The Role Of Gut Microbiota in Aging And Aging Related Neurodegenerative Disorders: Insights From Drosophila Model Part 2
Aug 23, 2024
The epigenetic mechanism also contributes to the role of microbiota in aging [31]. Epigenetic modifications contain DNA methylation, histone modification (acetylation and methylation), and non-coding RNAs.
In recent years, more and more studies have shown that there is a close relationship between epigenetic mechanisms and memory.
Epigenetic mechanisms refer to the genetic mechanism by which the expression state of genes is passed on to offspring cells through chemical markers, such as methylation and histone modification, without changing the DNA sequence itself. The study of epigenetic mechanisms has laid the foundation for understanding many human diseases and various behavioral manifestations, one of which is memory.
Memory is one of the indispensable abilities in our daily life, which we obtain through learning and experience accumulation. The memory of humans and animals can be affected by epigenetic mechanisms. For example, learning, memory, association, emotional response, and other cognitive processes involve many different types of chemical modification processes.
Epigenetic mechanisms can change neural activity between brain regions by regulating gene transcription activity, thereby affecting memory formation and storage. Studies have shown that some methylation and histone modification enzymes can regulate the expression of memory and learning-related genes. Therefore, in-depth research on epigenetic mechanisms will help us better understand the formation and preservation of memory.
In addition, during the process of memory formation and preservation, the synaptic connection between neurons is significantly enhanced. Epigenetic mechanisms can promote the generation and stabilization of memory synapses by regulating synaptic function. The local methylation state of neurons can also have a profound impact on the internal environment, learning, and evolution of early species.
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The histone demethylase KDM5 is responsible for histone H3K4me3 demethylation and regulates gene expression of transcriptionally active genes [32]. Whole-body or gut-specific disruption of KDM5 damages the intestinal epithelial barrier and decreases the number of species in the gut microbiota.
KDM5 mutant flies demonstrate a much shorter lifespan [33]. KDM5 mutation in Drosophila increases the level of Proteobacteria and decreases the level of Firmicutes.
At the orders level, Sphingomonadales, Enterobacteriales, and Xanthomonadales are dominant while Lactobacillales, Bacteroidales, and Bifidobacteriales are less abundant in KDM5 mutant flies.
Antibiotic treatment augments while probiotic treatment with L. plantarum L168 rescues these phenotypes. RNA sequencing reveals a critical role of KDM5 in the activation of the IMD pathway and the production of downstream factors, including diptericin A (DptA), attacin-B (AttB), and the RE isoform of peptidoglycan recognition protein LC (PGRP-LC-RE) [32].
These studies give evidence that microbiota may be regulated and work together with epigenetic mechanisms in the aging process.
2.4. Antiaging Therapy Targeting Microbiota in Drosophila
In parallel with the research on molecular mechanisms for microbiota in aging, scientists are devoted to identifying antiaging drugs targeting microbiota using the Drosophila model (Table 1).
Carrageenan oligosaccharide (CAO), derived from marine red algae, effectively improved the longevity, motility behavior, and fecundity by increasing the diversity of gut microbiota and the abundance of Commensalibacter in male Drosophila [34].
Agar oligosaccharide (AOS) is a marine prebiotic that promotes longevity and health. In the Drosophila model, AOS not only significantly activates intestinal immune-related IMD pathways but also augments the lifespan and resistance to oxidative stress [35].
AOS significantly decreases the diversity of microbiota in aged Drosophila. Among the dominant microbes in the gut, the abundance of Gluconobacter increases from 28.99% to 69.18% while Lactobacillus and Acetobacter are much lower.
Aqueous furbelow extracts (brown algae, Saccorhiza polyschides) could also increase the species richness of microbiota and extend the lifespan, especially in high-fat and drought diets [36].
Glucomannan hydrolysates (GMH) are derived from the root of the Amorphophallus konjac plant. It is found that GMH extends the lifespan and increases the abundance rather than diversity of Drosophila gut microbiota [37].
