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Nutrients Aug 2021Diet and dietary components have profound effects on the composition of the gut microbiota and are among the most important contributors to the alteration in bacterial... (Review)
Review
Diet and dietary components have profound effects on the composition of the gut microbiota and are among the most important contributors to the alteration in bacterial flora. This review examines the effects the "Western", "plant-based", "high-fat", "medical ketogenic", and "Mediterranean" diets have on the composition of the gut microbiota in both mice and human subjects. We show that specific dietary components that are commonly found in the "plant-based" and "Mediterranean" diet play a role in shifting the microbial composition. This review further evaluates the bacterial metabolites that are associated with diet, and their role in systemic inflammation and metabolic endotoxemia. Furthermore, the associations between diet/dietary components and altering bacterial composition, may lead to potential therapeutic targets for type II diabetes, obesity, and inflammatory diseases.
Topics: Animals; Diet; Diet, High-Fat; Diet, Ketogenic; Diet, Mediterranean; Diet, Vegetarian; Diet, Western; Endotoxemia; Gastrointestinal Microbiome; Humans; Inflammation; Mice; Nutritional Physiological Phenomena
PubMed: 34444955
DOI: 10.3390/nu13082795 -
Alcohol Research : Current Reviews 2015The excessive use of alcohol is a global problem causing many adverse pathological health effects and a significant financial health care burden. This review addresses... (Review)
Review
The excessive use of alcohol is a global problem causing many adverse pathological health effects and a significant financial health care burden. This review addresses the effect of alcohol consumption on the microbiota in the gastrointestinal tract (GIT). Although data are limited in humans, studies highlight the importance of changes in the intestinal microbiota in alcohol-related disorders. Alcohol-induced changes in the GIT microbiota composition and metabolic function may contribute to the well-established link between alcohol-induced oxidative stress, intestinal hyperpermeability to luminal bacterial products, and the subsequent development of alcoholic liver disease (ALD), as well as other diseases. In addition, clinical and preclinical data suggest that alcohol-related disorders are associated with quantitative and qualitative dysbiotic changes in the intestinal microbiota and may be associated with increased GIT inflammation, intestinal hyperpermeability resulting in endotoxemia, systemic inflammation, and tissue damage/organ pathologies including ALD. Thus, gut-directed interventions, such as probiotic and synbiotic modulation of the intestinal microbiota, should be considered and evaluated for prevention and treatment of alcohol-associated pathologies.
Topics: Alcohol Drinking; Alcoholism; Anti-Infective Agents, Local; Bacterial Translocation; Dysbiosis; Endotoxemia; Ethanol; Gastrointestinal Microbiome; Humans; Intestines; Liver Diseases, Alcoholic; Permeability; Probiotics
PubMed: 26695747
DOI: No ID Found -
International Journal of Molecular... Sep 2019Sepsis is defined as life-threatening organ dysfunction caused by the dysregulated host response to infection. Despite serious mortality and morbidity, no... (Review)
Review
Sepsis is defined as life-threatening organ dysfunction caused by the dysregulated host response to infection. Despite serious mortality and morbidity, no sepsis-specific drugs exist. Endotoxemia is often used to model the hyperinflammation associated with early sepsis. This model classically uses lipopolysaccharide (LPS) from Gram-negative pathogens to activate the immune system, leading to hyperinflammation, microcirculatory disturbances and death. Other toxins may also be used to activate the immune system including Gram-positive peptidoglycan (PG) and lipoteichoic acid (LTA). In addition to these standard toxins, other bacterial components can induce inflammation. These molecules activate different signaling pathways and produce different physiological responses which can be taken advantage of for sepsis modeling. Endotoxemia modeling can provide information on pathways to inflammation in sepsis and contribute to preclinical drug development.
Topics: Animals; Endotoxemia; Host-Pathogen Interactions; Humans; Inflammation; Lipopolysaccharides; Sepsis; Signal Transduction; Toxins, Biological
PubMed: 31491842
DOI: 10.3390/ijms20184341 -
The Journal of Clinical Investigation Nov 2017Acute lung injury is a leading cause of death in bacterial sepsis due to the wholesale destruction of the lung endothelial barrier, which results in protein-rich lung...
