infection impacts more than 30 million Americans and incurs an annual multi-billion dollar health care burden. We are currently engaged in studies examining the role of the sinus microbiome in mediating both acute and chronic sinusitis. We are also examining in pediatric populations, how perturbation to microbial communities in this niche may lead to community reassembly failure and chronic disease development.
HIV. Opportunistic pneumonias remain a leading cause of morbidity and mortality in HIV-infected persons worldwide. Our current research efforts focus on cross-sectional and longitudinal studies to characterize the bacterial, viral, and fungal microbiome present in the lungs of patients with acute and early HIV infection, chronic HIV infection, and opportunistic pneumonia. We are also engaged in studies examining the gastrointestinal microbiome of HIV-infected populations to examine relationships between microbiome composition and indices of immune suppression in these patients.
Selected Publications
1. Caffrey, P, Lynch, S.V., Flood, L., Finnan, S. and Oliynyk, M. Amphotericin biosynthesis in Streptomyces nodosus: deductions from analysis of polyketide synthase and late genes. Chemistry and Biology. 2001. 8:713-723. PMID: 11451671
2. Barak, Y., Thorne, S., Ackerley, D.F., Lynch, S.V., Contag, C. and Matin A.C. New enzyme for reductive cancer chemotherapy, YieF, and its improvement by directed evolution. Molecular Cancer Therapeutics. 2006. 5(1):97-103. PMID: 16432167
3. Lynch, S. V., Dixon, L., Brodie, E.L., Keyhan, M., Hu, P., Ackerley, D.F., Andersen, G.A. and Matin, A.C. Role of rapA Gene in Controlling Antibiotic Resistance of Uropathogenic Escherichia coli Biofilms. Antimicrobial Agents and Chemotherapy. 2007, 51(10):3650-8. PMID: 17664315
4. Augustin, D.A., Song, Y., Baek, M.S., Sawa, Y., Singh, G., Taylor, B., Rubio-Mills, A., Flanagan, J.L., Wiener-Kronish, J.P. and Lynch, S.V. The Effect of Lipopolysaccharide O-antigen Serotype on Type III Secretion of Pseudomonas aeruginosa. J. Bacteriol. 2007. 189:2203-2209. PMID: 17209027
5. Flanagan, J.L., Brodie, E.L., Weng, L., Lynch, S.V., Garcia, O., Brown, R., Hugenholtz, P., DeSantis, T.Z, Andersen, G.L., Wiener-Kronish, J.P. and Bristow, J. Loss of Bacterial Diversity During Antibiotic Treatment of Intubated Patients Colonized with Pseudomonas aeruginosa. Journal of Clinical Microbiology. 2007, 45(6):1954-1962. PMID: 17409203
6. El Solh, A.A., Amsterdam, D. Alhajhusain, A., Akinnusi, M., Saliba, R., Lynch, S.V., Wiener-Kronish, J., and Szarpa, K. Matrix Metalloproteins in Bronchoalveolar lavage fluid of patients with type III Pseudomonas aeruginosa Pneumonia. European Respiratory Journal. 2008 Sep 1;178(5):513-9. PMID: 19535150
7. El Solh AA, Akinnusi ME, Wiener-Kronish JP, Lynch SV, Pineda LA, Szarpa K. Persistent Infection with Pseudomonas aeruginosa in Ventilator Associated Pneumonia. American Journal of Respiratory and Critical Care Medicine 2008 Sep1;178(5):513-9. PMID: 18467510
8. Ivanov, I.I., Atarashi, K., Manel, N., Brodie, E.L., Shima, T., Karaoz, U. Wei, D., Goldfarb, K.C., Santee, C.A., Lynch, S.V., Imaoka, A. Itoh, K., Takeda, K., Umesaki, Y., Honda, K., and Littman, D.R. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell. 2009 Oct 30;139(3):485-98. PMID: 19836068
9. Montor WR, Huang J, Hu Y, Hainsworth E, Lynch S.V., Kronish JW, Ordonez CL, Logvinenko T, Lory S, LaBaer J. Genome-wide study of Pseudomonas aeruginosa outer membrane protein immunogenicity using self-assembling protein microarrays. Infection and Immunity. 2009 Nov;77(11):4877-86. PMID: 19737893
10. Fujimura, K.E., Johnson, C.C., Ownby, D.R., Cox, M.J., Brodie, E.L., Havstad, S.L., Zoratti, E.M., Woodcroft, K.J., Bobbitt, K.R., Wegienka, G., Boushey, H.A. and Lynch, S.V. Man's best friend? The effect of pet ownership on house dust microbial communities. J. Allergy Clin. Immunol. 2010 126(2):410-2. PMID: 20633927
