FSB presentation

Analysing implications of the gut microbiome in Alzheimer’s disease and the associated frontier of therapeutic strategies.

FSB presentation:

Freya Sanctuary

index

04. What is the GBA?

06. Gram-negative taxa

05. Model organisms

09. Enzyme intervention?

01. Why AD?

07. Proposed mechanism

11. Conclusions

10. Probiotic intervention?

03. GMB overview

02. AD overview

08. FMT intervention?

12. Questions...

01. Why Ad?

Alzheimer's disease (AD) is a neurodegenerative disease

55 million people with dementia world wide70% of these have ADLeading cause of death in England and Wales in 2022 (11.4%)Estimated costs $1.3 trillion in 2019Costs predicted to reach $2.8 trillion by 2030Psychological toll on relatives & caregiversNo cure despite millions invested in research annually.

Decline to motor skills, memory, language, and behaviour.

• Mitochondrial damage
• Oxidative stress

• Apoptosis

• Microglia activation
• Phagocytosis
• Immune response (chronic)
• Neuroinflammation

consequences:

Molecular basis:

Neurofibrillary tangles are composed of hyperphosphorylated Tau protein.Likely Aβ forms before NFT formation in AD... ...NFT formation occurs in normally ageing people, independent of Aβ plaques.

Characterised by Aβ plaques and neurofibrillary tangles (NFT).Amyloid precursor protein (unknown function) is processed by secretases and peptides Aβ40 and Aβ42 are formed.

02. AD overview

• Digestion & nutrient absorption
• Immune function
• Metabolism & weight
• Mental health
• Inflammation
• Vitamin production
• Drug metabolism

03. GMB overview

Humans have a mutualistic relationship with The gut microbiome (GMB)

Complex and dynamic communityMainly bacteria, but also archaea, fungi, and viruses.Established by 2 years of ageInfluenced by diet, antibiotics, geneticsImpacts physiology- health and disease.

- Anxiety, depression, ASD, Parkinson's

Implicated in many neurological conditionsMicrobial changes, intestinal permeability, sensory afferents, neuroactive molecules, immune responses, etc.

Implicated in neurodegenerative disorders like AD...

- Vagotomised mice (Bravo et al, 2011).

Conceptual channel between the cerebral and enteric NSLikley mediated by the vagus nerve, gut-produced hormones, and microbial metabolites

04. What is the GBA?

"the great abdominal brain" (18th Century)

Fantastic ameanability to genetic modificationConservation of key pathways and regulatorsHomologs to 70% of human disease genes.Relatively simple gut microbial compositionSerotonergic cluster afferent to the gut; functional similarity to vagus nerve.Behavioural changes easily measured.

Flies

05. model organisms

Mirror human gut anatomyMicrobial composition is similarComprehensive understanding of mice geneticsAvailability of many mouse modelsMammalian brainCan generate germ-free mice or microbiome depeleted miceBehavioural changes are easy to measure.

Mice

05. model organisms

Hseih and Chian (2023)

DptA improved learning performance

AttA reduces Aβ accumulation in brain

Intestinal AttA reduces oxidative stress in gut and brain

• Improved lifespan
• Reversal of learning deficits
• Reduced Aβ accumulation in the brain
• Reduced ROS in the gut and brain
• Improved gut integrity.

Upregulating AMPs that target gram-negative bacteria reduced AD pathologies - Attacin-A (AttA) and Dpitercin-A (DptA)Used an anti-gram-negative antibiotic to corroborate results.Can conclude a pathological correlation to gram-negative bacteria.

• Flies = Immune deficiency (IMD)
• Mammals = Toll-like receptor

06. Gram-negative bacteria

Anti-microbial peptides are found in the gut and brain of AD patients

AMPs defend against pathogenic microbes.Pathway responsible for AMP synthesis is conserved in across metazoa = NFkB

Dysregulated gram-negative bacteria in the gut results in oxidative stressIntestinal AMPs are relevant for mediating disease

Data are represented as mean ± SEM.Two-way ANOVA followed by multiple comparisons

Apramycin reduces Aβ-induced oxidative stress in the gut but not brain.

Hseih and Chian (2023)

Apramycin improved learning performance

Used an antibiotic against gram-negative bacteria to corroborate results (Apramycin)

06. Gram-negative bacteria

(Chen et al, 2022)

(Xia et al, 2023)

Treatment with these metabolites recapitulated results generated by B. fragilis = increased C/EBPβ expression, strong microglia activation, increased Aβ deposition, increased Aβ42 production, increased proinflammatory cytokines, cognitive deficits

• Widespread Aβ deposition,
• Significant elevation of Aβ42 in the brain
• Tau accumulation in the hippocampus
• Significant synapse reduction
• Cognitive deficit.

