Commensal Propionibacterium strain UF1 mitigates intestinal inflammation via Th17 cell regulation
Natacha Colliou, … , Shuzhao Li, Mansour Mohamadzadeh
Natacha Colliou, … , Shuzhao Li, Mansour Mohamadzadeh
Published September 25, 2017
Citation Information: J Clin Invest. 2017;127(11):3970-3986. https://doi.org/10.1172/JCI95376.
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Commensal Propionibacterium strain UF1 mitigates intestinal inflammation via Th17 cell regulation

Abstract

Consumption of human breast milk (HBM) attenuates the incidence of necrotizing enterocolitis (NEC), which remains a leading and intractable cause of mortality in preterm infants. Here, we report that this diminution correlates with alterations in the gut microbiota, particularly enrichment of Propionibacterium species. Transfaunation of microbiota from HBM-fed preterm infants or a newly identified and cultured Propionibacterium strain, P. UF1, to germfree mice conferred protection against pathogen infection and correlated with profound increases in intestinal Th17 cells. The induction of Th17 cells was dependent on bacterial dihydrolipoamide acetyltransferase (DlaT), a major protein expressed on the P. UF1 surface layer (S-layer). Binding of P. UF1 to its cognate receptor, SIGNR1, on dendritic cells resulted in the regulation of intestinal phagocytes. Importantly, transfer of P. UF1 profoundly mitigated induced NEC-like injury in neonatal mice. Together, these results mechanistically elucidate the protective effects of HBM and P. UF1–induced immunoregulation, which safeguard against proinflammatory diseases, including NEC.

Authors

Natacha Colliou, Yong Ge, Bikash Sahay, Minghao Gong, Mojgan Zadeh, Jennifer L. Owen, Josef Neu, William G. Farmerie, Francis Alonzo III, Ken Liu, Dean P. Jones, Shuzhao Li, Mansour Mohamadzadeh

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Figure 8

Regulation of intestinal immunity requires SIGNR1.

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Regulation of intestinal immunity requires SIGNR1. (A) Depiction of SIGN...
(A) Depiction of SIGNR1-hFc expression. The cDNA encoding SIGNR1-extracellular domain (exons 4–10) was fused to the Fc of human IgG1. (B) Western blot analysis of SIGNR1-hFc using anti-SIGNR1 antibody. (C) Binding of P. UF1 to SIGNR1 (blue), SIGNR3 (red), control fusion (yellow), or secondary (2nd) antibody (green). (D) Blocking SIGNR1-hFc binding to P. UF1 by zymozan. (E) Relative expression of Signr1 and Signr3 genes in colonic tissue from mice gavaged with P. UF1 or PBS (n = 5 tissues/group). (F) Representative data analyses of SIGNR1+ DCs derived from mice gavaged with P. UF1 or PBS (n = 4 mice/group). (G) Signr1+/+ and Signr1–/– mice were gavaged 4 times with PBS (red), P. UF1 (green), or ΔdlaT P. UF1 (blue) and orally infected with ΔactA L. m. One group of mice was infected with actA L. m3pep (gray), and colonic responses were analyzed 7 days later. Representative data of flow plots, percentages, and total cell counts of Th17 cells, Th1 cells, and IL-10+TGF-β+ Tregs (n = 4–5 mice/group). (H) Determination of ΔactA L. m burden in fecal samples of indicated groups (n = 4–5 fecal samples/group) in Signr1+/+ and Signr1–/– mice. (I) Socs1 expression by qRT-PCR in colonic tissue of ΔactA L. m–infected Signr1+/+ and Signr1–/– mice gavaged with P. UF1 or ΔdlaT P. UF1 (n = 5–7 samples/group). (J) Socs1 expression in BMDCs isolated from Signr1+/+ and Signr1–/– mice (n = 3 samples/group). BMDCs were treated with MEK inhibitor PD0325901 (PD) or PBS. Cells were incubated with P. UF1 (1:2 CFU) or PBS for 3 hours. Data are representative of 2 (D, E and G-J) or 3 independent experiments (B, C and F). Error bars indicate mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001, 2-tailed unpaired t test (E and F) or ANOVA plus Tukey post test (G–J).