Gut Leakage of Fungal-Derived Inflammatory Mediators: Part of a Gut-Liver-Kidney Axis in Bacterial Sepsis

Amornphimoltham, Panomwat; Yuen, Peter S.T.; Star, Robert A.; Leelahavanichkul, Asada

doi:10.1007/s10620-019-05581-y

Cited by 76 publications

(149 citation statements)

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“…To provide mechanistic data for the previously described phenomena, we studied the interactions of LPS, BG, and PA on inflammation (53,54) and mitochondrial function in hepatocytes (HepG2) and macrophages (RAW264.7 cells) (31). As such, PA, a representative saturated fatty acid, induced lipid accumulation, mild cytokine production, and amplified cytokine responses in HepG2 cells after stimulation with LPS plus BG (LPS + BG; Figures 8A-E).…”

Section: Additive Effect Between Endotoxin and (1→3)-β-d-glucan Towarmentioning

confidence: 97%

“…During gut leakage, intestinal Candida increases BG in gut contents that could be delivered to the liver and lymphatic system (31). In hepatocytes, an additive inflammatory effect of LPS was amplified by BG through the activation on Dectin-1, a receptor for BG, as the amplification was neutralized by a FIGURE 14 | The proposed hypothesis demonstrates gut leakage in mice fed a high-fat diet (HFD) treated with Candida is more severe than mice fed a HFD that were not treated with Candida due to prominent gut translocation of lipopolysaccharide (LPS) and (1→3)-β-D-glucan (BG), a major cell wall component of Gram-negative bacteria and Candida, respectively, that are delivered to liver and systemic circulation (31). Additive effect of LPS with BG (LPS + BG) on hepatocytes and macrophages is amplified by palmitic acid (PA), a pro-inflammatory saturated fatty acid, resulting in higher inflammatory status that enhances sepsis severity.…”

Section: Enhanced Inflammatory Responses Of Candida In Sepsis-obese Mmentioning

confidence: 99%

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Candida Administration Worsens Cecal Ligation and Puncture-Induced Sepsis in Obese Mice Through Gut Dysbiosis Enhanced Systemic Inflammation, Impact of Pathogen-Associated Molecules From Gut Translocation and Saturated Fatty Acid

et al. 2020

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Obesity induces gut leakage and elevates serum lipopolysaccharide (LPS), a major cell wall component of Gram-negative bacteria, through gut translocation. Because Candida albicans is prominent in human gut but not in mouse, C. albicans, a source of (1→3)-β-D-glucan (BG) in gut contents, was administered in high-fat diet (HFD)-induced obese mice at 1 week before sepsis induction by cecal ligation and puncture (CLP). As such, sepsis in Candida-administered obese mice was more severe than obese mice without Candida as determined by mortality, organ injury (liver and kidney), serum cytokines, gut leakage, endotoxemia, serum BG, and fecal Gram-negative bacteria (microbiome analysis). Mice subjected to CLP and fed a HFD, but not treated with Candida demonstrated a similar mortality to non-obese mice with more severe gut leakage and higher serum cytokines. In vitro experiments demonstrated that LPS plus BG (LPS + BG) induced higher supernatant cytokines from hepatocytes (HepG2) and macrophages (RAW264.7), compared with the activation by each molecule alone, and were amplified by palmitic acid, a representative saturated fatty acid. The energy production capacity of HepG2 cells was also decreased by LPS + BG compared with LPS alone as evaluated by extracellular flux analysis. However, Lactobacillus rhamnosus L34 (L34) improved

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Section: Additive Effect Between Endotoxin and (1→3)-β-d-glucan Towarmentioning

confidence: 97%

Section: Enhanced Inflammatory Responses Of Candida In Sepsis-obese Mmentioning

confidence: 99%

Candida Administration Worsens Cecal Ligation and Puncture-Induced Sepsis in Obese Mice Through Gut Dysbiosis Enhanced Systemic Inflammation, Impact of Pathogen-Associated Molecules From Gut Translocation and Saturated Fatty Acid

et al. 2020

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“…The human gut contains an abundance of Gram‐negative bacteria and Candida albicans , as well as components of pathogen‐associated molecular patterns (PAMP) specific to these organisms. These components, which come from the cell walls of Gram‐negative bacteria and C. albicans , include endotoxin (LPS) and 1,3‐β‐ d ‐glucan, respectively 37 . ‐ 39 C. albicans is a major inhabitant of the gut 40 and one of the most important conditional pathogenic organisms in the clinic 41 .…”

Section: Discussionmentioning

confidence: 99%

Paeonol ameliorates murine alcohol liver disease via mycobiota-mediated Dectin-1/IL-1β signaling pathway

et al. 2020

Journal of Leukocyte Biology

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Alcoholic liver disease (ALD) is caused by long‐term consumption of alcohol and has become an important social and medical problem. Intestinal fungal flora (mycobiota) play an important role in ALD, so we used the mycobiota as an entry point to explore the mechanism of action of Paeonol against ALD. Here, we found that Paeonol is effective against ALD inflammatory lesions and relieves liver fat lesions. Furthermore, we found that after the treatment of Paeonol, the fungal dysbiosis is improved, and the fungal abundance is reduced, and the translocation of β‐glucan to the liver and its mediated Dectin‐1/IL‐1β signaling pathway is blocked. Our study shows that paeonol ameliorated acute ALD‐related inflammatory injury to the liver by alleviating intestinal fungal dysbiosis and inhibiting the mycobiota‐mediated Dectin‐1/IL‐1β signaling pathway.

