TMAO reductase, a biomarker for gut permeability defect induced inflammation, in mouse model of chronic kidney disease and dextran sulfate solution-induced mucositis

Boonhai, Sompong; Bootdee, Kanthika; Saisorn, Wilasinee; Takkavatakarn, Kullaya; Sitticharoenchai, Patita; Tungsanga, Somkanya; Tiranathanagul, Khajohn; Leelahavanichkul, Asada

doi:10.12932/ap-100321-1084

Cited by 10 publications

(8 citation statements)

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“…The presence of lipopolysaccharide (LPS), a microbial molecule from Gram-negative bacteria, in blood has been clinically demonstrated as endotoxemia in several conditions, including sepsis [ 55 , 56 , 57 ], partly through gut barrier damage [ 1 , 22 , 24 , 58 ]. The activation of macrophages by LPS is possibly important in sepsis because macrophages are the innate immune cells responsible for the recognition of foreign molecules [ 51 , 59 ].…”

Section: Discussionmentioning

confidence: 99%

The Regulatory Roles of Ezh2 in Response to Lipopolysaccharide (LPS) in Macrophages and Mice with Conditional Ezh2 Deletion with LysM-Cre System

Kunanopparat

Leelahavanichkul

Visitchanakun

et al. 2023

IJMS

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The responses of macrophages to lipopolysaccharide (LPS) might determine the direction of clinical manifestations of sepsis, which is the immune response against severe infection. Meanwhile, the enhancer of zeste homologue 2 (Ezh2), a histone lysine methyltransferase of epigenetic regulation, might interfere with LPS response. Transcriptomic analysis on LPS-activated wild-type macrophages demonstrated an alteration of several epigenetic enzymes. Although the Ezh2-silencing macrophages (RAW264.7), using small interfering RNA (siRNA), indicated a non-different response to the control cells after a single LPS stimulation, the Ezh2-reducing cells demonstrated a less severe LPS tolerance, after two LPS stimulations, as determined by the higher supernatant TNF-α. With a single LPS stimulation, Ezh2 null (Ezh2flox/flox; LysM-Crecre/−) macrophages demonstrated lower supernatant TNF-α than Ezh2 control (Ezh2fl/fl; LysM-Cre−/−), perhaps due to an upregulation of Socs3, which is a suppressor of cytokine signaling 3, due to the loss of the Ezh2 gene. In LPS tolerance, Ezh2 null macrophages indicated higher supernatant TNF-α and IL-6 than the control, supporting an impact of the loss of the Ezh2 inhibitory gene. In parallel, Ezh2 null mice demonstrated lower serum TNF-α and IL-6 than the control mice after an LPS injection, indicating a less severe LPS-induced hyper-inflammation in Ezh2 null mice. On the other hand, there were similar serum cytokines after LPS tolerance and the non-reduction of serum cytokines after the second dose of LPS, indicating less severe LPS tolerance in Ezh2 null mice compared with control mice. In conclusion, an absence of Ezh2 in macrophages resulted in less severe LPS-induced inflammation, as indicated by low serum cytokines, with less severe LPS tolerance, as demonstrated by higher cytokine production, partly through the upregulated Socs3.

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Section: Discussionmentioning

confidence: 99%

The Regulatory Roles of Ezh2 in Response to Lipopolysaccharide (LPS) in Macrophages and Mice with Conditional Ezh2 Deletion with LysM-Cre System

Kunanopparat

Leelahavanichkul

Visitchanakun

et al. 2023

IJMS

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“…Blood samples (50 µL) were collected through tail vein nicking in several time-points. In parallel, dextran sulfate solution (DSS) (Sigma-Aldrich, St. Louis, MO, USA) was diluted into the mouse drinking water at 2 weeks after surgery at a concentration of 3% volume by volume (v/v) for 1 week to induce gut barrier defect, following previous publications [17,76,77]. The stool consistency was semi-quantitatively evaluated using the following score: 0, normal; 1, soft; 2, loose; 3, diarrhea, as previously published [78].…”

Section: Splenectomy and Dextran Sulfate Solutionmentioning

confidence: 99%

“…As such, epithelial tight junctions hold enterocytes together, forming the first phase of the intrinsic mucosal defense system as a selective physical barrier between the host and gut contents [15]. Increased gut permeability (gut barrier defect or leaky gut) causes augmentation on the translocation of viable pathogens, referred to as "gut translocation or gut bacterial translocation", or pathogen molecules, including LPS, through the gut wall into blood circulation [16,17]. Intestinal inflammation or severe systemic inflammation can cause leaky gut through the direct damage on tight junctions (such as hypoxia and inflammatory cells) and/or indirect injuries from enhanced intestinal pathogenic organisms (gut dysbiosis) [18,19].…”

Section: Introductionmentioning

confidence: 99%

Enhanced Bacteremia in Dextran Sulfate-Induced Colitis in Splenectomy Mice Correlates with Gut Dysbiosis and LPS Tolerance

