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Dissertation GRV 4-2-19 FINAL.pdf (3.57 MB)

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The Role of the Intestinal Microbiota in Lupus Nephritis

Valiente, Giancarlo Roberto
http://orcid.org/0000-0002-2453-2891
http://rave.ohiolink.edu/etdc/view?acc_num=osu1554166973286599

Abstract Details

2019, Doctor of Philosophy, Ohio State University, Biomedical Sciences.
The bacterial gut microbiota (GM) exerts substantial influence over the host immune system and dysbiosis of this microbial community has been associated with end-organ damage in chronic inflammatory conditions. Furthermore, so-called pathobiont commensal gut bacteria are known to promote disease. The role that pathobionts and GM dysbiosis play in the pathogenesis of systemic lupus erythematosus (SLE) or lupus nephritis (LN) is not fully appreciated. Given the significance of the microbiota-host relationship in human health and disease, we hypothesized that the GM potently influences the pathogenesis of lupus nephritis through the induction of host immune processes and that shifts in the bacterial GM would reflect what has been published in lupus patients. This thesis is focused on the ability of gut dysbiosis to promote kidney damage in a LN mouse model. The pathobiont commensal, segmented filamentous bacteria (SFB), is applied in this study to test this overall hypothesis. The first part of this thesis investigates aberrations in the host immune system due to intestinal microbiota dysbiosis in a LN mouse model. To explore this, we inoculated a spontaneous LN mouse model (NZM2410 model) with SFB before initiation of disease. We demonstrated that inoculation with SFB was associated with worsened renal dysfunction in these mice as observed by exacerbated glomerulonephritis lesions, glomerular and tubular immune complex deposition and interstitial inflammation. We also discovered that serum autoantibodies and proinflammatory cytokines were elevated in SFB positive mice versus controls. Importantly, SFB has been shown to upregulate proinflammatory Th17 cells and group 3 innate lymphoid cells (ILC3s). Initially, we expected to find infiltrating Th17 cells in the kidneys of SFB positive mice. While we did not detect intrarenal Th17 cells by immunohistochemistry, we demonstrated that SFB positive mice had significantly increased numbers of M2-like F4/80+CD206+ macrophages when compared to SFB negative mice. Lastly, we provided evidence that suggests SFB positive NZM2410 mice may harbor intestinal barrier abnormalities. A very recent human LN study also reported related findings. This particular finding suggests a potential mechanism by which commensal bacteria can activate the host immune system. In the subsequent segment of this thesis, we examined the makeup of the bacterial metagenome in the same LN mice with or without SFB and at two time points of disease. GM dysbiosis has been previously associated with SLE, however, only one study investigated this relationship in a less translatable model of LN. Using metagenomics analysis of the feces from NZM2410 mice at different stages of disease, we identified unique bacterial compositions at multiple taxonomic levels with respect to time of disease and SFB positivity. While reports show that lupus patients have reduced GM biodiversity compared to control subjects, we identified higher biodiversity in SFB positive versus negative mice at pre-/early and late disease. However, we demonstrated that many of the taxonomic shifts observed in our study, even certain genera, are in congruence with lupus-GM human studies. Finally, it was recently reported that a specific species of commensal bacteria was elevated in the gut of LN patients and that this bacterium may be a pathobiont. Although we did not detect this particular species in our dataset, we identified a highly related species group that is enriched in SFB positive versus SFB negative mice. Most importantly, we established that this species group is significantly enriched in SFB positive mice during late disease versus SFB positive mice at pre-/early disease. Collectively, the work presented herein helps to address an unfulfilled knowledge gap in autoimmunity. These findings suggest that changes to the commensal GM may be capable of exacerbating renal dysfunction and promoting a proinflammatory state in LN. Importantly, this work provides suggestions for novel therapeutic targets that may be useful in treating patients suffering from LN.
Wael Jarjour, M.D. (Advisor)
Amy Lovett-Racke, Ph.D. (Committee Chair)
Susheela Tridandapani, Ph.D. (Committee Member)
Aharon Freud, M.D., Ph.D. (Committee Member)
143 p.
Biomedical Research; Immunology
Gut microbiota; lupus; lupus nephritis; dysbiosis; kidney; SLE

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Citations

  • Valiente, G. R. (2019). The Role of the Intestinal Microbiota in Lupus Nephritis [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1554166973286599

    APA Style (7th edition)

  • Valiente, Giancarlo. The Role of the Intestinal Microbiota in Lupus Nephritis. 2019. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1554166973286599.

    MLA Style (8th edition)

  • Valiente, Giancarlo. "The Role of the Intestinal Microbiota in Lupus Nephritis." Doctoral dissertation, Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1554166973286599

    Chicago Manual of Style (17th edition)

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