What is the microbiome?

• Definitions

Organisms + genetic material + metabolites | | Microbiota | All the living organisms in the microbiome |

• Location: Mostly in the gut, but also:

  • Skin
  • Upper respiratory tract
  • Genitals

  Assume talking about gut unless state otherwise

• How big:

  • 30 Trillion (at least as many microbiota as human body cells)
  • Genome: 150x bacterial vs human genes
  • (& most of our 3Gb is identical): i.e. significant source of inter-individual phenotypic variability

• Evidence for shared evolutionary history – direct interface with human extra-cell & intra-cell pathways; mitochondria are most striking example (true endosymbionts)

The Microbiome as an organ system

• Effect on the host: Produce bioactive molecules:

  • Directly (i.e. microbial products) or;
  • Indirect (i.e. affect host production of molecules)

  Act locally (mainly gut lumen & mucosal cells) but also at a distance (gut-brain, gut-genital, gut-lung axes!)

• 4 main groups of bioactives:

  • Short chain fatty acids (made by fermenting dietary fibre)
    • e.g. butyrate: Functions as antiinflammatory & maintains metabolic homeostasis
  • Hormones (gut mucosa’s production influenced by microbiota): insulin, ghrelin, GLP1.
  • Neurotransmitters: dopamine, serotonin, GABA
  • Vitamins: B3, B6, B12, folate, vitamin K

• Function of these molecules: regulation of metabolism & inflammation

• Metabolism

  • Normal function: SCFAs, bile acids, endocannabinoids etc. interface directly with GPCR pathways —> Effects on glucose homeostasis, satiety, low oxidative/NO pathways
  • Dysregulation – opposite!

• Immunity / inflammation

  • Normal function: Help maintain mucosal barrier integrity/tight junctions, antimicrobial peptides, maintains shift to tolerogenic immune balance, especially in childhood.
  • Dysregulation:
    • Commensals replaced by pathobionts,
    • Increased PAMPs & TLR signalling, shift from tolerogenic to pro-inflammatory state
    • Increased gut permeability —> low level endotoxaemia —> distant effects

Associations with disease

• Loads of association studies: strongest links metabolism/inflammation:
  • Obesity
  • Diabetes
  • IBD
  • Bowel cancer
  • Allergies inc. asthma
  • Cardiovascular disease
• Really difficult to quantify the exact risk, as depends on how you define “abnormal microbiome”
  • Easier to measure association between clinical outcome & factors known to alter microbiome (e.g. antibiotics, formula milk, C-section)
  • But then issue of association/causation… for all we know that ‘abnormal’ microbiome is fighting against/in response to the disease state in question…
• More recent research tries to establish causality:
  • Inflammation seems to be common effector pathway
  • Animal models of disease induction:
    • Uses germ-free/Microbiome-deplete mice (NB: Also done in pigs, zebra fish, drosophila etc.).
    • Transfer phenotypes to mice by FMT from diseased mouse (or human)
    • Restore healthy phenotype by FMT from healthy mouse
    • In some models, disease phenotype is heritable in mouse pups (through early life microbiome programming)
    • Lots of disease models (e.g. airway hypersensitivity, gut inflammation, malignancies)
• Human interventional studies
  • Clostridioides difficile & Faecal Microbiota Transplant (FMT):
  • Not only is gut microbiome signal in C diff profoundly different to healthy, but FMT is the most effective treatment!
    • Vanc/fidaxo treat vegetative phase (but not spore germination, vs bezlo & FMT), & can exacerbate dysbiosis; 30% recurrence after 1 episode, 50% after 2nd
    • Rebyota - >70% efficacy in Phase III, FDA approved
  • IBD / IBS: FMT data strongest