Novel Insights into the Interaction between Enteropathogenic Bacteria, Pyroptosis and IBD.

Inflammatory bowel disease (IBD) is a chronic and recurrent inflammatory disease of the intestinal tract. The complex pathophysiological mechanisms of IBD include genetic susceptibility, environmental factors, and abnormal immune response of the gut microbiota. Gut microbiota forms a metabolic organ that contributes to human health by performing various physiological functions. The development of IBD is closely linked to the imbalance of gut microbiota. In IBD patients, this imbalance is mainly characterized by an increased abundance of pro-inflammatory microorganisms, specifically enteropathogenic bacteria. Pyroptosis is a form of programmed cell death that can be initiated by microbial infection or host factors. It occurs mostly after intracellular infection with bacteria or pathogens. Other than cell death, its primary effect is to release inflammatory mediators that trigger an inflammatory response in the host. Pyroptosis is an important component of innate immunity and can protect against intracellular risk factors via the inflammatory response. However, excessive activation can cause disease. Previous studies of IBD have indicated a complex relationship between gut microbiota and pyroptosis. Some enteropathogenic bacteria can activate the host's immune system to clear infected cells. This inhibits the proliferation of enteropathogenic bacteria by inducing pyroptosis and restoring the balance of gut microbiota. However, the initial inflammatory response and damage to the integrity of the intestinal barrier are crucial factors that elicit the onset of IBD and favor its progression. This review summarizes research on the role of several common enteropathogenic bacteria in the development of IBD through their induction of host cell pyroptosis. A better understanding of the complex interactions between gut microbiota and pyroptosis should lead to the identification of new targets and treatment options for IBD.

Pyroptosis in the Initiation and Progression of Atherosclerosis.

Pyroptosis, a newly discovered form of programmed cell death, is characterized by cell swelling, the protrusion of large bubbles from the plasma membrane and cell lysis. This death pathway is mediated by the pore formation of gasdermin D (GSDMD), which is activated by human caspase-1/caspase-4/caspase-5 (or mouse caspase-1/caspase11), and followed with the releasing of both cell contents and proinflammatory cytokines. Pyroptosis was initially found to function as an innate immune effector mechanism to facilitate host defense against pathogenic microorganisms, and subsequent studies revealed that pyroptosis also plays an eventful role in inflammatory immune diseases and tumor resistance. Recent studies have also shown that pyroptosis is involved in the initiation, the progression and complications of atherosclerosis. Here, we provide an overview of the role of pyroptosis in atherosclerosis by focusing on three important participating cells: ECs, macrophages, and SMCs. In addition, we also summarized drugs and stimuli that regulate the progression of atherosclerosis by influencing cell pyroptosis.

Gene variations in autism spectrum disorder are associated with alteration of gut microbiota, metabolites and cytokines.

The genetic variations and dysbiosis of gut microbiota are associated with ASD. However, the role of the microbiota in the etiology of ASD in terms of host genetic susceptibility remains unclear. This study aims to systematically explore the interplay between host genetic variation and gut microbiota in ASD children. Whole-exon sequencing was applied to 26 ASD children and 26 matched controls to identify the single nucleotide variations (SNVs) in ASD. Our previous study revealed alteration in gut microbiota and disorder of metabolism activity in ASD for this cohort. Systematic bioinformatic analyses were further performed to identify associations between SNVs and gut microbiota, as well as their metabolites. The ASD SNVs were significantly enriched in genes associated with innate immune response, protein glycosylation process, and retrograde axonal transport. These SNVs were also correlated with the microbiome composition and a broad aspect of microbial functions, especially metabolism. Additionally, the abundance of metabolites involved in the metabolic network of neurotransmitters was inferred to be causally related to specific SNVs and microbes. Furthermore, our data suggested that the interaction of host genetics and gut microbes may play a crucial role in the immune and metabolism homeostasis of ASD. This study may provide valuable clues to investigate the interaction of host genetic variations and gut microbiota in the pathogenesis of ASD.

Alteration in gut microbiota is associated with dysregulation of cytokines and glucocorticoid therapy in systemic lupus erythematosus.

