The Role Of Gut Microbiota in Aging And Aging Related Neurodegenerative Disorders: Insights From Drosophila Model Part 3

3.4. elav-Gal4;UAS-Aβ42 Model

AD like Drosophila models could also be established by directly expressing Aβ42 in a pan-neuronal manner. Our group has found that microbiota diversity increased dramatically with Aβ42 overexpression [55]. 

In recent years, research has found that the fruit fly model has made significant contributions to memory. Although we cannot deny that its experimental methods are somewhat cruel, scientists have explored how the body acquires and stores information by killing fruit flies and interfering with their senses such as vision, smell, and movement. These research results have been very important in promoting human cognitive science.

Through fruit fly experiments, researchers have revealed the connection between memory and genes and the nervous system and deepened our understanding of the mechanism of human memory formation. For example, by stimulating the fruit fly olfactory system, researchers have successfully discovered neurons related to short-term memory. These findings have important physiological and pathological guiding significance and provide new ideas for the treatment of human-related diseases.

At the same time, these research results also provide a reliable platform for model-based drug development. According to relevant studies, some neurons of fruit flies are particularly critical. If these neurons are interfered with by substances, the therapeutic effect of human diseases can be significantly improved.

Therefore, while actively exploring the fruit fly model, we must also follow relevant ethical and legal regulations to minimize harm to experimental animals. In the end, we believe that under the protection of reasonable ethics and laws, the fruit fly model will still make greater contributions to understanding human memory and treating human diseases. It can be seen that we need to improve memory, and Cistanche can significantly improve memory because it has antioxidant, anti-inflammatory, and anti-aging effects, which can help reduce oxidation and inflammatory reactions in the brain, thereby protecting the health of the nervous system. In addition, Cistanche can also promote the growth and repair of nerve cells, thereby enhancing the connectivity and function of neural networks. These effects can help improve memory, learning ability, and thinking speed, and can also prevent the occurrence of cognitive dysfunction and neurodegenerative diseases.

Click Know to improve short-term memory

As the dominant bacteria in the gut, the proportions of Acetobacteraceae and Lactobacillacea at the family level while Acetobacter and Lactobacillus at the genus level decrease dramatically in AD Drosophila. 

GC–MS reveals acetate is the most abundant SCFA and decreases dramatically in the AD group. Consistently, the level of SCFAs including acetate decreases significantly in fecal samples from pre-onset amnestic mild cognitive impairment (aMCI) and is further reduced more dramatically in AD patients [56]. Nagpal et al. report slightly decreased fecal acetate and propionate in mild cognitive impairment (MCI) patients [57]. 

Intragastric administration acetate rescues cognitive impairments and microglia activation in AD (APP/PS1) mice [58]. It should be noted that another study finds that there is no significant difference between acetate and propionate with decreased butyrate in the fecal samples of AD mice [59]. 

SCFAs have also been reported to be reduced in GF AD (APP/PS1) mice. SCFA supplementation increases Aβ plaque, plaque-associated microglia recruitment, and less intracellular Aβ in microglia [60]. 

Further experiments are required to clarify the role of SCFAs and other microbiota metabolites in AD pathogenesis. Enteric dysbiosis could be induced by oral infection with nonpathogenic enterobacteria (Ecc15) in adult flies [61]. 

The dysbiosis augments AD-like phenotypes in Drosophila expression Aβ42 in the brain without affecting the gut barrier, including declined lifespan, climbing ability, and increased neuronal loss. 

Enteric infection promotes the upregulation of the Drosophila TNF eiger and downstream JNK activity as well as the production of AMPs (Dpt, Drs, AttA, and CecA1) and ROS. 

The ROS-induced recruitment of plasmatocytes, functional macrophages in Drosophila, is increased in the brain of AD flies and triggers the TNF-JNK pathway after enteric dysbiosis. This work further highlights the essential role of microbiota-mediated gut-brain crosstalk in AD pathogenesis.

4. Gut Microbiota in Drosophila PD Model

4.1. Microbiota in Human PD

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder affecting the elderly population [62]. Its predominant pathological features are the death of dopaminergic (DA) neurons in the substantia nigra pars compacta and intraneuronal accumulations of Lewy bodies. 

