Although there is mounting evidence that the composition of gut microbial communities contributes to intestinal dysbiosis and systemic disease, we have very little understanding of the mechanisms involved. We have chosen to study model systems in which individual gut bacterial species promote robust disease phenotypes. We are screening for human commensal bacterial species that, following colonization of the gut, display distinct systemic activity, e.g. promoting autoimmune inflammation in the spinal cord or anti-tumor T cell responses following checkpoint immunotherapy. We wish to then identify the requisite bacterial genes and products and the host target cells that mediate the phenotype, and also characterize the impact of diet.

Autoimmunity

4A_growth_heatmap_20191009.png

In an earlier study, we showed that an intestinal bacterial species, Prevotella copri, is enriched in patients with new-onset rheumatoid arthritis (NORA) as compared to healthy controls, chronically treated RA patients, and psoriatic arthritis patients.  We are studying in collaboration with a consortium in the U.K. whether P. copri association with NORA can be found in other cohorts. We wish to determine whether there are genetic differences between Prevotella isolates from NORA patients and healthy controls, and whether Prevotella can trigger disease in mouse models of arthritis and colitis.  We have collected, sequenced, and assembled the genomes of over 80 Prevotella isolates from healthy controls and NORA patients, and found that much of the strain variation lies in differences among polysaccharide utilization loci. This likely explains differences in colonization with diverse strains among western and non-westernized countries.

We use the autoimmunity model experimental autoimmune encephalomyelitis (EAE) to investigate the role of microbiota in systemic disease. Induction of myelin-specific T cells results in inflammation of the spinal cord and in progressive paralysis. This process is blocked by treatment with antibiotics, but the pathogenesis can be re-established with distinct human-derived commensal strains selected for resistance to the antibiotics. This model thus offers the opportunity to study both the genetic requirements in bacteria and the host cellular and molecular targets of the microbial products.

Cancer Immunotherapy

Despite impressive efficacy of immune checkpoint blockade in certain solid malignancies, there is poor consistency across many cancers.  There is discrepancy between patients with remarkably similar histologic/genetic disease, and some patients demonstrate inexplicable recrudescence after several months despite lifelong remission in others.  As already suspected in bone marrow transplant patients, the diversity and specific quality of the gut microbiota is heavily implicated in this form of cancer immunotherapy.  In fact, multiple research and clinical groups have recently demonstrated the phenomenon of differential therapeutic response after modulation of the microbiota.  There is already some consensus that either gnotobiotic conditions or imposed antibiotic treatment abrogates baseline therapy responsiveness (concurrent with retrospective analysis of patient cohorts).  Several groups have also taken stool from responding and non-responding patients, and upon fecal matter transfer into mice, have again recapitulated therapeutic efficacy.  Therefore, a core interest in our lab is to construct robust mouse models of cancer with similar responsiveness to microbiota manipulations, and use this as a platform to better understand the mechanistic link between microbial colonization in the gut and changed immune responses in the distal tumor microenvironment.  We are also examining how commensal antigen-specific polarized T cell responses (including Th1, TH17, Treg, and CD8) influence the growth of transplanted and spontaneous tumors engineered to express microbial antigens as well as the efficacy of anti-CTLA-4 and anti-PD-1 checkpoint-blockade on such commensal-dependent responses.



Related Publications:

  • Fehlner-Peach H., Magnabosco C., Raghavan V., Scher J.U., Tett A., Cox L.M., Gottsegen C., Watters A., Wiltshire-Gordon, J.D., Segata, N., Bonneau, R., Littman DR., 2019. Distinct Polysaccharide Utilization Profiles of Human Intestinal Prevotella copri Isolates. Cell host & microbe, 2019 Nov 13;26(5):680-690.e5. PMID: 31726030

  • Kim, S., Kim, H., Yim, Y.S., Ha, S., Atarashi, K., Tan, T.G., Longman, R., Honda, K., Littman, D.R., Choi, G.B. & Huh, J.R. (2017) Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring. Nature 549, 528-532. PMID: 28902840

  • Choi, G.B., Wong, H., Yim, Y.S., Kim, S.V., Cai, Y., Hoeffer, C.A., Littman, D.R.* & Huh, J.R.* (2016)  The maternal RORγt/IL-17a pathway promotes autism-like phenotypes in offspring.  Science 351, 933-9. PMID: 26822608

  • Scher, J.U., Sczesnak, A., Longman, R.S., Segata, N., Ubeda, C., Bielski, C., Pamer, E.G., Abramson, S.B., Huttenhower, C., & Littman, D.R.  (2013) Prevotella copri defines a metagenomic enterotype that correlates with enhanced susceptibility to arthritis. eLife 2:e01202.  PMC3816614

  • Diehl, G.E., Longman, R.S., Zhang, J.X, Breart, B., Galan, C., Cuesta, A., Schwab, S.R. & Littman, D.R. (2013) Microbiota restricts trafficking of bacteria to mesenteric lymph nodes by CX3CR1hi cells.  Nature, 494:116-20.  PMID: 23334413