Abstract
Parkinson’s disease (PD) is a complicated neurodegenerative disease, characterized by the accumulation of α-synuclein (α-syn) in Lewy bodies and neurites, and massive loss of midbrain dopamine neurons. Increasing evidence suggests that gut microbiota and microbial metabolites are involved in the development of PD. Among these, short-chain fatty acids (SCFAs), the most abundant microbial metabolites, have been proven to play a key role in brain-gut communication. In this review, we analyze the role of SCFAs in the pathology of PD from multiple dimensions and summarize the alterations of SCFAs in PD patients as well as their correlation with motor and non-motor symptoms. Future research should focus on further elucidating the role of SCFAs in neuroinflammation, as well as develo** novel strategies employing SCFAs and their derivatives to treat PD.
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Introduction
Parkinson’s disease (PD) is the second most common neurodegenerative disease in the world, causing huge health and economic burdens on society. According to estimates, the frequency of PD will increase as the population ages and the mortality risk for PD patients has risen by 1.5–2.2 times [1, 126, 127]. In a clinical study, 16S rRNA sequencing was used to analyze the difference in gut microbiota among healthy people, iRBD, and PD patients. It was found that the number of SCFAs-producing bacteria in iRBD patients was not significantly reduced, while recognized or putative SCFAs-producing genera Faecalibacterium, Roseburia, and the Lachnospiraceae ND3007 group were consistently decreased in PD patients. A decrease in SCFAs-producing bacteria may be a prerequisite for the development of PD [128].
Various studies have demonstrated that SCFAs ameliorate sleep disturbance through immune, neural, and endocrine pathways [148]. In addition, the change in fecal SCFAs content cannot be used to evaluate the content of SCFAs in peripheral circulation or tissues. Therefore, the first case-control study on plasma SCFAs in PD patients has attracted the attention of scientists [149]. This study used gas chromatography to measure the plasma concentrations of SCFAs in 38 PD patients and 33 healthy controls. Before adjusting the covariates, no significant differences were found between the concentrations of AA, BA, and PA in PD patients and the control group, but after adjusting the covariates, the concentrations of AA in PD patients were significantly higher than those in the control group. This was speculated to be related to damage to the intestinal barrier and the leakage of intestinal SCFAs. These results indicate that the plasma SCFAs content may not change in parallel with the fecal SCFAs content. There are some limitations in this study, such as the small sample size and the absence of gut microbiological analysis. However, it is the first study to investigate the relationship between plasma SCFAs content and PD and it provided some new ideas. Based on this, Chen et al. investigated the association between the fecal and plasma levels of SCFAs in PD patients [146]. In addition, they analyzed the gut microbiota composition and evaluated its relationship with clinical severity in a large sample of 96 PD patients and 85 healthy controls, making up for the shortcomings of the previous study. Compared with the control group, the feces concentrations of acetate, propionate, and butyrate in PD patients were lower, but the plasma concentrations were higher. Later, Yang et al. reached a similar conclusion and found that the combination of fecal and plasma SCFAs could discriminate PD patients from healthy control subjects [121]. In addition, fecal AA and isobutyric acid in PD patients with constipation were lower compared to those without constipation, but plasma AA and PA were higher. Constipation may increase the permeability of the gut-blood barrier in patients with PD. However, different opinions can be found in other studies. Wu et al. found that serum PA and BA levels in PD patients were lower than those in the control group [150]. The serum PA level was negatively correlated with motor symptoms and Mini-mental State Examination scores and positively correlated with Hamilton Depression Scale scores. Interestingly, some studies also detected SCFAs in the urine and saliva of PD patients and found that BA in urine was elevated, while AA and PA in saliva were elevated [151, 152]. The relevant clinical research results are summarized in Table 2.
In conclusion, the alterations and significance of plasma SCFAs content in PD patients are uncertain. Some other metabolic pathways can produce SCFAs, such as plasma acetate, which can be derived from endogenous products of fatty acid oxidation [160]. Furthermore, SCFAs in plasma cannot directly represent their role in the CNS but are closer to their role in peripheral tissues. Therefore, it is of little significance to simply analyze the content of SCFAs in peripheral blood. We need to jointly analyze the changes of SCFAs in feces and plasma. Most SCFAs originating from the intestine are used for intestinal energy supply and liver metabolism, and only a few SCFAs enter the peripheral circulation. If it is determined that the plasma SCFAs content in PD patients increases and the fecal SCFAs content decreases, it may reflect the increased permeability of the intestinal mucosal barrier or dysfunction of the liver, which causes the “leak” in SCFAs.
Discussion
Due to the significant changes in SCFAs that occur in PD and the protective effect of SCFAs on the nervous system, a number of scholars have proposed the view that alterations in SCFAs are responsible for the pathogenesis of PD. From existing evidence, however, this view is somewhat exaggerated. Changes in SCFAs and SCFAs-producing bacteria are not disease-specific. Reductions in fecal SCFAs can also be observed in IBS, chronic kidney disease, and other neurodegenerative diseases [161,162,163]. In addition, the distribution of SCFAs and their receptors in the brain is relatively low, and there is a lack of strong evidence to prove the direct regulatory effect of SCFAs on specific neurons. In particular, a clear explanation for the causal relationship between SCFAs and specific pathological features of PD such as the loss of dopaminergic neurons and the formation of a Lewy body, is still lacking. Alterations in SCFAs are more likely to be secondary to dysbiosis of gut microbiota in the early stages of PD. The reduction in SCFAs-producing bacteria and destruction of the intestinal barrier leads to a decrease in fecal SCFAs and an increase in plasma SCFAs. This secondary change, in turn, exacerbates intestinal inflammation and systemic immune disorders, as well as damage to the BBB, leading to the infiltration of peripheral immune cells, toxins, and cytokines. A reduction in SCFAs also leads to abnormal brain-gut interaction, indirectly affecting the immune status and neuronal function within the brain. We think it necessary to elucidate the relationship between SCFAs and the aggregation and spread of α-syn in the gut, as both SCFAs deficiency and intestinal α-syn aggregation are early alterations in PD. Their causal relationship is key in proving a direct link between SCFAs and PD.
