Background/Purpose:

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. The role that pathobionts and GM dysbiosis play in the pathogenesis of systemic lupus erythematosus (SLE) or lupus nephritis (LN) is not fully appreciated. We hypothesized that the GM potently influences the pathogenesis of LN through the induction of host immune processes and that shifts in the bacterial GM would reflect what has been published in lupus patients. This project was 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.

Methods: Using oral gavage, we colonized NZM2410 mice with SFB- or no SFB-fecal homogenates in a sterile vivarium. Colonization was confirmed via repeated fecal DNA PCR analysis using SFB-specific primers. Serum was collected and mice were euthanized at 26 or 30 weeks. The severity of kidney damage was assessed via immunohistochemistry (IHC) and RNA-ISH. Flow cytometry was also performed on small intestinal lamina propria cells. To analyze the makeup of the fecal bacterial metagenome of these mice through 16S rDNA analysis we used Illumina 16S sequencing technology and compared the resulting reads to the Silva fecal bacterial metagenomics database.

Results:

We demonstrated that inoculation with SFB was associated with worse renal dysfunction and glomerulonephritis. We also discovered that serum autoantibodies and proinflammatory cytokines were elevated in SFB positive mice versus controls. Initially, we expected to find infiltrating Th17 cells in the kidneys of SFB positive mice. However, while we did not detect intra-renal Th17 cells by immunohistochemistry, we found that SFB positive mice had significantly increased numbers of M2-like F4/80+CD206+ macrophages when compared to SFB negative mice. Lastly, we show that SFB positive NZM2410 mice may harbor intestinal barrier dysfunction. 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. 

We identified unique bacterial compositions at multiple taxonomic levels with respect to time of disease and SFB positivity. We also show that many of the taxonomic shifts observed in our study, even within certain genera, are in congruence with lupus-GM human studies. Finally, we identified a particular Ruminococcus species group that is enriched in SFB positive versus SFB negative mice. Importantly, this group is significantly enriched in SFB positive mice during late disease versus SFB positive mice at pre-/early disease which suggests a disease activity.

Conclusion: Collectively, the work presented herein helps to address an unfulfilled knowledge gap in autoimmunity. Our findings suggest that changes to the commensal GM may have an important role in renal dysfunction and promoting an overall proinflammatory state in LN. Importantly, this work provides suggestions for novel therapeutic targets that may be useful in treating patients suffering from LN.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-role-of-the-intestinal-microbiota-in-lupus-nephritis/