Inulin is a fermentable dietary fiber contained in fruits, vegetables, and herbs. Inulin prolongs the lifespan only in male flies by impacting the gut microbiota. Lactobacillaceae is dominant in male flies on the standard diet, while Streptococcaceae is enriched in males fed with inulin [38].
In addition to saccharides, ursolic acid (UA), a natural triterpenoid, is beneficial to the climbing ability and lifespan of males in Drosophila [39]. UA affected the bacterial composition and population distribution of microbiota. Actinobacteria are the phyla demonstrating significant differences in abundance after UA supplementation.
Improved lifespan and locomotion are abolished when Drosophila is raised in axenic conditions, confirming that the antiaging effects of UA rely on gut microbiota. The same observations are also found for lithocholic acid (LCA), the secondary bile acid generated by gut microbiota from primary bile acids. Antibiotics inhibit its beneficial effects on lifespan extension [40].
"What doesn't kill you makes you stronger." Low doses of oxidants treatment at the larval stage, including tert-butyl hydroperoxide (tBH) and paraquat, increase the lifespan of Drosophila [41]. Mechanism study reveals that they decrease the A.
acetic, Komagataeibacter haptics, and Acetobacteraceae rather than Lactobacillus species in the gut. G418, an antibiotic targeting A. aceti and enriching L. plantarum, also promotes longevity.
The beneficial effects could be further transferred to the next generation. Further experiments show that A. acetic activates the IMD pathway and gut dysfunction during aging, which is abolished by tBDH treatment.
In addition to chemical treatment, physical factors such as visible light also influence aging. Treatment with 12 h light and 12 h dark by color-specific LED at the intensity of 600 lx and 100 lx, green light (550 ± 68 nm) rather than blue light (457 ± 30 nm) or red light (675 ± 75 nm) extends the lifespan of Drosophila [42].
Doxycycline (DOX), a chemical that inhibits bacterial load and diversity, abolished the antiaging effects of green light. In the future, noninvasive therapy based on physical stimulation could be developed for aging and aging-related disorders.
Although research into antiaging intervention has been progressing rapidly, it should be noted that several studies only demonstrate alteration of diversity and/or abundance of microbiota in parallel with lifespan extension after treatment [34–38].
Further experiments using axenic culture, antibiotics treatment, and reintroduction of microbial populations should be performed to clarify whether the antiaging effects of these therapeutic methods rely on targeting microbiota.
3. Gut Microbiota in Drosophila AD Model
3.1. Microbiota in Human AD
Alzheimer's disease (AD) is the most prevalent reason for dementia in the old population [43]. The pathological features of AD include amyloid plaque, hyperphosphorylation of tau protein, and neuronal loss [44].
Tau is a microtubule-associated protein and could be hyperphosphorylated in AD patients, which leads to its aggregation into tangles. Amyloid β (Aβ) is derived from sequential processing of APP by BACE and γ secretases.
Overproduction or inadequate clearance of Aβ leads to senile plaque formation. Mutations of APP and PS1/2 are usually found in early-onset familial Alzheimer's disease (FAD). However, as most AD cases are sporadic and late-onset, the etiology is still elusive.
It is reported that 85% of dementia patients have alterations in gut microbiota [45]. The diversity of gut microbiota is decreased significantly in AD patients [46].
The abundance of Bacteroides, Lachnospiraceae, E. rectale Butyrivibrio/Eubacterium/Clostridium Firmicutes, and Bifidobacterium is decreased while the load of Ruminococcus, Actinobacteria, Escherichia/Shigella, O. splanchnicus, Bacteroidetes increases significantly [46–49].
Among them, Escherichia Shigella, Odoribacter splanchnicus, and Klebsiella pneumonia have been proven to be associated with inflammatory states while Butyrivibrio and Eubacterium exert anti-inflammation effects. Increased prevalence of Bacteroides is associated with mild cognitive impairment (MCI) in patients without dementia [50].