By COX1/2 to form PUFA metabolites = 12-HHTrE and PGE2

• Exposure of Bacteroides fragilis lead to AD-like pathology

• Increased C/EBPβ expression and strong microglia activation

• Also enhanced the metabolism of Arachidonic acid (AA)

Express this pathway in mice neurons (Thy1-C/EBPβ)...

07. a proposed mechanism

gram-negative taxa activates transcription factors

Studies show that the AD GMB stimulates a pathway called C/EBPβ/AEP = activates expression of AEP (γ-secretase) = responsible for cleavage of APP and Tau

Cycle of neuroinflammation...

C/EBPβ is activated by pro-inflammatory cytokines and also controls COX enzyme expression.In turn AA metabolism is upregulated; increasing PUFA metabolites 12-HHTrE and PGE2. Feedback to activate more microglia and exacerbating neuroinflammation.

(Xia et al, 2023)

Treatment with these metabolites recapitulated results generated by B. fragilis = increased C/EBPβ expression, strong microglia activation, increased Aβ deposition, increased Aβ42 production, increased proinflammatory cytokines, cognitive deficits

Suggesting gram-negative bacteria exerts C/EBPβ/AEP signalling and microglia activation by 12-HHTrE and PGE2.

07. a proposed mechanism

Interventions...

What are the potential therapies for AD that utilise our developing knowledge on the GMB?

20+ years of researching potential targets of the amyloid cascade has been fruitless

Enzymes

FMT

Probiotics

• Cognitive improvement
• Reduced Aβ deposition and Tau phosphorylation in the brain
• Decreased pro-inflammatory markers and neuroinflammation

(Sun et al, 2019)

• Transplanting faecal matter from a wt donor to AD-model mice.
• Reversed changes to the GMB composition
• Relieved AD pathology

• Sun's AD-mice had decreased Bacteroidetes populations then reversed by FMT; this phylum is typically abundant in AD and its members contribute to AD pathology...
• Variability of results between individuals
• Reports of immune deficiencies following FMT
• Side-effects?

Considerations

Already succesfully used in GI disorders (Eg- Chrohn's disease), and also used in research to study effects of a dysregulated GMB in wt animals.

08. FMT intervention?

Faecal microbiota transplant (FMT) is able to modulate the GMB..

Disrupted lipid homeostasis is implicated in AD...

(Menden et al, 2022)

• Candida rugosa lipase (CRL) treatment is able to alter GMB composition, reduce microgliosis, and improve learning performance.

• Preventing the increase in elevation of unsaturated fatty acids seen in untreated AD-models.

• FMT into GMB-depleted mice showed memory improvement when AD-model faecal donor was treated with CRL

The lipase activity increased the variety of fatty acids... 1- Altering the GBM to normalise levels of fatty acids thereby decreasing oxidative stress and gliosis2- Stimulating vagal signalling via enteric afferents projecting to the brain causing reprogramming of microglia

???

Enzyme replacement therapy is widely used to treat symptoms of late-stage chronic pancreatitis- likely by altering GMB composition. (Nishiyama et al, 2018)

09. Enzyme intervention?

Prevented increased number of activated microglia, neurodegeneration, cognitive decline, Aβ deposition

Considerations.

• Mechanisms of actions not understood
• Founded on correlative research
• Human GMB is more complex than any model
• Side effects?

(Huang et al, 2021)

• Use of probiotic called Lactobacillus plantarum PS128

• Used AD-models + diabetogenic toxin that accelerates AD progression

• Half the models were treated with PS128 and the development of pathologies was measured.

• Was able to prevent AD-pathologies seen in untreated AD models

10. probiotic intervention?

= deeper probiotic research is needed to properly evaluate its therapeutic potential.

• The microbiome mediates many physiological aspects
• AD pathologies are correlated with gram-negative bacteria
• How the microbiome actions its affects is largely unknown
• Many factors within AD pathology- issue of causality
• One proposed mechanism for the microbiome in AD involves activation of signalling molecules and microglia

• Recent years have produced potential therapeutic avenues in research- need mechanistic detail before clinical appliation may be considered.

11. Conclusions

Microbiome research for neurodegenerative disorders represents a cutting-edge side of biology.

Questions?

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