nri.2017.7生态失调与免疫系统

缺乏Toll样受体（TLR）信号适配器的小鼠骨髓分化一级反应蛋白88（MYD88）----分明的肠道微生物群，粘膜相关细菌数量增加以及细菌向肠系膜淋巴结的易位增加

nri.2017.7 Dysbiosis and the immune system

• Types of dysbiosis
  • Bloom of pathobionts
    • Enterobacteriaceae
  • Loss of commensals
    • autism spectrum disorder ----Lactobacillus reuteri, Bacteroides fragilis
    • Clostridium difficile-induced inflammation----Clostridium scindens
  • Loss of diversity
    • alpha diversity
• Oringins of dysbiosis
  • Infection and inflammation
    • mouse models of infection with Citrobacter rodentium and Salmonella enterica subsp. enterica serovar Typhimurium
    • Inflammation induced by dextran sodium sulfate or genetic deficiency of interleukin-10 (Il10) in mice
    • inflammation-induced outgrowth of members of the Enterobacteriaceae family can promote the development of colorectal cancer and sepsis
  • Diet and xenobiotics
    • a low-fibre diet reduces microbial diversity in mice
    • a high-fat diet reduces microbial diversity in mice
    • antibiotics, sweeteners and dietary emulsifiers
  • Genetics
    • A twin study identified the abundance of multiple taxa of the intestinal microbiota influenced by host genetics
    • Genomic studies have identified an impact of host genetics on colonization with particular taxa in mice
    • the genetic influence on microbial composition may be involved in the manifestation of certain phenotypes
      • [eg] Christensenellaceae and low body mass index
  • Familial transmission
    • maternal factors alone do not suffice to explain an individual's microbiota assembly
    • Environmental transmission is additional importance
  • Other causes
    • circadian disruption
    • maternal high-fat diet
    • pregnancy
    • physical injury
• Immune control of microbial homeostasis
  • The innate immune system in the regulation of microbial composition
    • pattern recognition receptors (PRRs)
      • mice deficient in the Toll-like receptor (TLR) signalling adaptor myeloid differentiation primary response protein 88 (MYD88) ----distinct intestinal microbiota, increased numbers of mucosa-associated bacteria and increased translocation of bacteria to the mesenteric lymph nodes
        • flagellin sensor TLR5(-/-) ----alteration of intestinal microbiota leads to the manifestation of hyperphagia, metabolic syndrome, high levels of Enterobacteriaceae
        • Myd88(−/−)mice
      • NOD-like receptors (NLRs)
        • nucleotide-binding oligomerization domain-containing protein 1 (NOD1)(-/-)----bacterial population is expanded (Clostridiales, Bacteroidesspp., segmented filamentous bacteria (SFB) and Enterobacteriaceae)
        • Nod2(−/−)mice---- increased burden of commensals, increased proportion of mucosa-associated bacteria
          • human NOD2 deficiency
        • a failed study----well-designed experimental controls are important
        • NOD-, LRR- and pyrin domain-containing 6 (NLRP6) inflammasome----activating caspase 1， ASC speck formation, maintenaning of a stable microbial community in the intestine
          • deficiency of ASC and caspase 1----dysbiosis
        • α-defensins(-/-)---- normal bacterial numbers, altered microbial composition
        • antimicrobial lectin REGIIIγ (by Paneth cells ): separating the microbiota and the epithelial surface
        • RORγt+ ILCs ( innate lymphoid cells)----producing IL-22
        • T-bet+ ILCs----producing interferon-γ (IFNγ), tumour necrosis factor (TNF); regulating the composition of the microbiota
  • The adaptive immune system in the regulation of microbial composition
    • B cells
      • secretory IgA
    • T follicular helper (TFH) cells
      • programmed cell death protein 1 (PD1)----Regulating Bacterial communities and IgA production
    • Invariant natural killer T (iNKT) cells
      • responding to microbial glycolipids
    • intraepithelial lymphocytes
      • expressing γδ T cell receptors
• Impact of dysbiosis on the host immune system
  • Signalling to innate immunity
    • microbial cell components
      • different immunogenicity of LPS---stimulating TLR4, activating nuclear factor-κB and tolerating endotoxin
      • TLR2
    • metabolites
      • the bile acid conjugate taurine, the amino acid histamine and the polyamine spermine----influencing NLRP6 activity----the secretion of IL-18
      • IL-22
  • Signalling to adaptive immune cells
    • degradation of secretory IgA
• Dysbiosis and immunological diseases
  • IBD
  • Coeliac disease
  • Rheumatoid arthritis
  • T1D
  • Asthma
  • Multiple sclerosis
• Dysbiosis in diagnostics and therapy
  • Diagnostics
    • DNA sequencing for the identification of strains and their genomes, RNA sequencing for the determination of microbial gene activity, metabolome analysis
    • dysbiosis index
    • mucosal samples> luminal faecal samples
    • shotgun metagenomic sequencing, non-targeted metabolomics, microbial biomarkers
    • the diagnostic value of the microbiome may lie in differentiating subtypes of IBD that share common clinical symptoms as well as IBD and other intestinal inflammatory diseases
    • the microbiome as a diagnostic tool reaches far beyond the intestine
      • Parkinson disease
      • Alzheimer disease
  • therapy
    • faecal microbiota transplantation (FMT)
    • antibiotics
    • administration of probiotics
    • dietary prebiotics----personalized diets
    • a shift in the composition of the intestinal microbiota may have positive effects on the host: anticancer drug cyclophosphamide alters the intestinal microbial community----potentiating the anticancer effect of the drug
• Challenges and future avenues
  • [1] appropriate controls for definiting for a microbial ecosystem as dysbiosis
  • [2] the concept of dysbiosis deserves a functional rather than a taxonomic interpretation
  • [3] the extent and manifestation of dysbiosis seem to be highly context dependent. (particular microbial configuration----particular genomic mutation on disease susceptibilty, susceptibility to dysbiosis----host genotype and environmental microbial repertoire)
  • [4] insights into the molecular mechanisms that drive dysbiosis-associated pathologies----'probiotic' and 'postbiotics' intervention
• Abstract: In this Review, we categorize dysbiosis in conceptual terms and provide an overview of immunological associations; the causes and consequences of bacterial dysbiosis, and their involvement in the molecular aetiology of common diseases; and implications for the rational design of new therapeutic approaches. A molecular-level understanding of the origins of dysbiosis, its endogenous and environmental regulatory processes, and its downstream effects may enable us to develop microbiome-targeting therapies for a multitude of common immune-mediated diseases. ([1]changes in lifestyle and environmental factors>gene evolution----abnormal microbiome's composition and function, termed dysbiosis----focusing on bacterial of the gastrointestinal tract----common multifactorial diseases. [2]the healthy intestinal microbial community's characters. [3]the basic definition of dysbiosis is limited:interindividual variability, vertical transmission, housing effects, variations in pathogen screening in animal facilities and other factors, adaptations of the microbiome to altered environmental conditions or changes in the state of the host may be benificial or neutral or harmful----the use of a narrow definition of dysbiosis, namely statistically and functionally.)