L25- gut microbiome and ageing

microbiome definition

the genome of all the microorganisms (bacteria, archea, viruses and fungi), symbiotic and pathogenic, living in and on all vertebrates.

where in the body has the greatest density of bacteria

the gut has highest density on the planet

• healthy human gut can house at least 1000 different species of bacteria, the majority belonging to Bacteroidetes and Firmicutes

• Gut microbiome is genetically more complex than the human genome- and more dynamic; 316 million different genes

what are the benefits of the gut microbiome

1. protection against pathogens

2. synthesis of vitamins

3. immune system development

4. promotion of intestinal angiogenesis

5. promotion of fat storage

6. SCFA production by fermentation of dietary fibre

7. modulation of central nervous system

what are some conditions linked to dysbiosis

1. Obesity: Firmicutes prevalent, lower diversity. Probiotics (Lactobacillus, Bifidobacterium lactis) may help regulate

2. Type 2 diabetes

3. Irritable bowel syndrome (IBS)

4. Cardiovascular diseases caused by proinflammatory metabolites

5. may also correlate to ageing

what SCFAs

short chain fatty acids

(acetate, propionate, butyrate) are products of anaerobic fermentation of dietary fiber and resistant starch, and to a lesser extent of proteins.

what are the 3 roles of SCFAs (8)

1. provide energy substrate for colonocytes and hepatocytes

2. contribute to intestinal barrier integrity by upregulating the expression of tight junction proteins and mucus production

3. Immuno-effects: protect against inflammation (by inducing regulatory T-cell differentiation and IL secretion). Butyrate turns macrophages into super-killers

4. reduce the risk of colorectal cancer

5. increase insulin secretion by beta-pancreatic cells

6. effects on DNA homeostasis in the nuclei of gut and brain cells, by inhibiting a histone deacetylase (HDAC)

7. Regulate skeletal muscle metabolism and function

8. Modulate the central nervous system (CNS)

what us the brain gut connection

vagus nerve carries signals between brain, heart and gut

• CNS affects the gut motility, secretion, blood flow, nociception and immune function, which in turn affect the microbiome

Gut has peristaltic movement to push forward, initiated by vagus nerve 

What are the main pathways of the gut–brain axis?

• Neural: vagus nerve

• Hormonal: GLP-1, PYY

• Immune: interleukins

• Metabolic: SCFAs (acetate, propionate, butyrate)

• Key idea:
  Gut microbiota communicate with the brain via multiple systems

How does the gut–brain axis affect brain function?

• Key signals:

  • GLP-1 → insulin

  • PYY → satiety

  • Serotonin → mood/cognition

  • GABA → inhibitory

• Effects on brain:

  • Neurons, microglia, astrocytes, BBB

  • Inflammation & cognition

• Key idea:
  Gut health influences brain health; insulin spikes/metabolic dysfunction can be harmful

what is the possible relationship between SCFA/CNS and autism

• propionate has negative effects in mice (abnormal, repetitive behaviour, decreased social interaction)

• butyrate has beneficial ones (restores social interaction)

• dysbiosis (altered gut microbiome) in autistic children may increase toxic metabolite production (phenols, indols-derivates, p-cresols) and cytokine-mediated inflammation

what is the possible relationship between SCFA/CNS and depression

butyrate has beneficial effects (restores social interaction)

what is the possible relationship between SCFA/CNS and alzheimer’s disease

butyrate has beneficial effect by disrupting the interaction between amyloid-beta peptides

what is the possible relationship between SCFA/CNS and parkinson disease

butyrate prevents aggregation of alpha-synuclein (unfolded protein that accumulates in clumps called Lewy bodies)

how can the gut brain connection be studies

• Mice under germ free (GF, lack microbiome) vs specific pathogen free (SPF) housing conditions

• Young (6-10 weeks) vs old (96-104 weeks)

• Gene expressions (RNA sequencing) → Age-dependent “transcriptomic signature”- strongest

• changes in genes involved in cytoskeleton, immune function and mitochondrial function

• Old SPF vs GF differences in microglia: upregulation of ROS-promoting genes and ROS-response

• genes. ROS levels and mitochondrial function-ATP production

• Metabolomics: examine metabolites in serum, brain and faeces.

• Gut permeability, Fecal matter transfer from old/young mice into germ free mice

what is CML

N(6)-carboxymethyllysine metabolite is generated through oxidation and glycation of proteins. Elevated in certain diseases (AD) and ageing.

what microglia

a type of neuroglia (glial cell) located throughout the brain and spinal cord (10-15% of cells). The resident macrophage cells, the first and main form of active immune defence in the CNS;

how does CML leakage affect microglia in old mice

• Critical involvement of CML in oxidative stress and Mitochondrial disfunction of microglia of old mice

• Egress of CML from the gut (rather than oral CML) is Required for the harmful impact

• The gut microbiome changes with age and plays a key role in leakage from the aged gut

• Important role in microglia aging and presumably CNS aging

what are the 2 types of starch

1. rapidly digested starch

2. resistant starch

prebiotics

what is rapidly digested starch

(especially amyloidose, the branched starch) are reduced to glucose in the small intestine

what is resistant starch

(starch molecules, especially amylose, form crystalline regions that are resistant to digestion by our own enzymes). Similarly to dietary fibre, it is one of the best sources of SCFAs.

