GIS13 The Gut Microbiome In Complex Chronic Disease Flashcards
Microbiome vs Microbiota vs Dysbiosis
Microbiome:
- total collection of microbe
- aggregate of All microbial species, their Genomes, and the Ecosystem in which they interact
Microbiota:
- individual microbial species that constitute the microbiome
- formerly known as “the normal flora”
Dysbiosis:
- Imbalances in the **Composition and **Function of Microbiota
- associated with wide range of chronic diseases
Metagenomics
Culture-independent molecular assays
—> analysis of microbial **genomes to identify species and function
—> allow detection of microbes otherwise **cannot be cultured by conventional methods
Human microbiome studies
Understand the role of human microbiome in
- Maintenence of health
- Causation of disease
—> prevent and treat diseases
US human microbiome project (HMP)
European metagenomics of the human intestinal tract (MetaHIT)
HMP: describe composition and diversity of the microbial communities, create integrated dataset of biological properties
MetaHIT: establish association of human gut microbiome with health and disease, esp IBD and obesity
Core microbiome
Common set of microbial species / genes shared by most individuals
HMP: generated a catalogue of ~800 reference genomes from multiple body sites
MetaHIT: 40% of genes were shared by majority of individuals , 99% of genes were of bacterial origin
Variation in composition of microbiome
Considerable inter-individual variation (時地人)
- Anatomical site
- Person: host genetics
- Time: maximum diversity in adolescence, less diverse and less stable in old age
- Environment: diet, antibiotics
Adult gut microbiome
Main phyla:
- ***Firmicutes (gram +ve)
- ***Bacteroidetes (gram -ve)
- mainly ***anaerobes
Where do we get gut microbiota
- Transfer via placenta (almost sterile before birth)
- Vagina, faeces and skin during birth
—> differ by mode of delivery - Early feeding
—> ***breastfed: Bifidobacteria; formula-fed: more Bacteroides / Clostridium spp. - Solid food introduction
—> more like adult microbiome by 2-3 years, can digest wide range of food - Early life exposures
—> antibiotics
Barriers for microbes living in the gut
- Acidic environment
- Saliva and bile
- Immune system
- Attaching to intestinal wall
- Surviving the diet
Upper GI:
- ***highly acidic in stomach
- most gastric microbiota also found in oropharynx
- H pylori negative individuals: diversity of gastric microbiota higher
Small intestine:
- **higher bile concentration and **short transit time
- more challenging environment for microbial colonisers
- mostly ***Facultative Anaerobes
Large intestine:
- neutral to mildly acidic, **low oxygen, **slow flow rate
- largest microbial community in body
- mostly ***Obligate Anaerobes
Metabolic potential of gut microbes
- Metabolism of complex carbohydrates
- digest dietary fibre and ferment into ***short-chain fatty acid - Biotransformation of Bile acids
- Bile acids produced in liver degraded by intestinal bacteria and reabsorbed, completing ***enterohepatic cycle - Metabolism of ***Choline in liver
Impacts on host health
Rats raised in sterile environment have to eat 30% more calories to maintain same weight as rats with normal microbiome
***Gut microbiome function
- ***Digest carbohydrates, protein and fats
- Produce ***nutrients
- Biotin (vit B7), vitamin K - Trains immune system
- short-chain fatty acids (fermented by gut microbe) increase growth of gut epithelial cells and increase growth of ***lymphoid tissue
- immune system fights harmful bacteria but leaves helpful bacteria alone - Stops growth of pathogenic bacteria
- competition
- fermentation make colon ***more acidic: less attractive for bad bacteria - Modifies production of ***neurotransmitter
- Modifies ***drugs during metabolism
Factors influencing gut microbiome
- Antibiotics
- Prebiotics (益生元) / probiotics (益生菌)
- Dietary composition: microbiome respond changes in diet rapidly
- Losing weight
- Possibly other environmental exposures e.g. arsenic
How to identify gut microbiota
- Collect stool sample
- Extract genetic material
- Analyse genetic material
- recognise genetic sequences —> identify types of bacteria, viruses, fungi
- techniques:
—> **Biomarker sequencing (16S rRNA)
—> **Metagenomics (study of microbial genomes)
—> ***Metatranscriptomics (study of gene expression / RNA sequences)
Manipulation of gut microbiota
- Antibiotics
- Prebiotics: food ingredients that confer specific changes in gut microbiome and lead to beneficial effects in the host
- Probiotics: selection of microbes thought to confer benefit to host
- Faecal transplant
- Create germ-free animals then add back specific pathogens
Chronic disease relevance to microbiome
***Correlation is not causation
- Malnutrition
- mice receiving faecal transplant from twin with kwashiorkor lost more weight - Obesity:
- high BMI: higher ratio of Firmicutes to Bacteroides, more bacteria to digest carbohydrates, mice receiving faecal sample from obese human gained more fat mass —> common ground hypothesis: reproduction of distinct disease phenotype through transplantation of the dysbiotic disease-associated gut microbiota to a genetically susceptible rodent host - Diabetes
- Chinese with diabetes: decrease in butyrate-producing bacteria and increase in some opportunistic pathogen (Clostridium spp. and E. coli)
- Caucasians with insulin resistance: increased Lactobacillus and Clostridium spp.
- women received probiotics early in pregnancy show reduced gestational diabetes - Infections
- C. difficile infection: old age, hospitalisation, antibiotic exposure, IBD, chemotherapy —> less diversity of microbiota
- infusion of stool from healthy donor via colonoscopy / mouth —> C. difficile-associated diarrhoea stopped - Auto-immunity / allergy
- IBD: associated with diminished gut microbial diversity and early life antibiotic exposure —> faecal transplantation look promising
- Atopic diseases: childhood acquisition of gastric H. pylori may be associated with lower risk of asthma, child born by C-section may have higher risk of asthma, airway microbiota may be involved in asthma - Cardiovascular disease
- Gut microbiota may be involved in process of atherosclerosis - Cancer
- Fusobacterium numbers may be associated with increased risk of colorectal cancer, possibly through inflammatory mechanism
- Bacteroides may induce colitis and tumourigenesis by stimulating exaggerated immune response through T-helper 17 cells
- Colonic microbiota may affect expression of host genes involved in cell cycle regulation, thus inducing epithelial proliferation - Psychiatric disease
- Microbiota-gut-brain axis: microbiota may have effect on hypothalamic-pituitary-axis, regulating response to stress, digestive function, immune system, mood and emotions
- Higher Firmicutes : Bacteroides ratio in gut associated with irritable bowel syndrome and autism spectrum disorders
- Reduced diversity in gut microbiota associated with depression
Challenges of microbiota study
- Extracting clinical relevance from large amount of microbiome data
- Limited longitudinal and interventional studies so far (most studies under-powered and prone to ***reverse causation)
- Most studied focused primarily on bacterial rather than other species
- Bacterial genome databases remain incomplete (majority of genes have unknown functions)
Future directions
- Confirm causality for chronic disease
- Assess potential unintended consequences
- Find acceptable modes of treatment in human
- Resolved ethical, legal and regulatory issues
- Personalize treatment for humans