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“…DSS-induced gut bacterial translocation is determined by bacterial culture positive in mesenteric lymph node (MLN) despite the absence of bacteremia 24 . Also, MLN (delivering to thoracic duct) and portal vein (carrying to liver) are the important routes of the translocation from gut into blood circulation 25 . At sacrifice, MLNs (3-6 nodes) were homogenized, sonicated in PBS in different dilutions, directly streaked onto blood agar plates (Oxoid, Hampshire, UK) and incubated at 37 °C for 24 h before bacterial colony enumeration.…”

Section: Methodsmentioning

confidence: 99%

Leaky-gut enhanced lupus progression in the Fc gamma receptor-IIb deficient and pristane-induced mouse models of lupus

Thim-Uam

Surawut

Issara-Amphorn

et al. 2020

Sci Rep

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The influence of gut-leakage or gut-microbiota upon lupus progression was explored in 2 lupus mouse models. Pristane, administered in 4-wk-old wild-type (WT) female mice, induced lupus characteristics at 24-wk-old similar to the lupus-onset in FcGRIIb−/− mice. Gut-microbiota alteration was induced by co-housing together with the gavage of feces from 40-wk-old FcGRIIb−/− mice (symptomatic lupus). On the other hand, gut-leakage was induced by dextran sulfate solution (DSS). DSS and gutmicrobiota alteration induced high serum anti-dsDNA immunoglobulin (Ig) as early as 30 days post-DSS only in FcGRIIb−/− mice. DSS, but not gut-microbiota alteration, enhanced lupus characteristics (serum creatinine and proteinuria) in both lupus models (but not in WT) at 60 days post-DSS. Indeed, DSS induced the translocation of molecular components of gut-pathogens as determined by bacterial burdens in mesenteric lymph node (MLN), endotoxemia (gut-bacterial molecule) and serum (1→3)-β-Dglucan (BG) (gut-fungal molecule) as early as 15 days post-DSS together with enhanced MLN apoptosis in both WT and lupus mice. However, DSS induced spleen apoptosis in FcGRIIb−/− and Wt mice at 30 and 60 days post-DSS, respectively, suggesting the higher impact of gut-leakage against spleen of lupus mice. In addition, macrophages preconditioning with LPS plus BG were susceptible to starvationinduced apoptosis, predominantly in FcGRIIb−/− cell, implying the influence of gut-leakage upon cell stress. in summary, gut-leakage induced gut-translocation of organismal-molecules then enhanced the susceptibility of stress-induced apoptosis, predominantly in lupus. Subsequently, the higher burdens of apoptosis in lupus mice increased anti-dsDNA Ig and worsen lupus severity through immune complex deposition. Hence, therapeutic strategies addressing gut-leakage in lupus are interesting.Systemic lupus erythematosus (SLE) is a common autoimmune disease with multi-organ involvement 1 . Fc gamma receptor IIb (FcGRIIb) dysfunction polymorphism associates with SLE, particularly in Asian populations 2 , possibly due to malaria-based selection pressure 3 . Indeed, the overexpression of FcGRIIb, either in autoimmune-prone mouse strains or wild-type (WT) animals, heightened the threshold for induction of autoimmune disease 4 . The defects of FcGRIIb, the only inhibitory receptor in FcGR family, induce exaggerated immune responses and cause lupus 5 . As such, FcGRIIb−/− mouse is an established lupus mouse model with lupus characteristics as early as 20-24 wks old and develops full-blown lupus after 32-40 wks old 5,6 . In parallel, a single peritoneal injection creatinine index (UPCI; detail later) and serum anti-dsDNA immunoglobulin (Ig) before the further experiments. Symptomatic lupus was defined as increased serum anti-dsDNA Ig together with high level of UPCI and/ or serum Cr in comparison with age-matched control WT mice.Dextran sulfate solution (DSS) induced gut-leakage and co-housing with fecal gavage for gut microbiota alteration. Dextran sulfate solution (DSS) (Sigm...

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Gut Leakage of Fungal-Derived Inflammatory Mediators: Part of a Gut-Liver-Kidney Axis in Bacterial Sepsis

Cited by 76 publications

References 149 publications

Candida Administration Worsens Cecal Ligation and Puncture-Induced Sepsis in Obese Mice Through Gut Dysbiosis Enhanced Systemic Inflammation, Impact of Pathogen-Associated Molecules From Gut Translocation and Saturated Fatty Acid

Candida Administration Worsens Cecal Ligation and Puncture-Induced Sepsis in Obese Mice Through Gut Dysbiosis Enhanced Systemic Inflammation, Impact of Pathogen-Associated Molecules From Gut Translocation and Saturated Fatty Acid

Paeonol ameliorates murine alcohol liver disease via mycobiota-mediated Dectin-1/IL-1β signaling pathway

Leaky-gut enhanced lupus progression in the Fc gamma receptor-IIb deficient and pristane-induced mouse models of lupus

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