TY - JOUR
T1 - A Diet-Sensitive Commensal Lactobacillus Strain Mediates TLR7-Dependent Systemic Autoimmunity
AU - Zegarra-Ruiz, Daniel F.
AU - El Beidaq, Asmaa
AU - Iñiguez, Alonso J.
AU - Lubrano Di Ricco, Martina
AU - Manfredo Vieira, Silvio
AU - Ruff, William E.
AU - Mubiru, Derek
AU - Fine, Rebecca L.
AU - Sterpka, John
AU - Greiling, Teri M.
AU - Dehner, Carina
AU - Kriegel, Martin A.
N1 - Funding Information:
We would like to thank the O'Brien Kidney Center, the Mouse Metabolic Phenotyping Center, and the Pathology Tissue Microarray Facility at Yale for technical assistance. We thank the Palm lab for the use of an anaerobic chamber, Vivian Lim from the Pereira lab for assistance with bone marrow precursor studies, Minerva Ringland for assistance with in vivo studies, and Fatima Saldana (Baylor College of Medicine) for providing expertise in image processing. We also would like to thank Silvia Bolland (NIH) for providing TLR7.1 Tg mice and Akiko Iwasaki (Yale) for providing TLR7 KO mice. This work was supported by grants from the NIH ( K08AI095318 , R01AI118855 , T32AI07019 , and T32DK007017-39 ), the O’Brien Center at Yale (NIH P30DK079310 ), the Arthritis National Research Foundation , the Arthritis Foundation , the Lupus Research Institute , the HHMI Medical Research Fellows Program, and the Lupus Foundation of America . The human microbiome study was performed with assistance from the Yale Center for Clinical Investigation, which is supported by the Clinical and Translational Science Awards grant number UL1 RR024139 from the National Center for Research Resources , the National Center for Advancing Translational Science , and the NIH Roadmap for Medical Research.
Publisher Copyright:
© 2018 Elsevier Inc.
PY - 2019/1/9
Y1 - 2019/1/9
N2 - Western lifestyle is linked to autoimmune and metabolic diseases, driven by changes in diet and gut microbiota composition. Using Toll-like receptor 7 (TLR7)-dependent mouse models of systemic lupus erythematosus (SLE), we dissect dietary effects on the gut microbiota and find that Lactobacillus reuteri can drive autoimmunity but is ameliorated by dietary resistant starch (RS). Culture of internal organs and 16S rDNA sequencing revealed TLR7-dependent translocation of L. reuteri in mice and fecal enrichment of Lactobacillus in a subset of SLE patients. L. reuteri colonization worsened autoimmune manifestations under specific-pathogen-free and gnotobiotic conditions, notably increasing plasmacytoid dendritic cells (pDCs) and interferon signaling. However, RS suppressed the abundance and translocation of L. reuteri via short-chain fatty acids, which inhibited its growth. Additionally, RS decreased pDCs, interferon pathways, organ involvement, and mortality. Thus, RS exerts beneficial effects in lupus-prone hosts through suppressing a pathobiont that promotes interferon pathways implicated in the pathogenesis of human autoimmunity.
AB - Western lifestyle is linked to autoimmune and metabolic diseases, driven by changes in diet and gut microbiota composition. Using Toll-like receptor 7 (TLR7)-dependent mouse models of systemic lupus erythematosus (SLE), we dissect dietary effects on the gut microbiota and find that Lactobacillus reuteri can drive autoimmunity but is ameliorated by dietary resistant starch (RS). Culture of internal organs and 16S rDNA sequencing revealed TLR7-dependent translocation of L. reuteri in mice and fecal enrichment of Lactobacillus in a subset of SLE patients. L. reuteri colonization worsened autoimmune manifestations under specific-pathogen-free and gnotobiotic conditions, notably increasing plasmacytoid dendritic cells (pDCs) and interferon signaling. However, RS suppressed the abundance and translocation of L. reuteri via short-chain fatty acids, which inhibited its growth. Additionally, RS decreased pDCs, interferon pathways, organ involvement, and mortality. Thus, RS exerts beneficial effects in lupus-prone hosts through suppressing a pathobiont that promotes interferon pathways implicated in the pathogenesis of human autoimmunity.
KW - Clostridiaceae
KW - Clostridiales
KW - Lactobacillus
KW - Lactobacillus reuteri
KW - gut microbiota
KW - human SLE microbiome
KW - interferon
KW - plasmacytoid dendritic cells
KW - resistant starch
KW - systemic lupus erythematosus
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U2 - 10.1016/j.chom.2018.11.009
DO - 10.1016/j.chom.2018.11.009
M3 - Article
C2 - 30581114
AN - SCOPUS:85059368920
SN - 1931-3128
VL - 25
SP - 113-127.e6
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 1
ER -