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Uremia-induced systemic inflammation is partly caused by the dissemination of microbial molecules such as lipopolysaccharide and bacterial double-stranded DNA from leaked gut damaged by immune cells in response to the microbial molecules. Cyclic GMP–AMP synthase (cGAS) can recognize fragmented DNA and induce cGAMP synthesis for the activation of the stimulator of interferon genes (STING) pathway. To study the effect of cGAS in uremia-induced systemic inflammation, we performed bilateral nephrectomy (BNx) in wild-type and cGAS knock-out mice and found that the gut leakage and blood uremia from both groups were similar. However, serum cytokines (TNF-α and IL-6) and neutrophil extracellular traps (NETs) decreased significantly in cGAS−/− neutrophils after stimulation with LPS or bacterial cell-free DNA. Transcriptomic analysis of LPS-stimulated cGAS−/− neutrophils also confirmed the down-regulation of neutrophil effector functions. The extracellular flux analysis showed that cGAS−/− neutrophils exhibited a higher respiratory rate than wild-type neutrophils despite having similar mitochondrial abundance and function. Our results suggest that cGAS may control effector functions and the mitochondrial respiration of neutrophils in response to LPS or bacterial DNA. [ABSTRACT FROM AUTHOR]

Lupus nephritis is a severe manifestation of systemic lupus erythematosus (SLE). It is caused by immune dysregulation and kidney inflammation. In recent findings, gut microbiota potentially acts as primary mediators to enhance immune complex deposition, complement activation, and macrophage infiltration, and led to renal inflammation. Gut inflammation, known as leaky gut, allows pathogenic bacteria to enter the blood stream to form immune complexes which deposit on the kidney. Lymphocytes and macrophages induct a proinflammatory cytokine milieu that leads to kidney inflammation. Accumulating pieces of evidence from the field of gender bias, dietary habit, alcohol, smoking and antibiotic consumption were closely related to dysbiosis of gut microbiota in SLE. However, little is known about the causes of gut microbiota dysbiosis and the potential pathway that leads to lupus nephritis (LN) flare. In this review, we will bring into deeper insight for the potential link of gut microbiota on immune system with a particular focus on renal inflammation. Moreover, we also discuss the potential novel therapies that regulate gut composition to improve or complement the current treatment of LN. [ABSTRACT FROM AUTHOR]

Background: According to the leaky gut concept, microbial products (e.g., lipopolysaccharide, LPS) enter the circulation and mediate pro-inflammatory immunological responses. Higher plasma LPS levels have been reported in patients with various cardiovascular diseases, but not specifically during early atrial fibrillation (AF). Methods: We studied data and blood samples from patients presenting with first-diagnosed AF (FDAF) (n = 80) and 20 controls. Results: Circulating biomarkers that are suggestive of mucosal inflammation (zonulin, mucosal adhesion molecule MAdCAM-1) and intestinal epithelium damage (intestinal fatty acid binding protein, IFABP) were increased in the plasma of patients with FDAF when compared to patients with chronic cardiovascular diseases but without AF. Surrogate plasma markers of increased intestinal permeability (LPS, CD14, LPS-binding protein, gut-derived LPS-neutralising IgA antibodies, EndoCAbs) were detected during early AF. A reduced ratio of IgG/IgM EndoCAbs titres indicated chronic endotoxaemia. Collagen turnover biomarkers, which corresponded to the LPS values, suggested an association of gut-derived low-grade endotoxaemia with adverse structural remodelling. The LPS concentrations were higher in FDAF patients who experienced a major adverse cardiovascular event. Conclusions: Intestinal barrier dysfunction and microbial translocation accompany FDAF. Improving gut permeability and low-grade endotoxaemia might be a potential therapeutic approach to reducing the disease progression and cardiovascular complications in FDAF. [ABSTRACT FROM AUTHOR]

Uremia-induced systemic inflammation is partly caused by the dissemination of microbial molecules such as lipopolysaccharide and bacterial double-stranded DNA from leaked gut damaged by immune cells in response to the microbial molecules. Cyclic GMP–AMP synthase (cGAS) can recognize fragmented DNA and induce cGAMP synthesis for the activation of the stimulator of interferon genes (STING) pathway. To study the effect of cGAS in uremia-induced systemic inflammation, we performed bilateral nephrectomy (BNx) in wild-type and cGAS knock-out mice and found that the gut leakage and blood uremia from both groups were similar. However, serum cytokines (TNF-α and IL-6) and neutrophil extracellular traps (NETs) decreased significantly in cGAS−/− neutrophils after stimulation with LPS or bacterial cell-free DNA. Transcriptomic analysis of LPS-stimulated cGAS−/− neutrophils also confirmed the down-regulation of neutrophil effector functions. The extracellular flux analysis showed that cGAS−/− neutrophils exhibited a higher respiratory rate than wild-type neutrophils despite having similar mitochondrial abundance and function. Our results suggest that cGAS may control effector functions and the mitochondrial respiration of neutrophils in response to LPS or bacterial DNA.

