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
Abstract: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 Candi… Show more
“…3 A–H). Because (i) Gram-negative bacteria in the gut is a source of endotoxin (LPS) 7 , (ii) obesity enhances endotoxemia from gut translocation 25 and (iii) molecules from gut translocation is possibly directly transported to the liver through portal veins 7 , the reduced serum endotoxin in LA5 administered-obese mice implies the improved gut dysbiosis. Figure 1 Characteristics of mice fed with regular diet (RD) or high-fat diet (HFD) with or without Lactobacillus acidophilus LA5 (LA5) as determined by body weight ( A ), adipose tissue depots in several sites ( B – E ), subcutaneous fat thickness ( F ), fasting blood lipid profiles ( G – J ) and the representative figures of the subcutaneous fat thickness (original magnification × 200) ( K ) were demonstrated (n = 6–8/group for A – J ).…”
Section: Resultsmentioning
confidence: 99%
“…Probiotics are the most common treatment for gut dysbiosis 22 , 24 , 25 , 50 , attenuating obesity through several mechanisms such as the induction of energy-efficient microbiota, production of SCFAs, and promotion of intestinal hormones with anti-obesity properties 65 . Among several probiotics, Lactobacillus acidophilus demonstrates robust lactic acid production in comparison to other strains 66 that may strongly alter HFD-induced dysbiosis.…”
Section: Discussionmentioning
confidence: 99%
“…Because serum endotoxin could be detected in obesity 25 and saturated fatty acid-activated hepatocytes, the conditioned media from LA5 were incubated in HepG2 hepatocyte cell-line with palmitic acid (a representative saturated fatty acid) and/or endotoxin to see an impact of LA5 on hepatocytes. For the preparation of LA5 conditioned-media, LA5 at 0.1 McFarland standards (OD600) were incubated anaerobically for 48 h before supernatant collection and filtered with a 0.22-µm membrane filter (Minisart; Sartorius, Göttingen, Germany).…”
Section: Methodsmentioning
confidence: 99%
“…Although (i) Lactobacillus spp. attenuates gut dysbiosis in several animal models 20 – 25 and (ii) Lactobacillus acidophilus (LA), in combination with other probiotics, attenuates hyperlipidemia, overweight and obesity-induced hepatitis (steatohepatitis) 12 , 26 – 29 , the effect of LA alone upon obesity and steatohepatitis is still unclear. As such, it is easier to determine the impact of microbiota alteration after the administration of probiotics in a single strain than a combination of several strains.…”
Obesity, a major healthcare problem worldwide, induces metabolic endotoxemia through the gut translocation of lipopolysaccharides (LPS), a major cell wall component of Gram-negative bacteria, causing a chronic inflammatory state. A combination of several probiotics including Lactobacillus acidophilus 5 (LA5), a potent lactic acid-producing bacterium, has previously been shown to attenuate obesity. However, data on the correlation between a single administration of LA5 versus microbiota alteration might be helpful for the probiotic adjustment. LA5 was administered daily together with a high-fat diet (HFD) for 8 weeks in mice. Furthermore, the condition media of LA5 was also tested in a hepatocyte cell-line (HepG2 cells). Accordingly, LA5 attenuated obesity in mice as demonstrated by weight reduction, regional fat accumulation, lipidemia, liver injury (liver weight, lipid compositions, and liver enzyme), gut permeability defect, endotoxemia, and serum cytokines. Unsurprisingly, LA5 improved these parameters and acidified fecal pH leads to the attenuation of fecal dysbiosis. The fecal microbiome analysis in obese mice with or without LA5 indicated; (i) decreased Bacteroidetes (Gram-negative anaerobes that predominate in non-healthy conditions), (ii) reduced total fecal Gram-negative bacterial burdens (the sources of gut LPS), (iii) enhanced Firmicutes (Gram-positive bacteria with potential benefits) and (iv) increased Verrucomycobia, especially Akkermansia muciniphila, a bacterium with the anti-obesity property. With LA5 administration, A. muciniphila in the colon were more than 2,000 folds higher than the regular diet mice as determined by 16S rRNA. Besides, LA5 produced anti-inflammatory molecules with a similar molecular weight to LPS that reduced cytokine production in LPS-activated HepG2 cells. In conclusion, LA5 attenuated obesity through (i) gut dysbiosis attenuation, partly through the promotion of A. muciniphila (probiotics with the difficulty in preparation processes), (ii) reduced endotoxemia, and (iii) possibly decreased liver injury by producing the anti-inflammatory molecules.