what are raw legumes, why are they good

a source of resistant starch

(beans, pulses, lentils) are very high in amylose (up to 40% of the total starch, or 30% of the dry weight). Boiling legumes reduces the resistant starch (RS) to only 4- 5% of their DW. Cooling o/n may increase the RS slightly.

what are the 2 types of fibre

1. soluble fibre

2. insoluble fibre

prebiotics

what is soluble fibre

• gelatinous texture (jama)

• has demulcent properties that protect the stomach (gastritic, heartburn)

• helps treat constipation and reduce cholesterol

what is insoluble fibre

• dry texture (wheat bran)

• it satisfies the appetite and has a laxative effect (obesity)

• reduces cholesterol

• contained in whole grains, nuts and seeds

what are some features of irritable bowel syndrome (IBS)

• 10% of elderly are affected

• strong genetic component

• begins in young adults

• symptoms (abdominal pain and cramps, bloating, diarrhea or constipation

what are some features of inflammatory bowel disease (IBD)

Crohn’s disease, Ulcerative colitis):

• Helicobacter hepaticus

• early and late onset (10-15% diagn. at >60 years of age, especially for colitis)

• elderly more at risk of complications, including venous trombosis

describe infection with Clostridium difficile

• anaerob, lives in soil

• 5% people are carrier

• risk factors: hospital stay, oral antibiotics, compromised immune system, age > 65 years

what are some features gastrointestinal cancer

Helicobacter pilori

-1:100 risk over lifetime

-age >65 years

what are some features colorectal cancer

-1: 24 risk over lifetime

- age >70 years

how does the intestinal epithelium act as a firewall

• The intestinal epithelium forms a protective barrier maintaining gut homeostasis

• Interacts with microbiota, metabolites, and immune responses (inflammation)

• With ageing:

  • Altered microbiota + ↑ inflammation

  • Reduced stem cell function → poorer repair

  • Increased cellular senescence

→ Overall: barrier integrity declines (“leaky gut”) → systemic inflammation and disease risk

Increased permeability of the ageing gut — what changes occur?

• Normal: tight epithelial barrier prevents leakage from lumen

• Ageing:

  • Disrupted tight junctions

  • Epithelial cell damage/loss (enterocytes)

  • Impaired stem cell regeneration

• Result:

  • Bacteria/toxins leak across barrier (“leaky gut”)

  • Local + systemic inflammation increases

→ Contributes to ageing-related diseases and overall decline

what aerobes are found in the gut

Bacteroides, Firmicutes, Prevotella, Ruminococcus

• prevent the overgrowth of harmful bacteria by competing for nutrients and attachment sites to the mucus membranes of the gut

what anaerobes are found in the gut

Peptostreptococcus, Bifidobacterium, Lactobacillus, and Clostridium

• prevent the overgrowth of harmful bacteria by competing for nutrients and attachment sites to the mucus membranes of the gut

how does the composition of the gut change throughout ageing

• Young adults in the same geographical area have relatively similar gut microbiomes

• From the mid age, their microbiome appear to progressively change, acquiring an “unique” signature in old age.

• The more their microbiome have changed, the healthier the individual appeared in old age

how does the microbiome of older people in poorer health produce

The microbiome of elderly people in poorer health (more medication, higher cholesterol and triglycerides, lower levels of vitamin D, less active, could not walk too fast) appeared to have changed less from the mid age, and was associated with significantly decreased survival in the course of a 4-year follow-up!

How do age-related changes in diet and microbiota affect the gut barrier?

• In ageing: ↓ dietary fibre, ↑ processed food

• When fibre is low: Bacteroides switch to feeding on the mucus layer

• Mucus layer = protective barrier lining the gut

• Result: thinning of mucus → weakened barrier

What are the downstream consequences of a weakened gut barrier in ageing?

• Reduced barrier → microbes trigger immune response

• Persistent activation → chronic inflammation

• Chronic inflammation contributes to:

  • Heart disease

  • Diabetes

  • Cancer

  • Osteoarthritis

→ Key idea: Microbes that were beneficial earlier can become harmful in old age

Phenol metabolites in ageing — what do they indicate?

• Phenols (e.g. p-cresol, phenylacetylglutamine) = gut bacterial products (from phenylalanine/tyrosine)

• Associated with increased frailty in elderly (long-term care residents)

• BUT phenylacetylglutamine also ↑ in centenarians & long-lived mice
  → Role is complex/context-dependent

Indole metabolites in ageing — effects?

• Indoles (from tryptophan metabolism) associated with:

  • Improved physical function in older adults

• Reduced in obese individuals

• Experimental evidence:

  • ↓ liver inflammation

  • Protect against colitis

→ Generally protective/beneficial metabolites

How can gut inflammation in the elderly be alleviated?

1. Diet changes: ↑ fibre, probiotics, complex carbs, polyphenols

2. Fecal microbiota transplant (FMT): beneficial effects

3. Oral SCFAs and other metabolites

4. Immune modulation:

   • Anti-TNF

   • Anti-IL-23

   • Regulatory T-cell therapies

Risks/limitations of microbiome-based therapies (e.g. FMT)?

• May expand antibiotic resistance genes via horizontal transfer

• Growth of beneficial microbes may produce metabolites that support pathobionts

→ Interventions must be carefully controlled

whera are phenols and indoles from

• Phenols = gut bacterial products of phenylalanine & tyrosine

• Indoles = gut bacterial products of tryptophan (measured in plasma

→ Key idea: Different amino acid-derived metabolites have distinct (context-dependent) effects on ageing and inflammation