A Diet-Sensitive Commensal Lactobacillus Strain Mediates TLR7-Dependent Systemic Autoimmunity

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 reu...

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Bibliographic Details
Published in:Cell host & microbe 2019-01, Vol.25 (1), p.113-127.e6
Main Authors: Zegarra-Ruiz, Daniel F., El Beidaq, Asmaa, Iñiguez, Alonso J., Lubrano Di Ricco, Martina, Manfredo Vieira, Silvio, Ruff, William E., Mubiru, Derek, Fine, Rebecca L., Sterpka, John, Greiling, Teri M., Dehner, Carina, Kriegel, Martin A.
Format: Article
Language:English
Subjects:
Animals
Autoimmunity
Clostridiaceae
Clostridiales
Dendritic Cells - metabolism
Diet
Diet Therapy
Disease Models, Animal
DNA, Ribosomal - genetics
Fatty Acids, Volatile - antagonists & inhibitors
Fatty Acids, Volatile - metabolism
Feces - microbiology
Female
Gastrointestinal Microbiome
Germ-Free Life
Glomerulonephritis - pathology
gut microbiota
human SLE microbiome
Humans
Hypersensitivity
interferon
Interferon Type I - metabolism
Kidney - pathology
Lactobacillus
Lactobacillus - drug effects
Lactobacillus - genetics
Lactobacillus - pathogenicity
Lactobacillus reuteri
Lupus Erythematosus, Systemic - microbiology
Lupus Erythematosus, Systemic - mortality
Lupus Erythematosus, Systemic - pathology
Membrane Glycoproteins - metabolism
Mice
Mice, Inbred C57BL
plasmacytoid dendritic cells
resistant starch
RNA, Ribosomal, 16S - genetics
Starch
Survival Rate
systemic lupus erythematosus
Toll-Like Receptor 7 - metabolism
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Summary: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. [Display omitted] •L. reuteri colonizes lupus-prone hosts and translocates to MLN, liver, and spleen•L. reuteri exacerbates TLR7-dependent lupus in conventional and germ-free mice•Resistant starch ameliorates pDCs, type I IFN pathways, and lupus-related mortality•Starch diet-derived short-chain fatty acids suppress L. reuteri in vitro and in vivo The role of commensals in autoimmunity remains unclear. Zegarra-Ruiz et al. report that Lactobacillus reuteri is enriched in lupus models driven by innate inflammation. L. reuteri engages type I interferon pathways worsening autoimmune manifestations. L. reuteri overgrowth is suppressed by metabolites from a special starch diet, thereby improving lupus outcome.
ISSN:1931-3128
1934-6069
DOI:10.1016/j.chom.2018.11.009