Acute lung injury is a leading cause of death in bacterial sepsis due to the wholesale destruction of the lung endothelial barrier, which results in protein-rich lung edema, influx of proinflammatory leukocytes, and intractable hypoxemia. Pyroptosis is a form of programmed lytic cell death that is triggered by inflammatory caspases, but little is known about its role in EC death and acute lung injury. Here, we show that systemic exposure to the bacterial endotoxin lipopolysaccharide (LPS) causes severe endothelial pyroptosis that is mediated by the inflammatory caspases, human caspases 4/5 in human ECs, or the murine homolog caspase-11 in mice in vivo. In caspase-11-deficient mice, BM transplantation with WT hematopoietic cells did not abrogate endotoxemia-induced acute lung injury, indicating a central role for nonhematopoietic caspase-11 in endotoxemia. Additionally, conditional deletion of caspase-11 in ECs reduced endotoxemia-induced lung edema, neutrophil accumulation, and death. These results establish the requisite role of endothelial pyroptosis in endotoxemic tissue injury and suggest that endothelial inflammatory caspases are an important therapeutic target for acute lung injury.
Topics: Animals; Case-Control Studies; Caspases; Caspases, Initiator; Cells, Cultured; Endothelial Cells; Endothelium, Vascular; Endotoxemia; Female; Humans; Interleukin-1beta; Lipopolysaccharides; Lung; Lung Injury; Male; Mice, Inbred C57BL; Mice, Knockout; Pyroptosis; Toll-Like Receptor 4
PubMed: 28990935
DOI: 10.1172/JCI94495 -
Immunity Dec 2019Excessive activation of the coagulation system leads to life-threatening disseminated intravascular coagulation (DIC). Here, we examined the mechanisms underlying the...
Excessive activation of the coagulation system leads to life-threatening disseminated intravascular coagulation (DIC). Here, we examined the mechanisms underlying the activation of coagulation by lipopolysaccharide (LPS), the major cell-wall component of Gram-negative bacteria. We found that caspase-11, a cytosolic LPS receptor, activated the coagulation cascade. Caspase-11 enhanced the activation of tissue factor (TF), an initiator of coagulation, through triggering the formation of gasdermin D (GSDMD) pores and subsequent phosphatidylserine exposure, in a manner independent of cell death. GSDMD pores mediated calcium influx, which induced phosphatidylserine exposure through transmembrane protein 16F, a calcium-dependent phospholipid scramblase. Deletion of Casp11, ablation of Gsdmd, or neutralization of phosphatidylserine or TF prevented LPS-induced DIC. In septic patients, plasma concentrations of interleukin (IL)-1α and IL-1β, biomarkers of GSDMD activation, correlated with phosphatidylserine exposure in peripheral leukocytes and DIC scores. Our findings mechanistically link immune recognition of LPS to coagulation, with implications for the treatment of DIC.
Topics: Animals; Blood Coagulation; Caspases, Initiator; Cell Line, Tumor; Disseminated Intravascular Coagulation; Endotoxemia; Enzyme Activation; HT29 Cells; HeLa Cells; Humans; Interleukin-1alpha; Interleukin-1beta; Intracellular Signaling Peptides and Proteins; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Mice, Knockout; Phosphate-Binding Proteins; Phosphatidylserines; Pyroptosis; Signal Transduction; Thromboplastin
PubMed: 31836429
DOI: 10.1016/j.immuni.2019.11.005 -
Microbiome Dec 2022Mounting experimental evidence has shown that the gut microbiota plays a significant role in the pathogenesis of mastitis, and clinical investigations have found that...
BACKGROUND
Mounting experimental evidence has shown that the gut microbiota plays a significant role in the pathogenesis of mastitis, and clinical investigations have found that the occurrence of mastitis is correlated with ruminal dysbiosis. However, the underlying mechanism by which the ruminal microbiota participates in the development of mastitis remains unknown.
RESULTS
In the present study, we found that cows with clinical mastitis had marked systemic inflammation, which was associated with significant ruminal dysbiosis, especially enriched Proteobacteria in the rumen. Ruminal microbiota transplantation from mastitis cows (M-RMT) to mice induced mastitis symptoms in recipient mice along with increased mammary proinflammatory signature activation of the TLR4-cGAS-STING-NF-κB/NLRP3 pathways. M-RMT also induced mucosal inflammation and impaired intestinal barrier integrity, leading to increased endotoxemia and systemic inflammation. Moreover, we showed that M-RMT mirrored ruminal microbiota disruption in the gut of recipient mice, as evidenced by enriched Proteobacteria and similar bacterial functions, which were correlated with most proinflammatory parameters and serum lipopolysaccharide (LPS) levels in mice. Recurrent low-grade LPS treatment mirrored gut dysbiosis-induced endotoxemia and caused severe mastitis in mice. Furthermore, we found that gut dysbiosis-derived LPS reduced host alkaline phosphatase activity by activating neuraminidase (Neu), which facilitates low-grade LPS exposure and E. coli-induced mastitis in mice. Conversely, treatment with calf intestinal alkaline phosphatase or the Neu inhibitor zanamivir alleviated low-grade LPS exposure and E. coli-induced mastitis in mice.
