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Intestinal microbial metabolite stercobilin involvement in the chronic inflammation of ob/ob mice.

ABSTRACT: It is crucial that the host and intestinal microflora interact and influence each other to maintain homeostasis and trigger pathological processes. Recent studies have shown that transplantation of the murine intestinal content to recipient germ-free mice enables transmission of the donor's phenotypes, such as low level chronic inflammation associated with lifestyle-related diseases. These findings indicate that intestinal bacteria produce some molecules to trigger pathological signals. However, fecal microbial metabolites that induce obesity and the type II diabetic phenotype have not been fully clarified. Here, we showed that the intestinal bacterial metabolite stercobilin, a pigment of feces, induced proinflammatory activities including TNF-? and IL-1? induction in mouse macrophage RAW264 cells. Proinflammatory stercobilin levels were significantly higher in ob/ob mice feces than in the feces of control C57BL/6?J mice. Moreover, in this study, we detected stercobilin in mice plasma for the first time, and the levels were higher in ob/ob mice than that of C57BL/6?J mice. Therefore, stercobilin is potentially reabsorbed, circulated through the blood system, and contributes to low level chronic inflammation in ob/ob mice. Since, stercobilin is a bioactive metabolite, it could be a potentially promising biomarker for diagnosis. Further analyses to elucidate the metabolic rate and the reabsorption mechanism of stercobilin may provide possible therapeutic and preventive targets.

SUBMITTER: Sanada S

PROVIDER: S-EPMC7160104 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Intestinal microbial metabolite stercobilin involvement in the chronic inflammation of ob/ob mice.

Sanada Shunsuke S Suzuki Takuji T Nagata Akika A Hashidume Tsutomu T Yoshikawa Yuko Y Miyoshi Noriyuki N

Scientific reports 20200415 1

It is crucial that the host and intestinal microflora interact and influence each other to maintain homeostasis and trigger pathological processes. Recent studies have shown that transplantation of the murine intestinal content to recipient germ-free mice enables transmission of the donor's phenotypes, such as low level chronic inflammation associated with lifestyle-related diseases. These findings indicate that intestinal bacteria produce some molecules to trigger pathological signals. However, ...[more]

PMID: 32296105

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Project description:ObjectiveObesity increases morbidity and resource utilization in sepsis patients. Sepsis transitions from early/hyper-inflammatory to late/hypo-inflammatory phase. Majority of sepsis-mortality occurs during the late sepsis; no therapies exist to treat late sepsis. In lean mice, we have shown that sirtuins (SIRTs) modulate this transition. Here, we investigated the role of sirtuins, especially the adipose-tissue abundant SIRT-2 on transition from early to late sepsis in obese with sepsis.MethodsSepsis was induced using cecal ligation and puncture (CLP) in ob/ob mice. We measured microvascular inflammation in response to lipopolysaccharide/normal saline re-stimulation as a "second-hit" (marker of immune function) at different time points to track phases of sepsis in ob/ob mice. We determined SIRT-2 expression during different phases of sepsis. We studied the effect of SIRT-2 inhibition during the hypo-inflammatory phase on immune function and 7-day survival. We used a RAW264.7 (RAW) cell model of sepsis for mechanistic studies. We confirmed key findings in diet induced obese (DIO) mice with sepsis.ResultsWe observed that the ob/ob-septic mice showed an enhanced early inflammation and a persistent and prolonged hypo-inflammatory phase when compared to WT mice. Unlike WT mice that showed increased SIRT1 expression, we found that SIRT2 levels were increased in ob/ob mice during hypo-inflammation. SIRT-2 inhibition in ob/ob mice during the hypo-inflammatory phase of sepsis reversed the repressed microvascular inflammation in vivo via activation of endothelial cells and circulating leukocytes and significantly improved survival. We confirmed the key finding of the role of SIRT2 during hypo-inflammatory phase of sepsis in this project in DIO-sepsis mice. Mechanistically, in the sepsis cell model, SIRT-2 expression modulated inflammatory response by deacetylation of NFκBp65.ConclusionSIRT-2 regulates microvascular inflammation in obese mice with sepsis and may provide a novel treatment target for obesity with sepsis.

Project description:BackgroundDespite effective antiretroviral therapy (ART), patients with chronic human immunodeficiency virus (HIV) infection have increased microbial translocation and systemic inflammation. Alterations in the intestinal microbiota may play a role in microbial translocation and inflammation.MethodsWe profiled the fecal microbiota by pyrosequencing the gene encoding 16S ribosomal RNA (rRNA) and measured markers of microbial translocation and systemic inflammation in 21 patients who had chronic HIV infection and were receiving suppressive ART (cases) and 16 HIV-uninfected controls.ResultsThe fecal microbial community composition was significantly different between cases and controls. The relative abundance of Proteobacteria, Gammaproteobacteria, Enterobacteriales, Enterobacteriaceae, Erysipelotrichi, Erysipelotrichales, Erysipelotrichaceae, and Barnesiella was significantly enriched in cases, whereas that of Rikenellaceae and Alistipes was depleted. The plasma soluble CD14 level (sCD14) was significantly higher and the endotoxin core immunoglobulin M (IgM) level lower in cases, compared with controls. There were significant positive correlations between the relative abundances of Enterobacteriales and Enterobacteriaceae and the sCD14 level; the relative abundances of Gammaproteobacteria, Enterobacteriales, and Enterobacteriaceae and the interleukin 1β (IL-1β) level; the relative abundances of Enterobacteriales and Enterobacteriaceae and the interferon γ level; and the relative abundances of Erysipelotrichi and Barnesiella and the TNF-α level. There were negative correlations between endotoxin core IgM and IL-1β levels.ConclusionsPatients who have chronic HIV infection and are receiving suppressive ART display intestinal dysbiosis associated with increased microbial translocation and significant associations between specific taxa and markers of microbial translocation and systemic inflammation. This was an exploratory study, the findings of which need to be confirmed.

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Intestinal microbial metabolite stercobilin involvement in the chronic inflammation of ob/ob mice.

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Intestinal microbial metabolite stercobilin involvement in the chronic inflammation of ob/ob mice.

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