Lupus nephritis is a severe manifestation of systemic lupus erythematosus (SLE). It is caused by immune dysregulation and kidney inflammation. In recent findings, gut microbiota potentially acts as primary mediators to enhance immune complex deposition, complement activation, and macrophage infiltration, and led to renal inflammation. Gut inflammation, known as leaky gut, allows pathogenic bacteria to enter the blood stream to form immune complexes which deposit on the kidney. Lymphocytes and macrophages induct a proinflammatory cytokine milieu that leads to kidney inflammation. Accumulating pieces of evidence from the field of gender bias, dietary habit, alcohol, smoking and antibiotic consumption were closely related to dysbiosis of gut microbiota in SLE. However, little is known about the causes of gut microbiota dysbiosis and the potential pathway that leads to lupus nephritis (LN) flare. In this review, we will bring into deeper insight for the potential link of gut microbiota on immune system with a particular focus on renal inflammation. Moreover, we also discuss the potential novel therapies that regulate gut composition to improve or complement the current treatment of LN.

Background: According to the leaky gut concept, microbial products (e.g., lipopolysaccharide, LPS) enter the circulation and mediate pro-inflammatory immunological responses. Higher plasma LPS levels have been reported in patients with various cardiovascular diseases, but not specifically during early atrial fibrillation (AF). Methods: We studied data and blood samples from patients presenting with first-diagnosed AF (FDAF) (n = 80) and 20 controls. Results: Circulating biomarkers that are suggestive of mucosal inflammation (zonulin, mucosal adhesion molecule MAdCAM-1) and intestinal epithelium damage (intestinal fatty acid binding protein, IFABP) were increased in the plasma of patients with FDAF when compared to patients with chronic cardiovascular diseases but without AF. Surrogate plasma markers of increased intestinal permeability (LPS, CD14, LPS-binding protein, gut-derived LPS-neutralising IgA antibodies, EndoCAbs) were detected during early AF. A reduced ratio of IgG/IgM EndoCAbs titres indicated chronic endotoxaemia. Collagen turnover biomarkers, which corresponded to the LPS values, suggested an association of gut-derived low-grade endotoxaemia with adverse structural remodelling. The LPS concentrations were higher in FDAF patients who experienced a major adverse cardiovascular event. Conclusions: Intestinal barrier dysfunction and microbial translocation accompany FDAF. Improving gut permeability and low-grade endotoxaemia might be a potential therapeutic approach to reducing the disease progression and cardiovascular complications in FDAF.

The gut microbiota is extremely important for the health of the host across its lifespan. Recent studies have elucidated connections between the gut microbiota and neurological disease and disorders such as depression, anxiety, Alzheimer’s disease (AD), autism, and a host of other brain illnesses. Dysbiosis of the normal gut flora can have negative consequences for humans, especially throughout key periods during our lifespan as the gut microbes change with age in both phenotype and number of bacterial species. Neurologic diseases, mental disorders, and euthymic states are influenced by alterations in the metabolites produced by gut microbial milieu. We introduce a new concept, namely, the mycobiota and microbiota-gut-brain neuroendocrine axis and discuss co-metabolism with emphasis on means to influence or correct disruptions to normal gut flora throughout the lifespan from early development to old age. These changes involve inflammation and involve the permeability of barriers, such as the intestine blood barrier, the blood–brain barrier, and others. The mycobiota and microbiota–gut–brain axis offer new research horizons and represents a great potential target for new therapeutics, including approaches based around inflammatory disruptive process, genetically engineered drug delivery systems, diseased cell culling “kill switches„, phage-like therapies, medicinal chemistry, or microbial parabiosis to name a few.

The gut microbiota is extremely important for the health of the host across its lifespan. Recent studies have elucidated connections between the gut microbiota and neurological disease and disorders such as depression, anxiety, Alzheimer's disease (AD), autism, and a host of other brain illnesses. Dysbiosis of the normal gut flora can have negative consequences for humans, especially throughout key periods during our lifespan as the gut microbes change with age in both phenotype and number of bacterial species. Neurologic diseases, mental disorders, and euthymic states are influenced by alterations in the metabolites produced by gut microbial milieu. We introduce a new concept, namely, the mycobiota and microbiota-gut-brain neuroendocrine axis and discuss co-metabolism with emphasis on means to influence or correct disruptions to normal gut flora throughout the lifespan from early development to old age. These changes involve inflammation and involve the permeability of barriers, such as the intestine blood barrier, the blood–brain barrier, and others. The mycobiota and microbiota–gut–brain axis offer new research horizons and represents a great potential target for new therapeutics, including approaches based around inflammatory disruptive process, genetically engineered drug delivery systems, diseased cell culling "kill switches", phage-like therapies, medicinal chemistry, or microbial parabiosis to name a few. [ABSTRACT FROM AUTHOR]