A growing corpus of evidence implicates the involvement of the commensal microbiota and immune cytokines in the initiation and progression of systemic lupus erythematosus (SLE). Glucocorticoids have been widely used in the treatment of SLE patients, however, glucocorticoid treatment carries a higher risk of other diseases. Using the 16S rRNA technique, we investigated the differences between the gut microbiota associated with the immune cytokines of SLE and relevant glucocorticoid treatment in a female cohort of 20 healthy control subjects (HC), 17 subjects with SLE (SLE-G), and 20 SLE patients having undergone glucocorticoid treatment (SLE+G). We observed that the diversity and structure of the microbial community in SLE+G patients were significantly changed compared to that of SLE-G patients, whereas the gut microbial community of the SLE+G group showed a similarity with the HC group, which implicate that the shift in the gut microbiome could represent a return to homeostasis. Furthermore, the up-regulations of immune cytokines in SLE-G were identified as closely related to gut dysbiosis, which indicates that the overrepresented genera in SLE patients may play roles in regulating expression level of these immune cytokines. This associated analysis of gut microbiota, glucocorticoid therapy, and immune factors might provide novel and insightful clues revealing the pathogenesis of SLE patients.

Altered gut microbial profile is associated with abnormal metabolism activity of Autism Spectrum Disorder.

Autism Spectrum Disorder (ASD) is a severe neurodevelopmental disorder. To enhance the understanding of the gut microbiota structure in ASD children at different ages as well as the relationship between gut microbiota and fecal metabolites, we first used the 16S rRNA sequencing to evaluate the gut microbial population in a cohort of 143 children aged 2-13 years old. We found that the α-diversity of ASD group showed no significant change with age, while the TD group showed increased α-diversity with age, which indicates that the compositional development of the gut microbiota in ASD varies at different ages in ways that are not consistent with TD group. Recent studies have shown that chronic constipation is one of the most commonly obvious gastrointestinal (GI) symptoms along with ASD core symptoms. To further investigate the potential interaction effects between ASD and GI symptoms, the 30 C-ASD and their aged-matched TD were picked out to perform metagenomics analysis. We observed that C-ASD group displayed decreased diversity, depletion of species of Sutterella, Prevotella, and Bacteroides as well as dysregulation of associated metabolism activities, which may involve in the pathogenesis of C-ASD. Consistent with metagenomic analysis, liquid chromatography-mass spectrometry (LC/MS) revealed some of the differential metabolites between C-ASD and TD group were involved in the metabolic network of neurotransmitters including serotonin, dopamine, histidine, and GABA. Furthermore, we found these differences in metabolites were associated with altered abundance of specific bacteria. The study suggested possible future modalities for ASD intervention through targeting the specific bacteria associated with neurotransmitter metabolism.

Alteration in gut microbiota associated with hepatitis B and non-hepatitis virus related hepatocellular carcinoma.

BACKGROUND: The onset of hepatocellular carcinoma (HCC) ranked fifth malignancies all over the world. Increasing evidences showed that the distribution of HCC was related to the incidence of chronic hepatitis B virus (HBV) infection and other factors, such as alcoholism, aflatoxin B1 ingestion and obesity. Recent studies demonstrated that gut dysbiosis plays an important role in liver diseases. However, the researches on gut microbiota of HBV and non-HBV non-HCV related HCC have not been reported. In this study, we investigated the differences between the gut microbiota of HBV related HCC (B-HCC) and non-HBV non-HCV related HCC (NBNC-HCC), finally found some potential bacteria, linking different pathological mechanism of both types of HCCs. RESULTS: We carried out 16S rRNA analyses in a cohort of 33 healthy controls, 35 individuals with HBV related HCC (B-HCC) and 22 individuals with non-HBV non-HCV (NBNC) related HCC (NBNC-HCC). We found that the species richness of fecal microbiota of B-HCC patients was much higher than other two groups. Interestingly, the feces of NBNC-HCC patients harbored more potential pro-inflammatory bacteria (Escherichia-Shigella, Enterococcus) and reduced levels of Faecalibacterium, Ruminococcus, Ruminoclostridium which results in decrease potential of anti-inflammatory short-chain fatty acids. The feces of NBNC-HCC patients had relatively fewer abundance of multiple biological pathways related to amino acid and glucose metabolism, but high level of transport and secretion in some types. However, the B-HCC patients had opposite results of bacterial composition and associated multiple biological pathways versus NBNC-HCC patients. Meanwhile, we found that aberrant network of gut microbiota occurred differently in B-HCC and NBNC-HCC patients. CONCLUSIONS: Our study indicated that B-HCC and NBNC-HCC patients showed differential abundance of bacteria involved in different functions or biological pathways. We suggested the modification of specific gut microbiota may provide the therapeutic benefit for B-HCC and NBNC-HCC.