In addition, it must be emphasized again that the relationship between SCFAs and neuroinflammation requires further clarification. Although we concluded that SCFAs remain predominantly neuroprotective in the presence of intestinal flora, there are studies with contradictory findings. In particular, one study found that oral administration of sodium butyrate to MPTP mice under SPF conditions surprisingly increased neuroinflammation and increased the loss of dopamine neurons [115]. Paradoxical results were also observed in models of Alzheimer’s disease, amyloidosis, and neuropathic pain [95, 164, 165]. Differences in the effect of SCFAs on neuroinflammation are related to many factors, such as microbiological control levels for laboratory animals, the method of administration, mixture or single drug administration, and the drug concentration. Future research should explore the effects of different types and concentrations of SCFAs on the immune function of the brain in both germ-free and conventional environments, and determine the optimal doses and types to promote brain health and immune function. Clarifying the role of SCFAs in the neuroimmune system under physiological conditions is a prerequisite for understanding their effects on neuroinflammation in PD.
To date, there is still no effective treatment for PD, and symptomatic treatment is still the main therapeutic option. Therefore, early diagnosis and treatment are crucial. Early changes in SCFAs combined with other more specific diagnostic aids, such as real-time vibration-induced protein amplification with high sensitivity and specificity for abnormally folded α-syn, can be used to identify fibrillar α-syn in biological fluids [166], as well as in conjunction with early detection of prodromal symptoms, such as RBD, to better diagnose PD at an early stage. Direct injection or oral administration of SCFAs as treatment is unreasonable and unrealistic in clinical practice. Therefore, SCFAs-producing probiotics and prebiotics are very promising alternatives, as they could effectively avoid the absorption of SCFAs in the upper digestive tract, which will better simulate the absorption and action mode of SCFAs in vivo. Prebiotics with specific chemical structures can be selected or designed to achieve an increase in the targeting of SCFAs and SCFAs-producing bacteria in the colon [167]. Many probiotics and prebiotics have been proven to be effective in improving PD by increasing the production of SCFAs. In MPTP mice, oral administration of Bifidobacterium breve CCFM1067 protected the blood-brain and intestinal barriers from damage by improving intestinal microecology and increasing the synthesis of SCFAs [168]. In ASO mice, a prebiotic diet modulated the activation of microglia and motor deficits by altering gut microbiome composition and the content of SCFAs [97]. Synbiotics are compound preparations of probiotics and prebiotics, which can more effectively exert the physiological activity of probiotics. Polymannuronic acid (PM) and Lacticaseibacillus rhamnosus GG (LGG) in combination were found to have much better neuroprotective effects on PD than PM or LGG alone [169], indicating the therapeutic potential of synbiotics in PD. Also worthy of attention are medicinal plants, such as Mucuna pruriens (Mp) and Withania somnifera (Ws), which are rich in crude protein, essential fatty acids, and starch. They not only promote the production of SCFAs, but also have many bioactive components, such as ursolic acid in Mp and chlorogenic acid in Ws, and both showed potent anti-Parkinsonian activity in a toxin-induced Parkinsonian mouse model [100, 170].
Conclusion
In this review, we comprehensively summarize the relationship between SCFAs and PD from pathology to the clinic. Significant alterations in SCFAs are present in patients with PD and are closely associated with motor symptoms and non-motor symptoms. SCFAs affect the pathological progress of PD through multiple dimensions. In the future, more attention should be paid to the diagnostic and therapeutic value of SCFAs for PD. There are still some problems that need to be solved urgently. First, we need to clarify the regulatory mechanism of SCFAs on microglia. Direct central regulation or indirect peripheral regulation? Second, the decrease in fecal SCFAs in PD patients is now a consensus, but the significance and alteration of plasma SCFAs need to be further confirmed, including in other tissues. Third, it is necessary to identify a stable and highly recognized PD model with specific non-motor symptoms to verify the therapeutic potential of SCFAs in non-motor symptoms. Fourth, the value of SCFAs-producing probiotics, prebiotics, and synbiotics in PD deserves further development. Some shortcomings in this review should also be noted. The study of SCFAs-producing bacteria in PD has not been summarized. In addition, we did not focus on the interaction between SCFAs and other metabolites. It is hoped that future research and reviews will add to these aspects.
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Acknowledgements
This review was supported by the Jiangsu Provincial Key R&D Program (BE2018658), Jiangsu Provincial Medical Key Discipline (ZDXK202217), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).
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Duan, WX., Wang, F., Liu, JY. et al. Relationship Between Short-chain Fatty Acids and Parkinson’s Disease: A Review from Pathology to Clinic. Neurosci. Bull. 40, 500–516 (2024). https://doi.org/10.1007/s12264-023-01123-9
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DOI: https://doi.org/10.1007/s12264-023-01123-9