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Aging‐related Changes in Gut Microbiome Mediate Septic Kidney Injury
Author(s) -
Colbert James F,
Ford Joshay A,
Dailey Kyrie L,
Frank Daniel N,
Faubel Sarah,
Schmidt Eric P
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.184.5
Subject(s) - sepsis , acute kidney injury , medicine , population , kidney , lipocalin , microbiome , renal function , immunology , gastroenterology , bioinformatics , biology , environmental health
BACKGROUND Sepsis, a dysregulated systemic response to infection, is a major cause of morbidity and mortality worldwide. Older adults are particularly vulnerable to this syndrome, as evidenced by higher sepsis incidence and mortality. It is well established that the development of organ failure, specifically acute kidney injury (AKI), is a strong predictor of mortality during sepsis and occurs more frequently in the aging population. Despite this association, the mechanisms underlying the development of septic AKI remain undetermined. Extensive prior research attempting to interrupt or reverse septic organ injury has yielded no successful therapies in humans. Given these past failures, it is crucial to investigate novel concepts driving septic AKI and resulting mortality in the aging population. METHODS We used two distinct models of experimental sepsis to induce kidney injury in young (8–12 weeks) and aged (20–24 months) C57BL/6 mice. One model (cecal ligation and puncture, CLP) induces sepsis via leakage of the host cecal microbiome into the peritoneal space. A second model (fecal slurry) allows for direct introduction of different microbiota (isolated from the stool of young vs. aged mice) into the peritoneum. We collected plasma, urine, and kidneys 24 hours after the onset of experimental sepsis. Sham mice and intraperitoneal saline injection mice served as contemporaneous controls in both age groups. We measured kidney injury by markers of glomerular filtration (Blood Urea Nitrogen, BUN), tubular injury (kidney homogenate neutrophil gelatinase‐associated lipocalin (NGAL) by qRT‐PCR), and inflammation (kidney homogenate interleukin‐6 (IL‐6) by qRT‐PCR). RESULTS Aged mice demonstrate worsened septic AKI compared to young mice after experimental sepsis induced by CLP. Kidney injury in aged mice demonstrated a predominance of glomerular dysfunction (as measured by BUN), with less tubular injury (NGAL) or inflammatory changes (IL‐6). Additionally, septic AKI (as measured by BUN) was exaggerated in young mice exposed to the intraperitoneal injection of fecal slurry collected from aged mice, as compared to fecal slurry collected from young mice. CONCLUSIONS Our preliminary data indicate that sepsis associated AKI in aged mice is primarily a consequence of glomerular dysfunction. Strikingly, our observations suggest that the CLP‐induced glomerular dysfunction in aged mice is driven by increased virulence of the aged gut microbiome. Support or Funding Information JFC is supported by the Denver VA Geriatrics, Research, Educational, and Clinical Center (GRECC) JFC was previously supported by National Institute of Health Grant T32AG000279