Gut Microbiota-Modulated Metabolomic Profiling Shapes the Etiology and Pathogenesis of Autoimmune Diseases
10 Sep 2021-Vol. 9, Iss: 9, pp 1930
TL;DR: In this paper, the authors describe studies on the profiling of gut microbial signatures for the modulation of immunological homeostasis in multiple inflammatory diseases, elucidate their critical roles in the etiology and pathogenesis of autoimmune diseases, and discuss the implications of these findings for these disorders.
Abstract: Autoimmunity is a complex and multifaceted process that contributes to widespread functional decline that affects multiple organs and tissues. The pandemic of autoimmune diseases, which are a global health concern, augments in both the prevalence and incidence of autoimmune diseases, including type 1 diabetes, multiple sclerosis, and rheumatoid arthritis. The development of autoimmune diseases is phenotypically associated with gut microbiota-modulated features at the molecular and cellular levels. The etiology and pathogenesis of autoimmune diseases comprise the alterations of immune systems with the innate and adaptive immune cell infiltration into specific organs and the augmented production of proinflammatory cytokines stimulated by commensal microbiota. However, the relative importance and mechanistic interrelationships between the gut microbial community and the immune system during progression of autoimmune diseases are still not well understood. In this review, we describe studies on the profiling of gut microbial signatures for the modulation of immunological homeostasis in multiple inflammatory diseases, elucidate their critical roles in the etiology and pathogenesis of autoimmune diseases, and discuss the implications of these findings for these disorders. Targeting intestinal microbiome and its metabolomic associations with the phenotype of autoimmunity will enable the progress of developing new therapeutic strategies to counteract microorganism-related immune dysfunction in these autoimmune diseases.
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TL;DR: This study uncovered distinct mechanistic modules that link host and microbiome processes with fatal outcomes to SARS-CoV-2 infection and these features may be useful to identify at risk individuals, but also highlight a role for the microbiome in modifying hyperinflammatory responses to Sars-Cov-2 and other infectious agents.
Abstract: ABSTRACT Protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and associated clinical sequelae requires well-coordinated metabolic and immune responses that limit viral spread and promote recovery of damaged systems. However, the role of the gut microbiota in regulating these responses has not been thoroughly investigated. In order to identify mechanisms underpinning microbiota interactions with host immune and metabolic systems that influence coronavirus disease 2019 (COVID-19) outcomes, we performed a multi-omics analysis on hospitalized COVID-19 patients and compared those with the most severe outcome (i.e. death, n = 41) to those with severe non-fatal disease (n = 89), or mild/moderate disease (n = 42), that recovered. A distinct subset of 8 cytokines (e.g. TSLP) and 140 metabolites (e.g. quinolinate) in sera identified those with a fatal outcome to infection. In addition, elevated levels of multiple pathobionts and lower levels of protective or anti-inflammatory microbes were observed in the fecal microbiome of those with the poorest clinical outcomes. Weighted gene correlation network analysis (WGCNA) identified modules that associated severity-associated cytokines with tryptophan metabolism, coagulation-linked fibrinopeptides, and bile acids with multiple pathobionts, such as Enterococcus. In contrast, less severe clinical outcomes are associated with clusters of anti-inflammatory microbes such as Bifidobacterium or Ruminococcus, short chain fatty acids (SCFAs) and IL-17A. Our study uncovered distinct mechanistic modules that link host and microbiome processes with fatal outcomes to SARS-CoV-2 infection. These features may be useful to identify at risk individuals, but also highlight a role for the microbiome in modifying hyperinflammatory responses to SARS-CoV-2 and other infectious agents.
26 citations
TL;DR: In this article , the authors evaluated changes of diversity, richness, and composition of intestinal microbiota in children with multisystem inflammatory syndrome in children (MIS-C) compared to healthy controls.
Abstract: Microbiota composition may play a role in the development, prognosis, or post-infection of COVID-19. There are studies evaluating the microbiota composition at the time of diagnosis and during the course of COVID-19, especially in adults, while studies in children are limited and no study available in children with multisystem inflammatory syndrome in children (MIS-C). This study was planned to compare intestinal microbiota composition in children diagnosed with MIS-C and acute COVID-19 infection with healthy children. In this prospective multicenter study, 25 children diagnosed with MIS-C, 20 with COVID-19 infection, and 19 healthy children were included. Intestinal microbiota composition was evaluated by 16 s rRNA gene sequencing. We observed changes of diversity, richness, and composition of intestinal microbiota in MIS-C cases compared to COVID-19 cases and in the healthy controls. The Shannon index was higher in the MIS-C group than the healthy controls (p < 0.01). At phylum level, in the MIS-C group, a significantly higher relative abundance of Bacteroidetes and lower abundance of Firmicutes was found compared to the control group. Intestinal microbiota composition changed in MIS-C cases compared to COVID-19 and healthy controls, and Faecalibacterium prausnitzii decreased; Bacteroides uniformis, Bacteroides plebeius, Clostridium ramosum, Eubacterium dolichum, Eggerthella lenta, Bacillus thermoamylovorans, Prevotella tannerae, and Bacteroides coprophilus were dominant in children with MIS-C. At species level, we observed decreased Faecalibacterium prausnitzii, and increased Eubacterium dolichum, Eggerthella lenta, and Bacillus thermoamylovorans in children with MIS-C and increased Bifidobacterium adolescentis and Dorea formicigenerasus in the COVID-19 group. Our study is the first to evaluate the microbiota composition in MIS-C cases. There is a substantial change in the composition of the gut microbiota: (1) reduction of F. prausnitzii in children with MIS-C and COVID-19; (2) an increase of Eggerthella lenta which is related with autoimmunity; and (3) the predominance of E. dolichum is associated with metabolic dysfunctions and obesity in children with MIS-C. Conclusions: Alterations of the intestinal microbiota might be part of pathogenesis of predisposing factor for MIS-C. It would be beneficial to conduct more extensive studies on the cause-effect relationship of these changes in microbiota composition and their effects on long-term prognosis.