11. Rauch, M. and Lynch, S.V. Probiotic manipulation of the gastrointestinal microbiota. Gut Microbes. 2010. 1(5):1-4.
12. Lemon, K.P., Klepac-Ceraj, V., Schiffer, H.K., Brodie, E.L., Lynch, S.V. and Kolter, R. Comparative Analyses of the Bacterial Microbiota of the Human Nostril and Oropharynx. MBIO. 2010. 22;1(3). PMID: 20802827
13. Cox, M.J., Allgaier, M., Taylor, B., Baek, M.S., Huang, Y.J., Daly, R.A., Karaoz, U., Andersen, G.L., Brown, R., Fujimura, K.E., Wu, B., Tran, D., Kofff, J., Kleinhenz, M.E., Nielson, D., Brodie, E.L. and Lynch, S.V. Airway Microbiota and Pathogen Abundance in Age-Stratified Cystic Fibrosis Patients. (PLoS One PLoS One. 2010 Jun 23;5(6):e11044). PMID: 20585638
14. Singh, G., Wu, B., Baek, M.S., Camargo, A., Nguyen, A., Slusher, N.A., Srinivasan, R., Wiener-Kronish, J.P. and Lynch, S.V. Secretion of Pseudomonas aeruginosa Type III Cytotoxins is Dependent on Pseudomonas Quinolone Signal Concentration. Microbial Pathogenesis. 2010. 49(4):196-203. PMID: 20570614
15. Lynch SV, Flanagan JL, Sawa T, Fang A, Baek MS, Rubio-Mills A, Ajayi T, Yanagihara K, Hirakata Y, Kohno S, Misset B, Nguyen JC, Wiener-Kronish JP. Polymorphisms in the Pseudomonas aeruginosa type III secretion protein, PcrV - Implications for anti-PcrV immunotherapy. Microb Pathog. 2010 48(6):197-204. PMID: 20211240
16. Vanja Klepac-Ceraj, Katherine P. Lemon, Thomas R. Martin, Martin Allgaier, Steven W. Kembel, Alixandra A. Knapp, Stephen Lory, Eoin L. Brodie, Susan V. Lynch, Brendan J.M. Bohannan, Jessica Green, Brian A. Maurer and Roberto Kolter. Cystic fibrosis lung disease severity markers correlate with bacterial community structure. Environ Microbiol. 2010. 12(5):1293-303. PMID: 20192960
17. Cox, M., Huang, Y.J., Fujimura, K., Liu, J., McKean, M., Brodie, E.L., Boushey, H., Cabana, M. and Lynch, S.V. Lactobacillus casei Abundance is Associated with Profound Shifts in the Infant Gut Microbiome. PLoS One. 2010 Jan 18;5(1). PMID: 20090909
18. Huang Y.J., Kim E., Cox M.J., Brown R., Wiener-Kronish J.P., Lynch S.V. A Persistent and Diverse Airway Microbiome in Chronic Obstructive Pulmonary Disease. OMICS - a Journal of Integrative Biology. 2010 Feb;14(1):9-59. PMID: 20141328
19. Huang, Y.J., Nelson, C.E., Brodie, E.L., DeSantis, T.Z., Baek, M.S., Liu, J., Woyke, T., Allgaier, M., Bristow, J., Wiener-Kronish, J.P., Sutherland, R., King, T.S., Icitovic, N., Martin, R.J., Asthma Clinical Research Network Investigators, Boushey, H.A., and Lynch, S.V. Airway Microbiota and Bronchial Hyperresponsiveness in Patients with Sub-optimally Controlled Asthma. J Allergy Clin. Immunol. J Allergy Clin Immunol. 2011 Feb;127(2):372-381.e1-3. Epub 2010 Dec 30. PMID: 21194740
20. Fricks-Lima, J., Hendrickson, C.M., Allgaier, M., Zhuo, H., Wiener-Kronish, J.P., Lynch, S.V., Yang, K. Differences in Biofilm Formation and Antimicrobial Resistance of Pseudomonas aeruginosa Isolated from Airways of Mechanically Ventilated Patients and Cystic Fibrosis Patients. Int. J. Antimicrob. Agents. 2011 Mar 5. PMID: 21382698
21. Saulnier DM, Riehle K, Mistretta TA, Diaz MA, Mandal D, Raza S, Weidler EM, Qin X, Coarfa C, Milosavljevic A, Petrosino JF, Highlander S, Gibbs R, Lynch SV, Shulman RJ, Versalovic J Gastrointestinal microbiome signatures of pediatric patients with irritable bowel syndrome. Gastroenterology. 2011 Nov;141(5):1782-91.
22. Havstad S, Wegienka G, Zoratti EM, Lynch SV, Boushey HA, Nicholas C, Ownby DR, Johnson CC. Effect of prenatal indoor pet exposure on the trajectory of total IgE levels in early childhood. J Allergy Clin Immunol. 2011 Aug 4.
