Gut Microbiota & Immuno-Metabolism

Ecological community of commensal, symbiotic & pathogenic microorganisms found in and on multicellular organisms

location: skin, mouth, nose, lung, digestive tract, vagina

50% of human cells are microbes (half-human in eukaryotic cell composition, have more bacterial genes in the gut than human genes)

2-3 kg of total mass are human-associated microbiota

composition & density evolve through the gastric tract

some evolve & some appear ->changes in pH, anaerobic, nutrient-availability

important to understand gut microbiota-host dialog for promoting health & therapeutic development

bacteria

archae

fungi

viruses

->bacteria most studied up until now

method to study microbiota composition

cultivation tested before genetics but some require very specific environmental factors

extract DNA of tissue (for gut feces used)

sequence 16S ribosomal genes to identify the main phylogenic composition

identify microbial sequences, variants & polymorphisms in the sample

functional community: compare sequences to reference genome/database

->identify genes, pathway & relative frequencies in sample

with NGS/WGS not only 16S but everything

Metatranscriptomics, metaproteomics, metametabolomics (critical for immune function& health)

get function

identify interactions between expressed genes, proteins & metabolic products in sample

Actinobacteria

Bacteroidetes

Firmicutes

Proteobacteria

can be the same but in different proportions between microbiomes

healthy gut microbiota: 90% of gut microbiota belong to firmicutes & bacteroidetes phyla

determined by multiple environmental factors

quality linked to diversity & amount in childhood

delivery procedure: C-section doesn’t provide beneficial vaginal microbiota ->help inoculate digestive tract, compensate by collecting vaginal microbiota

breast-feeding: lots of pre-biotics in maternal blood & skin bacteria of the mother

genetic background

evolves through life & depends on intrinsic & extrinsic pathways

age (host-metabolism, hormonal system), antibiotics (alter gut microbiota), diet, lifestyle (sport/tobacco/alcohol)

prevention of pathogens colonization

dietary fats absorption

innate & adaptive immunity

colonization resistance

intestinal architecture regulation

gut permeability regulation

immune system & barrier function

help to digest, absorb nutrients&produce vitamins

AA synthesis, dietary fats absorption, fat-soluble vitamins absorption, calorie removal, lipid energy metabolism, activation of glucose homeostasis

good microbiota: immunotherapy, vaccination, control of infection

bad microbiota: autoimmunity, allergy, metabolic syndrome

microbiota plays a fundamental role in the induction, education & function of the mammalian immune system

IEC (intraepithelial lymphocytes)

myeloid cells

CD4+ T-cells

ILCs

in the lamina propria

microbiota kept away from epithelial cells by the mucus

Immune activation: pro-inflammatory Th17/Th1 ->protect from infection

B-cell activation: sIgA ->secretory IgA released & helps shape bacterial growth

Immune tolerance: Tregs ->don’t destroy gut tissue & good microbiota

Anti-microbial peptide secretion/tissue repair: REGIIIg &IL-22->control bacterial growth, avoid overgrowth & protection from pathogens

—>produce signals shaping immunity by microbiota

Immune tolerance: contributes to gut tissue protection, prevents auto-immune disease, improves obesity&metabolic syndromes

decreases colon cancer incidence, local & systemic chronic inflammation

immune activation: contributes to gut tissue repair, local formation of synthetic Th17 pool, tonic immunity,

increases cancer immunosurveillance, improves cancer immunotherapy

antimicrobial peptides & sIgA production

directly modulate the immune system

salt: pro-inflammatory

milk-exosaccharides & vitamin D: anti-inflammatory

fiber: prebiotic->not digestible by us, digested/fermented by beneficial bacteria->produce important metabolites like SCFA

SCFA: short chain fatty acids anti-inflammatory (acetate, propriate & bytriate)

vitamin A: converted to retinoid acid->anti-inflammatory

microbial ecosystem imbalance on or inside the body

healthy microbiota (diverse)

pathogen expands

if too much harmful

less diverse/healthy food or antibiotics

due to drugs or diets (no dietary fibers)

often transient ->microbiota highly resilient

colonization neonatal

maturation from perinatal/infant to healthy mature

acute disturbance (transient disturbance) -> diet /antibiotics ->recovery possible

or chronic disturbance (persistent dysbiosis)

partial recovery from transient to persistent dysbiosis

autoimmunity (including T1D)

infections

cancer development

gut-brain-axis (depression, Parkinson, Alzheimer)