“…3 A–H). Because (i) Gram-negative bacteria in the gut is a source of endotoxin (LPS) 7 , (ii) obesity enhances endotoxemia from gut translocation 25 and (iii) molecules from gut translocation is possibly directly transported to the liver through portal veins 7 , the reduced serum endotoxin in LA5 administered-obese mice implies the improved gut dysbiosis. Figure 1 Characteristics of mice fed with regular diet (RD) or high-fat diet (HFD) with or without Lactobacillus acidophilus LA5 (LA5) as determined by body weight ( A ), adipose tissue depots in several sites ( B – E ), subcutaneous fat thickness ( F ), fasting blood lipid profiles ( G – J ) and the representative figures of the subcutaneous fat thickness (original magnification × 200) ( K ) were demonstrated (n = 6–8/group for A – J ).…”
Section: Resultsmentioning
confidence: 99%
“…Probiotics are the most common treatment for gut dysbiosis 22 , 24 , 25 , 50 , attenuating obesity through several mechanisms such as the induction of energy-efficient microbiota, production of SCFAs, and promotion of intestinal hormones with anti-obesity properties 65 . Among several probiotics, Lactobacillus acidophilus demonstrates robust lactic acid production in comparison to other strains 66 that may strongly alter HFD-induced dysbiosis.…”
Section: Discussionmentioning
confidence: 99%
“…Because serum endotoxin could be detected in obesity 25 and saturated fatty acid-activated hepatocytes, the conditioned media from LA5 were incubated in HepG2 hepatocyte cell-line with palmitic acid (a representative saturated fatty acid) and/or endotoxin to see an impact of LA5 on hepatocytes. For the preparation of LA5 conditioned-media, LA5 at 0.1 McFarland standards (OD600) were incubated anaerobically for 48 h before supernatant collection and filtered with a 0.22-µm membrane filter (Minisart; Sartorius, Göttingen, Germany).…”
Section: Methodsmentioning
confidence: 99%
“…Although (i) Lactobacillus spp. attenuates gut dysbiosis in several animal models 20 – 25 and (ii) Lactobacillus acidophilus (LA), in combination with other probiotics, attenuates hyperlipidemia, overweight and obesity-induced hepatitis (steatohepatitis) 12 , 26 – 29 , the effect of LA alone upon obesity and steatohepatitis is still unclear. As such, it is easier to determine the impact of microbiota alteration after the administration of probiotics in a single strain than a combination of several strains.…”
Obesity, a major healthcare problem worldwide, induces metabolic endotoxemia through the gut translocation of lipopolysaccharides (LPS), a major cell wall component of Gram-negative bacteria, causing a chronic inflammatory state. A combination of several probiotics including Lactobacillus acidophilus 5 (LA5), a potent lactic acid-producing bacterium, has previously been shown to attenuate obesity. However, data on the correlation between a single administration of LA5 versus microbiota alteration might be helpful for the probiotic adjustment. LA5 was administered daily together with a high-fat diet (HFD) for 8 weeks in mice. Furthermore, the condition media of LA5 was also tested in a hepatocyte cell-line (HepG2 cells). Accordingly, LA5 attenuated obesity in mice as demonstrated by weight reduction, regional fat accumulation, lipidemia, liver injury (liver weight, lipid compositions, and liver enzyme), gut permeability defect, endotoxemia, and serum cytokines. Unsurprisingly, LA5 improved these parameters and acidified fecal pH leads to the attenuation of fecal dysbiosis. The fecal microbiome analysis in obese mice with or without LA5 indicated; (i) decreased Bacteroidetes (Gram-negative anaerobes that predominate in non-healthy conditions), (ii) reduced total fecal Gram-negative bacterial burdens (the sources of gut LPS), (iii) enhanced Firmicutes (Gram-positive bacteria with potential benefits) and (iv) increased Verrucomycobia, especially Akkermansia muciniphila, a bacterium with the anti-obesity property. With LA5 administration, A. muciniphila in the colon were more than 2,000 folds higher than the regular diet mice as determined by 16S rRNA. Besides, LA5 produced anti-inflammatory molecules with a similar molecular weight to LPS that reduced cytokine production in LPS-activated HepG2 cells. In conclusion, LA5 attenuated obesity through (i) gut dysbiosis attenuation, partly through the promotion of A. muciniphila (probiotics with the difficulty in preparation processes), (ii) reduced endotoxemia, and (iii) possibly decreased liver injury by producing the anti-inflammatory molecules.