The gut microbiota is altered in PD patients [63]. The abundance of Prevotellaceae, Blautia, Coprococcus, Roseburia, Faecalibacterium, and Prevotella decreased while Enterobacteriaceae, E. coli, Ralstonia, Lactobacillus, Bifidobacterium, Verrucomicrobiaceae, Bacteroides, Parabacteroides, Akkermansia, Butyricimonas, Veillonella, Odoribacter, Mucispirillum, and Bilophila increase in the gut microbiota of PD patients [63–67]. 

A subsequent increase in gut permeability could also be found [64]. Among the decreased microbial organisms, the genera of Blautia, Coprococcus, and Roseburia could produce anti-inflammatory butyrate [65]. 

The abundance of Bacteroides is decreased in PD patients with tremors compared to those without this symptom, indicating that the severity of PD correlates with microbiota alteration [67]. SCFAs are significantly downregulated in the gut of PD patients, exerting profound effects on inflammation and gut barrier damage in PD progression [68].

4.2. elav- Gal4;UAS-Synuclein Model

As the main component of Lewy bodies, α-synuclein contributes to PD by aggregation into insoluble filaments. Multiplication or mutation (A53T, A30P, or E46K) of α-synuclein is found in familial forms of PD patients [62]. 

The virgin elavC155-GAL4 line is crossed to UAS-α-synucleinA53T males to make the F1 offspring express A53T α-synuclein in the brain as a PD model. Treatment with phenolic acid metabolites, including 3-HBA, 3,4-diHBA, and 3-HPPA, inhibits the formation of α-synuclein dimers and trimers in vitro and improves the climbing ability of PD flies in vivo [69]. B. 

ovatus was able to convert flavanols catechin and epicatechin (C/EC) into DHCA, 3,4-diHBA, and 3-HBA. Additionally, B. ovatus, E. 

Atlanta and E. coli are also able to generate DHCA, 3-HPPA, 3,4-diHBA, and 3-HBA through a C/EC-independent process. This study reveals that gut microbiota potentially modulates dietary flavanols to protect against PD pathogenesis.

4.3. PINK1 Mutant Model

Mitochondria function-related genes, including the Parkin, DJ-1, and PTEN-induced putative kinase 1 (PINK1), are identified as PD-associated genes. PINK1 is a nucleus-encoded gene and is targeted to mitochondria. 

Animal models with PINK mutation demonstrate fragmented mitochondrial cristae, sensitive to oxidative stress, accompanied by locomotion defects and DA neuron loss. Drosophila PINK1 mutants (PINK1B9) demonstrate reduced lifespan, climbing and flight defects, degenerated flight muscle, and loss of DA neurons in the PPL1 region, which could be rescued by EGCG supplement [70]. 

The decreased microbiota diversity is also rescued by EGCG in PINK1B9 flies. EGCG decreases Proteobacteria and increases Firmicutes and Bacteroidetes at the phylum level in PD flies. 

As the dominant genus in the Drosophila microbiota, the abundance of Acetobacter and Lactobacillus is inhibited after EGCG treatment in PINK1B9 flies. Gut microbial alteration induced by Lactobacillus plantarum KJ01 strain blunts the EGCG-mediated rescue effect on the fly locomotion in genetic PD model (PINK1B9 flies) and genetic × environmental model (rotenone-exposed PINK1B9 flies). 

This study proposes the key function of microbiota in the neuroprotective role of EGCG in PD.

5. Conclusions and Future Perspective

It should be noted that most of the studies mentioned above were performed either in female [20,22,27,32,33,37,39,55,69] or male [21,24–26,28,29,34,35,41,52,53,61,70] models. It has been found that the abundance of A. 

pasteurianus, L. plantarum, and L. fructivorans alter similarly both in aged male and female Drosophila [71]. However, both w 1118 and canton S female flies harbor more Enterococcus, which may interfere with the colonization of Acetobacter and Lactobacillus during aging. 

Accordingly, female flies live much longer than males both in low yeast and high yeast medium [72]. Males also demonstrate more aging-dependent DA neuron loss and locomotion defects [73]. 

Further investigation is required to validate whether microbiota contributes to the sex-dependent difference in aging and neurodegeneration. With the advantages of simple microbial community composition, Drosophila is a powerful tool to clarify the contribution of microbiota to aging and aging-related neurodegeneration. 