12 citations
TL;DR: The ameliorative effects of TFP on RA is revealed through the chemical crosstalk that exists between the gut microbiota and its host, and also further enriches the understandings of the pathogenesis of RA.
Abstract: Twenty-Five Wei’er Tea Pills (TFP), a traditional Tibetan medicine, has shown to have a promising therapeutic effect in patients with Rheumatoid arthritis (RA), as well as being safe. Nonetheless, there have been limited pharmacological studies that have explored this therapeutic option. As gut microbiota has been proven to have a critical role in the pathogenesis of RA, this study aims to explore and reveal relevant ways by which TFP interacts with the chemical crosstalk between the gut microbiome and its host. 16S rRNA sequencing, combined with un-targeted metabolomics, were conducted on collagen-induced arthritis (CIA) rats. CIA model rats treated with TFP showed significant improvement in weight gain, pathological phenomena in joints, as well as decreased serum levels of TNF-α, IL-6 and increased level of IL-4 and IL-10. Significant dysfunction in the gut microbiome and alteration in serum metabolites were observed in CIA model rats, which were restored by TFP treatment. Coherence analysis indicated that TFP modulated the pathways of histidine metabolism, phenylalanine metabolism, alanine, aspartate, glutamate metabolism, amino sugar and nucleotide sugar metabolism owing to the abundances of Lactobacillus, Bacteroides, Prevotellaceae_UCG-001 and Christensenellaceae_R-7_group in the gut microflora. The corresponding metabolites involved L-histidine, histamine, phenylethylamine, asparagine, L-aspartic acid, D-fructose 1-phosphate, D-Mannose 6-phosphate, D-Glucose 6-phosphate, and Glucose 1-phosphate. In conclusion, this study reveals the ameliorative effects of TFP on RA through the chemical crosstalk that exists between the gut microbiota and its host, and also further enriches our understandings of the pathogenesis of RA.
8 citations
TL;DR: In infections occurring in patients with tuberculosis-diabetes or diabetic foot, granulysin, HNP1, H NP2,HNP3, human beta-defensin 2 (HBD2), and cathelicidins are responsible for pathogen clearance.
Abstract: Antimicrobial peptides (AMPs) have recently become widely publicized because they have the potential to function in alternative therapies as “natural” antibiotics, with their main advantage being a broad spectrum of activity. The potential for antimicrobial peptides to treat diabetes mellitus (DM) has been reported. In diabetes mellitus type I (T1D), cathelicidin-related antimicrobial peptide (CRAMP), cathelicidin antimicrobial peptide (CAMP) and mouse-β- defensin 14 (mBD14) are positively affected. Decreased levels of LL-37 and human neutrophil peptide 1-3 (HNP1-3) have been reported in diabetes mellitus type II (T2D) relative to healthy patients. Moreover, AMPs from amphibians and social wasps have antidiabetic effects. In infections occurring in patients with tuberculosis-diabetes or diabetic foot, granulysin, HNP1, HNP2, HNP3, human beta-defensin 2 (HBD2), and cathelicidins are responsible for pathogen clearance. An interesting alternative is also the use of modified M13 bacteriophages containing encapsulated AMPs genes or phagemids.
4 citations
TL;DR: Current progress in integrated genomic data analysis is reviewed, and cases where data integration would lead to significant advances in the authors' ability to predict how the environment may impact on their health are discussed.
Abstract: Epidemiological and associative research from humans and animals identifies correlations between the environment and health impacts. The environment—health inter-relationship is effected through an individual’s underlying genetic variation and mediated by mechanisms that include the changes to gene regulation that are associated with the diversity of phenotypes we exhibit. However, the causal relationships have yet to be established, in part because the associations are reduced to individual interactions and the combinatorial effects are rarely studied. This problem is exacerbated by the fact that our genomes are highly dynamic; they integrate information across multiple levels (from linear sequence, to structural organisation, to temporal variation) each of which is open to and responds to environmental influence. To unravel the complexities of the genomic basis of human disease, and in particular non-communicable diseases that are also influenced by the environment (e.g., obesity, type II diabetes, cancer, multiple sclerosis, some neurodegenerative diseases, inflammatory bowel disease, rheumatoid arthritis) it is imperative that we fully integrate multiple layers of genomic data. Here we review current progress in integrated genomic data analysis, and discuss cases where data integration would lead to significant advances in our ability to predict how the environment may impact on our health. We also outline limitations which should form the basis of future research questions. In so doing, this review will lay the foundations for future research into the impact of the environment on our health.
4 citations
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