“…On the other hand, gut permeability barrier consists of only a single layer of the gut epithelium with an approximate surface area at 32 m 2 that separates between the host and the organisms in gut contents [ 6 ]. As such, gut permeability defect (gut leakage) leads to the translocation of several organismal molecules from the gut into blood circulation [ 7 , 8 , 9 , 10 , 11 ]. Subsequently, gut translocation of these organismal molecules, referred to as pathogen associated molecular patterns (PAMPs), profoundly induces systemic inflammation [ 5 ].…”
Systemic inflammation, from gut translocation of organismal molecules, might worsen uremic complications in acute kidney injury (AKI). The monitoring of gut permeability integrity and/or organismal molecules in AKI might be clinically beneficial. Due to the less prominence of Candida albicans in human intestine compared with mouse gut, C. albicans were orally administered in bilateral nephrectomy (BiN) mice. Gut dysbiosis, using microbiome analysis, and gut permeability defect (gut leakage), which was determined by fluorescein isothiocyanate-dextran and intestinal tight-junction immunofluorescent staining, in mice with BiN-Candida was more severe than BiN without Candida. Additionally, profound gut leakage in BiN-Candida also resulted in gut translocation of lipopolysaccharide (LPS) and (1→3)-β-D-glucan (BG), the organismal components from gut contents, that induced more severe systemic inflammation than BiN without Candida. The co-presentation of LPS and BG in mouse serum enhanced inflammatory responses. As such, LPS with Whole Glucan Particle (WGP, a representative BG) induced more severe macrophage responses than LPS alone as determined by supernatant cytokines and gene expression of downstream signals (NFκB, Malt-1 and Syk). Meanwhile, WGP alone did not induced the responses. In parallel, WGP (with or without LPS), but not LPS alone, accelerated macrophage ATP production (extracellular flux analysis) through the upregulation of genes in mitochondria and glycolysis pathway (using RNA sequencing analysis), without the induction of cell activities. These data indicated a WGP pre-conditioning effect on cell energy augmentation. In conclusion, Candida in BiN mice accelerated gut translocation of BG that augmented cell energy status and enhanced pro-inflammatory macrophage responses. Hence, gut fungi and BG were associated with the enhanced systemic inflammation in acute uremia.
The epidemy of metabolic syndrome (MetS) is typically preceded by adoption of a “risky” lifestyle (e.g., dietary habit) among populations. Evidence shows that those with low socioeconomic status (SES) are at an increased risk for MetS. To investigate this, we recruited 123 obese subjects (body mass index [BMI] ≥ 30) from Chicago. Multi‐omic data were collected to interrogate fecal microbiota, systemic markers of inflammation and immune activation, plasma metabolites, and plasma glycans. Intestinal permeability was measured using the sugar permeability testing. Our results suggest a heterogenous metabolic dysregulation among obese populations who are at risk of MetS. Systemic inflammation, linked to poor diet, intestinal microbiome dysbiosis, and gut barrier dysfunction may explain the development of MetS in these individuals. Our analysis revealed 37 key features associated with increased numbers of MetS features. These features were used to construct a composite metabolic‐inflammatory (MI) score that was able to predict progression of MetS among at‐risk individuals. The MI score was correlated with several markers of poor diet quality as well as lower levels of gut microbial diversity and abnormalities in several species of bacteria. This study reveals novel targets to reduce the burden of MetS and suggests access to healthy food options as a practical intervention.
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