Several Drosophila models have been established to clarify the underlying mechanisms for AD, including elav-Gal4; UAS-BACE/UAS-APP model, elav-Gal4; UASAβ42 model, and GMR-Aβ42 model, which facilitates the research on the contribution of microbiota to AD pathogenesis.
3.2. elav-Gal4;UAS-BACE/UAS-APP Model
The elav-Gal4 line pan-neuronally expresses the driver protein Gal4 under the promoter of the elav gene. When they cross with the UAS-BACE/UAS-APP line, the resulting F1 flies with the genotype leave-Gal4; UAS-BACE/UAS-APP produce Aβ in the brain and demonstrate neurodegeneration phenotypes.
Kefir is a natural probiotic drink constituted by Lactobacillus kefiranofaciens (21.96%), Lactobacillus kefiri (0.2%), Acetobacter fabarum (0.17%), Lactococcus lactis (0.004%) and Rickettsiales (0.001%) [51].
Kefir-treated AD like Drosophila demonstrates improved lifespan and climbing ability as compared with the water or milk-treated group. Liquid-liquid partitioning separates Kefir metabolites into four fractions with increasing polarity: hexane (Hex), dichloromethane (DCM), ethyl acetate (EtOAc), and n-butanol (But-OH).
All the fractions improve the climbing ability and AD-like vacuolar lesions while EtOAc (0.5 mg/mL) and ButOH (0.5 mg/mL) fractions extend the lifespan of AD-like Drosophila.
GC–MS analysis identifies 117 compounds shared by all fractions, including short-chain fatty acids (SCFAs) which are downregulated in AD Drosophila and mice. The synbiotic formulation could be obtained by a combination of a probiotic formulation (Lactobacillus plantarum NCIMB 8826 (Lp8826), L. fermentum NCIMB 5221 (Lf5221), and Bifidobacteria longum spp.
infantis NCIMB 702255 (Bi702255)) and with 0.5% of TFLA (polyphenol plant extract from the gastrointestinal tonic Triphala) powder [52].
Synbiotic treatment ameliorates neurodegeneration as measured by survivability, motility, Aβ accumulation, and acetylcholinesterase (ACh) activity fly heads. Mechanism study reveals that synbiotic treatment decreases the expression of Drosophila insulin-like peptide (dip)2, dilp3, and INR and upregulates downstream transcription factor dFOXO in insulin signaling of AD flies.
The upregulation of innate immune factor dual oxidase, IMD, and IMD downstream factors (cytokine-like immune mediator Relish, Attacin A, Diptercin, Defensin) is abolished in AD flies by synbiotic feeding.
Synbiotic treatment also reduces the level of total oxidants, and lipid peroxidation (LPO) and rescues the activity of the ETC complexes. The beneficial effects of synbiotic feeding rely on PPARγ as proved by bisphenol A diglycidyl ether (BADGE), a PPARγ antagonist treatment.
3.3. GMR-Aβ42 Model
When UAS-Aβ42 virgins are crossed with glass multimer reporter-Gal4 (GMR-Gal4) males, the offspring will demonstrate a rough eye phenotype as neurodegeneration. It is widely used in screening assays for AD-associated mechanisms.
Eye malformation of GMR-Aβ42 flies could be reversed prevalently by Lactobacillus sakei Probio65, Lactobacillus paracasei 0291, and Lactobacillus plantarum DR7 (DR7), accompanied by reduced abundance of Wolbachia and increased abundance of Stenotrophomonas and Acetobacter in gut microbiota [53,54].
PICRUSt analysis, a tool to construct predicted functional metagenomes, shows that Wolbachia is positively correlated with neurodegeneration, such as Parkinson's, Huntington's, and Alzheimer's diseases, while Stenotrophomonas and Acetobacter have the opposite effects.
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