CONCLUSIONS
Our results suggest that ruminal dysbiosis-derived low-grade endotoxemia can cause mastitis and aggravate pathogen-induced mastitis by impairing host anti-inflammatory enzymes, which implies that regulating the ruminal or gut microbiota to prevent low-grade systemic inflammation is a potential strategy for mastitis intervention. Video Abstract.
Topics: Female; Humans; Animals; Cattle; Mice; Dysbiosis; Endotoxemia; Lipopolysaccharides; Alkaline Phosphatase; Escherichia coli; Mastitis; Anti-Inflammatory Agents; Inflammation; Proteobacteria
PubMed: 36451232
DOI: 10.1186/s40168-022-01402-z -
Nature Communications Jun 2015Obesity is associated with low-grade chronic inflammation and intestinal dysbiosis. Ganoderma lucidum is a medicinal mushroom used in traditional Chinese medicine with...
Obesity is associated with low-grade chronic inflammation and intestinal dysbiosis. Ganoderma lucidum is a medicinal mushroom used in traditional Chinese medicine with putative anti-diabetic effects. Here, we show that a water extract of Ganoderma lucidum mycelium (WEGL) reduces body weight, inflammation and insulin resistance in mice fed a high-fat diet (HFD). Our data indicate that WEGL not only reverses HFD-induced gut dysbiosis-as indicated by the decreased Firmicutes-to-Bacteroidetes ratios and endotoxin-bearing Proteobacteria levels-but also maintains intestinal barrier integrity and reduces metabolic endotoxemia. The anti-obesity and microbiota-modulating effects are transmissible via horizontal faeces transfer from WEGL-treated mice to HFD-fed mice. We further show that high molecular weight polysaccharides (>300 kDa) isolated from the WEGL extract produce similar anti-obesity and microbiota-modulating effects. Our results indicate that G. lucidum and its high molecular weight polysaccharides may be used as prebiotic agents to prevent gut dysbiosis and obesity-related metabolic disorders in obese individuals.
Topics: Animals; Bacteroides; Body Weight; Diet, High-Fat; Drugs, Chinese Herbal; Dysbiosis; Endotoxemia; Fecal Microbiota Transplantation; Firmicutes; Fungal Polysaccharides; Gastrointestinal Microbiome; Inflammation; Insulin Resistance; Intestinal Mucosa; Intestines; Mice; Obesity; Permeability; Plant Extracts; Proteobacteria; Reishi
PubMed: 26102296
DOI: 10.1038/ncomms8489 -
Redox Biology Dec 2022Aging is considered a state of low grade inflammation, occurring in the absence of any overt infection often referred to as 'inflammaging'. Maintaining intestinal...
Aging is considered a state of low grade inflammation, occurring in the absence of any overt infection often referred to as 'inflammaging'. Maintaining intestinal homeostasis may be a target to extend a healthier status in older adults. Here, we report that even in healthy older men low grade bacterial endotoxemia is prevalent. In addition, employing multiple mouse models, we also show that while intestinal microbiota composition changes significantly during aging, fecal microbiota transplantation to old mice does not protect against aging-associated intestinal barrier dysfunction in small intestine. Rather, intestinal NO homeostasis and arginine metabolism mediated through arginase and NO synthesis is altered in small intestine of aging mice. Treatment with the arginase inhibitor norNOHA prevented aging-associated intestinal barrier dysfunction, low grade endotoxemia and delayed the onset of senescence in peripheral tissue e.g., liver. Intestinal arginine and NO metabolisms could be a target in the prevention of aging-associated intestinal barrier dysfunction and subsequently decline and 'inflammaging'.
Topics: Animals; Mice; Aging; Arginase; Arginine; Endotoxemia; Intestines; Nitric Oxide
PubMed: 36356464
DOI: 10.1016/j.redox.2022.102528 -
Scientific Reports Jan 2020Circulating lipopolysaccharide (LPS) concentrations are often elevated in patients with sepsis or various endogenous diseases related to bacterial translocation from the...
