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Gut microbiota–dependent modulation of innate immunity and lymph node remodeling affects cardiac allograft outcomes
Jonathan S. Bromberg, … , Colin C. Brinkman, Emmanuel F. Mongodin
Jonathan S. Bromberg, … , Colin C. Brinkman, Emmanuel F. Mongodin
Published October 4, 2018
Citation Information: JCI Insight. 2018;3(19):e121045. https://doi.org/10.1172/jci.insight.121045.
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Research Article Microbiology Transplantation

Gut microbiota–dependent modulation of innate immunity and lymph node remodeling affects cardiac allograft outcomes

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Abstract

We hypothesized that the gut microbiota influences survival of murine cardiac allografts through modulation of immunity. Antibiotic pretreated mice received vascularized cardiac allografts and fecal microbiota transfer (FMT), along with tacrolimus immunosuppression. FMT source samples were from normal, pregnant (immune suppressed), or spontaneously colitic (inflammation) mice. Bifidobacterium pseudolongum (B. pseudolongum) in pregnant FMT recipients was associated with prolonged allograft survival and lower inflammation and fibrosis, while normal or colitic FMT resulted in inferior survival and worse histology. Transfer of B. pseudolongum alone resulted in reduced inflammation and fibrosis. Stimulation of DC and macrophage lines with B. pseudolongum induced the antiinflammatory cytokine IL-10 and homeostatic chemokine CCL19 but induced lesser amounts of the proinflammatory cytokines TNFα and IL-6. In contrast, LPS and Desulfovibrio desulfuricans (D. desulfuricans), more abundant in colitic FMT, induced a more inflammatory cytokine response. Analysis of mesenteric and peripheral lymph node structure showed that B. pseudolongum gavage resulted in a higher laminin α4/α5 ratio in the lymph node cortical ridge, indicative of a suppressive environment, while D. desulfuricans resulted in a lower laminin α4/α5 ratio, supportive of inflammation. Discrete gut bacterial species alter immunity and may predict graft outcomes through stimulation of myeloid cells and shifts in lymph node structure and permissiveness.

Authors

Jonathan S. Bromberg, Lauren Hittle, Yanbao Xiong, Vikas Saxena, Eoghan M. Smyth, Lushen Li, Tianshu Zhang, Chelsea Wagner, W. Florian Fricke, Thomas Simon, Colin C. Brinkman, Emmanuel F. Mongodin

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Figure 1

Characterization of differences in the gut microbiota structure and composition of fecal microbiota transplant (FMT) source samples from normal, colitic, and pregnant mice.

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Characterization of differences in the gut microbiota structure and comp...
(A) Violin plot of α-diversity (Shannon diversity index). Shannon was significantly lower in normal vs. colitic mice (Tukey’s HSD, P = 0.014). (B) Principal Coordinate Analysis (PCoA) plots of Jensen–Shannon divergence computed on Cumulative Sum Scaling–normalized (CSS-normalized) datasets between gut microbiota FMT source samples. Ellipses represent the 95% CI by FMT source sample. ANOSIM testing revealed significantly different clusters between the 3 FMT source groups (R = 0.794, P = 0.001). (C) Box plots showing the distribution of the top 25 genus-level bacterial taxa across the 3 FMT groups. Hinges represent the first and third quartiles, with the second quartile (median) displayed by the black line inside each box; whiskers denote the 1.5 interquartile range. Asterisks denote significant differential relative abundance (DESeq2 at level P < 0.05) of taxa compared between colitic or pregnant to normal source FMT samples. n = 5 for each FMT group.

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