Thim-Uam

Makjaroen

Issara-Amphorn

et al. 2022

IJMS

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Because both endotoxemia and gut dysbiosis post-splenectomy might be associated with systemic infection, the susceptibility against infection was tested by dextran sulfate solution (DSS)-induced colitis and lipopolysaccharide (LPS) injection models in splenectomy mice with macrophage experiments. Here, splenectomy induced a gut barrier defect (FITC-dextran assay, endotoxemia, bacteria in mesenteric lymph nodes, and the loss of enterocyte tight junction) and gut dysbiosis (increased Proteobacteria by fecal microbiome analysis) without systemic inflammation (serum IL-6). In parallel, DSS induced more severe mucositis in splenectomy mice than sham-DSS mice, as indicated by mortality, stool consistency, gut barrier defect, serum cytokines, and blood bacterial burdens. The presence of green fluorescent-producing (GFP) E. coli in the spleen of sham-DSS mice after an oral gavage supported a crucial role of the spleen in the control of bacteria from gut translocation. Additionally, LPS administration in splenectomy mice induced lower serum cytokines (TNF-α and IL-6) than LPS-administered sham mice, perhaps due to LPS tolerance from pre-existing post-splenectomy endotoxemia. In macrophages, LPS tolerance (sequential LPS stimulation) demonstrated lower cell activities than the single LPS stimulation, as indicated by the reduction in supernatant cytokines, pro-inflammatory genes (iNOS and IL-1β), cell energy status (extracellular flux analysis), and enzymes of the glycolysis pathway (proteomic analysis). In conclusion, a gut barrier defect after splenectomy was vulnerable to enterocyte injury (such as DSS), which caused severe bacteremia due to defects in microbial control (asplenia) and endotoxemia-induced LPS tolerance. Hence, gut dysbiosis and gut bacterial translocation in patients with a splenectomy might be associated with systemic infection, and gut-barrier monitoring or intestinal tight-junction strengthening may be useful.

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“…However, the plasma leakage in the critical phase might have more intestinal impacts than the febrile phase that is severe enough to cause intestinal dysbiosis as indicated here by a higher abundance of Bacteroidaceae and Escheriachia in blood bacteriome or the increased lactulose-digestible bacteria by others (Clausen & Mortensen, 1997) (LMER test interference). The direct intestinal immunofluorescent-based histopathology (Boonhai et al, 2021) or other methods of gut barrier evaluation are interesting to use. Nevertheless, an increase in the abundance of these Gram-negative bacteria in the intestine possibly elevates LPS in gut contents and induces a higher level of endotoxemia in severe dengue infection.…”

Section: Discussionmentioning

confidence: 99%

Abnormal Blood Bacteriome, Gut Dysbiosis, and Progression to Severe Dengue Disease

Chancharoenthana

Kamolratanakul

Ariyanon

et al. 2022

Front. Cell. Infect. Microbiol.

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Despite a well-known association between gut barrier defect (leaky gut) and several diseases, data on translocation of pathogen molecules, including bacterial DNA (blood bacteriome), lipopolysaccharide (LPS), and serum (1→3)-β-D-glucan (BG), from the gut to the blood circulation (gut translocation) in dengue are still less studied. Perhaps, dengue infection might induce gut translocation of several pathogenic molecules that affect the disease severity. At the enrollment, there were 31 dengue cases in febrile and critical phases at 4.1 ± 0.3 days and 6.4 ± 1.1 days of illness, respectively, with the leaky gut as indicated by positive lactulose-to-mannitol excretion ratio. With blood bacteriome, the patients with critical phase (more severe dengue; n = 23) demonstrated more predominant abundance in Bacteroidetes and Escherichia spp. with the lower Bifidobacteria when compared with the healthy control (n = 5). Meanwhile, most of the blood bacteriome results in dengue with febrile stage (n = 8) were comparable to the control, except for the lower Bifidobacteria in dengue cases. Additionally, endotoxemia at the enrollment was demonstrated in five (62.5%) and 19 (82.6%) patients with febrile and critical phases, respectively, while serum BG was detectable in two (25%) and 20 (87%) patients with febrile and critical phases, respectively. There were higher peripheral blood non-classical monocytes and natural killer cells (NK cells) at the enrollment in patients with febrile phage than in the cases with critical stage. Then, non-classical monocytes (CD14-CD16+) and NK cells (CD56+CD16-) increased at 4 and 7 days of illness in the cases with critical and febrile stages, respectively, the elevation of LPS and/or BG in serum on day 7 was also associated with the increase in monocytes, NK cells, and cytotoxic T cells. In summary, enhanced Proteobacteria (pathogenic bacteria from blood bacteriomes) along with increased endotoxemia and serum BG (leaky gut syndrome) might be collaborated with the impaired microbial control (lower non-classical monocytes and NK cells) in the critical cases and causing more severe disease of dengue infection.

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TMAO reductase, a biomarker for gut permeability defect induced inflammation, in mouse model of chronic kidney disease and dextran sulfate solution-induced mucositis

Cited by 10 publications

References 0 publications

The Regulatory Roles of Ezh2 in Response to Lipopolysaccharide (LPS) in Macrophages and Mice with Conditional Ezh2 Deletion with LysM-Cre System

The Regulatory Roles of Ezh2 in Response to Lipopolysaccharide (LPS) in Macrophages and Mice with Conditional Ezh2 Deletion with LysM-Cre System

Enhanced Bacteremia in Dextran Sulfate-Induced Colitis in Splenectomy Mice Correlates with Gut Dysbiosis and LPS Tolerance

Abnormal Blood Bacteriome, Gut Dysbiosis, and Progression to Severe Dengue Disease

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