->microbiota affect neurological functions ->converts tryptophane in serotonin

metabolic disorders (involved in the digestion process): T2D, obesity, NAFLD (non alcoholic fatty liver disease)

gut barrier integrity

microbiota

immunity

good microbiota: increased mucus production prevents bacteria from getting in contact with the immune system

produced SCFAs ->↑tight junctions, promotes their production & improves gut barrier integrity

Tregs produce anti-inflammatory IL-10

dysbiosis: less mucus & microbiota come closer to epithelium->stimulate the immune system

less fiber->↓SCFAs ->leaky epithelial barrier->translocation of bacterial antigen/LPS

Th1 cells produce proinflammatory IFNg

hyperplasia

↑cell number, adiponectin, insulin sensitivity

↓FFA release, pro-inflammatory cytokines, immune cell recruitment, hypoxia & fibrosis

hypertrophy

↑cell size, FFA release, pro-inflammatory cytokines, immune cell recruitment, hypoxia & fibrosis

↓adiponectin & insulin sensitivity

complication in obesity

ectopic lipid deposition (liver)

NAFLD

insulin resistance

T2D

CVD

inverted ration of bacteroidetes:firmicutes

epithelium: IEC differentiation, tight junction function, intestinal barrier integrity, pathogen colonization & energy harvest, reduced SCFA production

circulatory system: metabolic endotoxemia (LPS) passes gut barrier & goes in blood & infects tissue

liver: lipogenesis, inflammation, oxidative stress, insulin resistance (LPS recognized by TLR4->systemic inflammation)

adipose tissue: inflammation, oxidative stress, macrophage infiltration, insulin resistance

less abundant in obese people & improvement if supplemented

suggests that modulation of microbiota improved metabolic parameters

pilot & prove of concept (but no clinical trials for food supplementation)

increased: glycemia, insulin sensitivity

decreased: insulinemia, insulin resistance, white blood cell count, total cholesterol

leaky gut

adipocyte normally sensitive to insulin

LPS reaches adipocyte & triggers TLR4 ->secretion of pro-inflammatory cytokine IL-6

recruitment of macrophages

IL-6 works autocrine & paracrine ->SOCS3 production

SOCS3 inhibits insulin signaling ->insulin resistance

auto-immunity can also be triggered by microbiota dysbiosis

good microbiota ->T-cell tolerant

increase in bad microbiota ->T-cell activation allows overreaction & tolerance break->T1D

not enough fibers & high fat affects liver->increased inflammation & impaired lipid metabolism

can evolve towards cirrhosis

NAFL: lipogenesis->dyslipidemia, insulin resistance, obesity, metabolic syndrome, T2D

NASH (nonalcoholic steatohepatitis): inflammation-> lipid peroxidation, mitochondrial dysfunction, oxidative stress, apoptosis, pro-inflammatory cytokine activation

cirrhosis: fibrosis->advanced cell damage & scaring (collagen instead of functional cells), tissue destruction can evolve into liver cancer

some bacteria overexpressed & some decreased in comparison to normal

collect stool from healthy & transfer into receiver -> used against Ab-resistant bacteria

under clinical trials in cancer immunotherapy

can be transferred in pills->don’t affect microbiota function

perspectives: development for treatment against multi-drug resistant pathogens

risk evaluation/prevention, indications ->towards standardized therapeutic development

non-digestible food ingredients that beneficially affect the host by selectively stimulating the growth & activity of one species or a limited number of species of bacteria in the colon (oligosaccharides, insulin, fructose oligosaccharides, fiber, fiber supplements)

good bacteria->help its growth with fibers/prebiotics

inhibited by salt

decreased fat mass & increased insulin sensitivity & gut barrier function

some fibers acetogenic ->help generation of acetate (SCFA)

leek

mushrooms

garlic

onions

sweet potato

banana

apples

->decrease of body fat mass, lipid deposition in the liver (NAFLD) & improve insulin resistance

lice micro-organisms that, when administered in adequate amounts, confer a health benefit to the host

Akkermancia muciniphila

faecalibacterium prausnitzii

yogurt

sauerkraut

cheese

beer (display diversified microbiota)

you are what you eat

take care of microbiota