Circulating lipopolysaccharide (LPS) concentrations are often elevated in patients with sepsis or various endogenous diseases related to bacterial translocation from the gut. Systemic inflammatory responses induced by endotoxemia induce severe involuntary loss of skeletal muscle, termed muscle wasting, which adversely affects the survival and functional outcomes of these patients. Currently, no drugs are available for the treatment of endotoxemia-induced skeletal muscle wasting. Here, we tested the effects of TAK-242, a Toll-like receptor 4 (TLR4)-specific signalling inhibitor, on myotube atrophy in vitro and muscle wasting in vivo induced by endotoxin. LPS treatment of murine C2C12 myotubes induced an inflammatory response (increased nuclear factor-κB activity and interleukin-6 and tumour necrosis factor-α expression) and activated the ubiquitin-proteasome and autophagy proteolytic pathways (increased atrogin-1/MAFbx, MuRF1, and LC-II expression), resulting in myotube atrophy. In mice, LPS injection increased the same inflammatory and proteolytic pathways in skeletal muscle and induced atrophy, resulting in reduced grip strength. Notably, pretreatment of cells or mice with TAK-242 reduced or reversed all the detrimental effects of LPS in vitro and in vivo. Collectively, our results indicate that pharmacological inhibition of TLR4 signalling may be a novel therapeutic intervention for endotoxemia-induced muscle wasting.
Topics: Animals; Cell Line; Disease Models, Animal; Endotoxemia; Interleukin-6; Lipopolysaccharides; Male; Mice; Muscle Fibers, Skeletal; Muscular Atrophy; NF-kappa B; Signal Transduction; Sulfonamides; Tumor Necrosis Factor-alpha
PubMed: 31959927
DOI: 10.1038/s41598-020-57714-3 -
Redox Biology Feb 2023Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is the major enzyme responsible for metabolizing toxic acetaldehyde to acetate and acts as a protective or defensive...
Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is the major enzyme responsible for metabolizing toxic acetaldehyde to acetate and acts as a protective or defensive protein against various disease states associated with alcohol use disorder (AUD), including alcohol-related liver disease (ARLD). We hypothesized that Aldh2-knockout (KO) mice are more susceptible to binge alcohol-mediated liver injury than wild-type (WT) mice through increased oxidative stress, gut leakiness and endotoxemia. Therefore, this study aimed to investigate the protective role of ALDH2 in binge alcohol-induced gut permeability, endotoxemia, and acute inflammatory liver injury by exposing Aldh2-KO or WT mice to a single oral dose of binge alcohol 3.5, 4.0, or 5.0 g/kg. Our findings showed for the first time that ALDH2 deficiency in Aldh2-KO mice increases their sensitivity to binge alcohol-induced oxidative and nitrative stress, enterocyte apoptosis, and nitration of gut tight junction (TJ) and adherent junction (AJ) proteins, leading to their degradation. These resulted in gut leakiness and endotoxemia in Aldh2-KO mice after exposure to a single dose of ethanol even at 3.5 g/kg, while no changes were observed in the corresponding WT mice. The elevated serum endotoxin (lipopolysaccharide, LPS) and bacterial translocation contributed to systemic inflammation, hepatocyte apoptosis, and subsequently acute liver injury through the gut-liver axis. Treatment with Daidzin, an ALDH2 inhibitor, exacerbated ethanol-induced cell permeability and reduced TJ/AJ proteins in T84 human colon cells. These changes were reversed by Alda-1, an ALDH2 activator. Furthermore, CRISPR/Cas9-mediated knockout of ALDH2 in T84 cells increased alcohol-mediated cell damage and paracellular permeability. All these findings demonstrate the critical role of ALDH2 in alcohol-induced epithelial barrier dysfunction and suggest that ALDH2 deficiency or gene mutation in humans is a risk factor for alcohol-mediated gut and liver injury, and that ALDH2 could be an important therapeutic target against alcohol-associated tissue or organ damage.
Topics: Animals; Humans; Mice; Aldehyde Dehydrogenase, Mitochondrial; Endotoxemia; Ethanol; Liver Diseases, Alcoholic; Mice, Knockout; Intestinal Diseases
PubMed: 36528936
DOI: 10.1016/j.redox.2022.102577