23. Song Y, Baer M, Srinivasan R, Lima J, Yarranton G, Bebbington C, Lynch SV. PcrV antibody-antibiotic combination improves survival in Pseudomonas aeruginosa-infected mice. Eur J Clin Microbiol Infect Dis. 2011 Dec 21. PMID: 22187351
24. Huang YJ, Lynch SV. The emerging relationship between the airway microbiota and chronic respiratory disease: clinical implications. Expert Rev Respir Med. 2011 Dec;5(6):809-21. PMID: 22082166
25. Nagalingam NA, Lynch SV. Role of the microbiota in inflammatory bowel diseases. Inflamm Bowel Dis. 2011 Sep 20. doi: 10.1002/ibd.21866. PMID: 21936031
26. Xu X, Zhang H, Song Y, Lynch SV, Lowell CA, Wiener-Kronish JP, Caughey GH. Strain-dependent induction of neutrophil histamine production and cell death by Pseudomonas aeruginosa. Leukoc Biol. 2011 Nov 10. PMID: 22075928
27. Rauch M, Lynch SV. The potential for probiotic manipulation of the gastrointestinal microbiome. Curr Opin Biotechnol. 2011 Nov 30. PMID: 22137452.
28. Huang, Y. Lynch, S.V., Wiener-Kronish, J.P. From Microbe to Microbiota – Considering Microbial Community Composition in Infections and Airway Diseases. Am J Respir Crit Care Med. 2012 Apr 1;185(7):691-2. No abstract available. PMID: 22467799
29. Ramsey BW, Banks-Schlegel S, Accurso FJ, Boucher RC, Cutting GR, Engelhardt JF, Guggino WB, Karp CL, Knowles MR, Kolls JK, LiPuma JJ, Lynch S, McCray PB Jr, Rubenstein RC, Singh PK, Sorscher E, Welsh M. Future directions in early cystic fibrosis lung disease research: an NHLBI workshop report. Am J Respir Crit Care Med. 2012 Apr 15;185(8):887-92. Epub 2012 Feb 3. PMID: 22312017
30. Scanlan PD, Buckling A, Kong W, Wild Y, Lynch SV, Harrison F. Gut dysbiosis in cystic fibrosis. J Cyst Fibros. 2012 Apr 24. PMID: 22538067
31. Schwarzer C, Fu Z, Patanwala M, Hum L, Lopez-Guzman M, Illek B, Kong W, Lynch SV, Machen TE. Pseudomonas aeruginosabiofilm-associated homoserine lactone C12 rapidly activates apoptosis in airway epithelia. Cell Microbiol. 2012 Jan 10. doi: 10.1111/j.1462-5822.2012.01753.x.
32. Gonzalez CF, Tchigvintsev A, Brown G, Flick R, Evdokimova E, Xu X, Osipiuk J, Cuff ME, Lynch S, Joachimiak A, Savchenko A, Yakunin AF. Structure and activity of the Pseudomonas aeruginosa hotdog-fold thioesterases PA5202 and PA2801. Biochem J. 2012 Jun 15;444(3):445-55. PMID: 22439787
33. Iwai S, Fei M, Huang D, Fong S, Subramanian A, Grieco K, Lynch SV, Huang L. Oral and Airway Microbiota in HIV-Infected Pneumonia Patients. J Clin Microbiol. 2012 Sep;50(9):2995-3002. PMID: 22760045
34. Han MK, Huang YJ, Lipuma JJ, Boushey HA, Boucher RC, Cookson WO, Curtis JL, Erb-Downward J, Lynch SV, Sethi S, Toews GB, Young VB, Wolfgang MC, Huffnagle GB, Martinez FJ. Significance of the microbiome in obstructive lung disease. Thorax. 2012 May;67(5):456-63. PMID: 22318161
35. Nagalingam NA, Lynch SV. Role of the microbiota in inflammatory bowel diseases. Inflamm Bowel Dis. 2012 May;18(5):968-84. doi: 10.1002/ibd.21866. Epub 2011 Sep 20. PMID: 21936031
36. Abreu, N.A., Song, Y., Mandal, D., Roediger, F.C., Pletcher, S.D., Goldberg, A.N. and Lynch, S.V. Coincident Sinus Microbiota Depletion and Corynebacterium tuberculostearicum Outgrowth Represent a Novel Etiology for Chronic Rhinosinusitis. Sci Transl Med. 2012 Sep 12;4(151):151ra124.
37. Fujimura KE, Rauch M, Matsui E, Iwai S, Calatroni A, Lynn H, Mitchell H, Johnson CC, Gern JE, Togias A, Boushey HA, Kennedy S, Lynch SV. Development of a standardized approach for environmental microbiota investigations related to asthma development in children. J. Microbiol. Methods. 2012 Sep 4. [Epub ahead of print]
38. Lynch, S.V., Goldfarb, K.C., Wild, Y., Kong, W., De Lisle, R.C., Brodie, E.L. Cystic Fibrosis Transmembrane gene Knockout in Mice Dramatically Impacts Gastrointestinal Microbiota Composition. (In press, Gut Microbes).