Aging-induced alteration of microbiota before gut damage, could act on various signaling pathways via metabolites and exert beneficial or detrimental effects on longevity and neurodegeneration (Figure 1). 

Intervention strategies targeting Drosophila microbiota either by chemical or physical treatment have been developed to improve healthy aging. Many findings from Drosophila have been proven to be highly conserved in mammals, further validating the value of this model in aging and neurodegeneration-related microbiota research.

Author Contributions: Conceptualization, Y.K.; writing-original draft preparation, Y.K., and L.W.; writing-review and editing, Y.K. and B.J.; project administration, Y.K.; funding acquisition, Y.K. All authors have read and agreed to the published version of the manuscript.

Funding: This research was funded by the National Natural Science Foundation of China, grant number 31200804; the Fundamental Research Funds for the Central Universities, Southeast University Ministry of Education, China, grant number. 2242020K40127; the Key Laboratory for Experimental Teratology of the Ministry of Education, Shandong University.

Institutional Review Board Statement: Not applicable.

Informed Consent Statement: Not applicable.

Data Availability Statement: Not applicable.

Acknowledgments: We thank our colleagues at SEU for their helpful suggestions.

Conflicts of Interest: The authors declare no conflict of interest.

References

1. López-Otín, C.; Blasco, M.A.; Partridge, L.; Serrano, M.; Kroemer, G. The Hallmarks of Aging. Cell 2013, 153, 1194–1217. [CrossRef] 

2. Bartels, T.; De Schepper, S.; Hong, S. Microglia modulate neurodegeneration in Alzheimer's and Parkinson's diseases. Science 2020, 370, 66–69. [CrossRef] 

3. Kim, S.; Jazwinski, S.M. The Gut Microbiota and Healthy Aging: A Mini-Review. Gerontology 2018, 64, 513–520. [CrossRef] 

4. Erkosar, B.; Leulier, F. Transient adult microbiota, gut homeostasis, and longevity: Novel insights from the Drosophila model. FEBS Lett. 2014, 588, 4250–4257. [CrossRef] 

5. Bana, B.; Cabreiro, F. The Microbiome and Aging. Annu. Rev. Genet. 2019, 53, 239–261. [CrossRef] 

6. McGurk, L.; Berson, A.; Bonini, N.M. Drosophila as an In Vivo Model for Human Neurodegenerative Disease. Genetics 2015, 201, 377–402. [CrossRef] 

7. Piper, M.D.W.; Partridge, L. Drosophila as a model for aging. Biochim. Biophys. Acta (BBA)-Mol. Basis Dis. 2018, 1864, 2707–2717. [CrossRef] 

8. Shin, S.C.; Kim, S.-H.; You, H.; Kim, B.; Kim, A.C.; Lee, K.-A.; Yoon, J.-H.; Ryu, J.-H.; Lee, W.-J. Drosophila Microbiome Modulates Host Developmental and Metabolic Homeostasis via Insulin Signaling. Science 2011, 334, 670–674. [CrossRef] [PubMed] 

9. Storelli, G.; Defaye, A.; Erkosar, B.; Hols, P.; Royet, J.; Leulier, F. Lactobacillus plantarum Promotes Drosophila Systemic Growth by Modulating Hormonal Signals through TOR-Dependent Nutrient Sensing. Cell Metab. 2011, 14, 403–414. [CrossRef] [PubMed] 

10. Schwarzer, M.; Makki, K.; Storelli, G.; Machuca-Gayet, I.; Srutkova, D.; Hermanova, P.; Martino, M.E.; Balmand, S.; Hudcovic, T.; Heddi, A.; et al. Lactobacillus plantarum strain maintains the growth of infant mice during chronic undernutrition. Science 2016, 351, 854–857. [CrossRef] [PubMed] 

11. Yatsunenko, T.; Rey, F.E.; Manary, M.; Trehan, I.; Dominguez-Bello, M.G.; Contreras, M.; Magris, M.; Hidalgo, G.; Baldassano, R.N.; Anokhin, A.; et al. The human gut microbiome is viewed across age and geography. Nature 2012, 486, 222–227. [CrossRef] [PubMed] 

12. Ragonnaud, E.; Biragyn, A. Gut microbiota as the key controllers of "healthy" aging of elderly people. Immun. Aging 2021, 18, 1–11. [CrossRef] [PubMed]

For more information:1950477648nn@gmail.com