by Lewis Chang, PhD
Not all heroes are muscle-bound and wear capes. There is a tiny, almost invisible, hero that lives in our gut and promotes our health and wellbeing. Its name, Akkermansia muciniphila, may be a mouthful, but it’s time to get to know this hero better, as its health-promoting effects have earned it the reputation as a next-generation beneficial bacteria.1

​Gut health is intricately connected to human health in ways that surprise us. Our gut is home to trillions of bacteria, fungi, and other microorganisms that form a complex ecosystem known as the gut microbiome. A healthy gut microbiome promotes proper digestion, strengthens our immune system to fight off infections and diseases, helps regulate our metabolism and weight, and influences our mood and brain function. On the other hand, an imbalance in the gut microbiome can lead to various health issues, including digestive problems like bloating, diarrhea, and constipation. It can also weaken our immune system, making us more susceptible to infections and inflammation.2 Additionally, an imbalanced gut microbiome has been linked to conditions such as obesity, metabolic disorders, mental health disorders, and autoimmune diseases.

Enter Akkermansia muciniphila and why it’s a guardian of our gut
The layer of mucus in our gut acts as a natural defence barrier, crucial for keeping our intestines healthy. Akkermansia muciniphila, unlike many of the known probiotic species in the gut, is unique for living inside the mucus layer, where it can interact closely with intestinal epithelial and immune cells. It feeds on mucins (key components of mucus) and produces beneficial substances called short-chain fatty acids (SCFAs), which have anti-inflammatory and antioxidant properties, improve insulin sensitivity, and help regulate appetite.3 Numerous studies have uncovered actions of Akkermansia muciniphila in the gut. For example:

• It enhances mucin production by increasing the number and density of goblet cells (mucin-producing cells), which helps restore the thickness of the mucus layer.4
• It enhances the integrity of the intestinal lining by boosting the expression of proteins that strengthen the tight junctions between cells.5
• One of its membrane proteins, Amuc_1100, interacts with toll-like receptor 2 (TLR2), triggering anti-inflammatory pathways and preventing the passage of harmful substances (such as lipopolysaccharides (LPS)).6
• The short-chain fatty acid (SCFA) acetate produced by Akkermansia muciniphila supports the growth of other beneficial bacteria, such as Faecalibacterium prausnitzii, which is known for producing another beneficial SCFA, butyrate.7 

It is believed that through reinforcing gut barrier function, Akkermansia muciniphila supports various bodily functions, such as energy, lipid and glucose metabolism, as well as immune responses.1

The connection between Akkermansia muciniphila and metabolic health
Akkermansia muciniphilia, has garnered significant attention due to its relative abundance.  The reason behind this growing interest lies in the compelling links observed between low levels of this species and various health conditions, including obesity, type 2 diabetes, high blood pressure, and liver diseases.9-14

Conversely, when Akkermansia muciniphila is more abundant in the gut, it tends to be associated with a healthier body weight, less body fat, and better insulin sensitivity.9,15 Furthermore, animal studies have shown Akkermansia muciniphila reverses metabolic disorders, weight gain caused by a high-fat diet, metabolic endotoxemia, inflammation in fat tissues, and insulin resistance.8

Given the correlation between abundance of Akkermansia muciniphila and health status, efforts have been made to restore and promote abundance of Akkermansia muciniphila, such as increasing intake of polyphenol-rich foods (e.g., EGCG),16,17 supplementing selected probiotic strains,18,19 and exercise.20 This unique species is now available in supplemental form, allowing a direct route to augment Akkermansia muciniphila abundance.

In a clinical study conducted by Patrice Cani, PhD, Willam de Vos, PhD and their colleagues, they examined the health-promoting potential of this microbe in people who were overweight or obese and had insulin-resistance.21 Thirty-two volunteers received either placebo (inactive medicine), live Akkermansia muciniphila (10 billion CFU/day), or pasteurized Akkermansia muciniphila (30 billion total fluorescent unit (TFU)/day) for three months and were asked not to change their diet and exercise habits. At the end of study, researchers found supplementation with Akkermansia muciniphila to be safe and well-tolerated and demonstrated improvements in metabolic syndrome risk factors, such as total cholesterol and insulin resistance, as well as body weight, fat mass, and hip circumference. Importantly, the pasteurized (heat-inactivated) form of Akkermansia muciniphila, not the live form, improved insulin resistance and reduced insulinemia and total cholesterol, as well as parameters elevated in obesity and glucose intolerance (i.e., white blood cell counts) and inflammation (i.e., LPS). These findings suggest the pasteurized form of Akkermansia muciniphila is more effective for addressing metabolic syndrome risk factors.21

Who can benefit from Akkermansia muciniphila supplementation?
The unique attributes of this tiny hero, Akkermansia muciniphila, has gained its recognition as a valuable player in gut and metabolic health.1 While a balanced diet and regular exercise are the cornerstones for maintaining healthy weight and minimizing metabolic syndrome risks, this next-generation bacteria, pasteurized Akkermansia muciniphila, offers a novel solution to support metabolic health in those who are overweight or obese.

Citations

1. Cani PD et al. Akkermansia muciniphila: paradigm for next-generation beneficial microorganisms. Nat Rev Gastroenterol Hepatol. 2022;19:625-637.
2. Cani PD. Gut microbiota – at the intersection of everything? Nat Rev Gastroenterol Hepatol. 2017;14(6):321-322.
3. Derrien M et al. Akkermansia muciniphila gen. nov., sp. nov., a human intestinal mucin-degrading bacterium. Int J Syst Evol Microbiol. 2004;54(Pt 5):1469-1476.
4. Zhu L et al. Akkermansia muciniphila protects intestinal mucosa from damage caused by S. pullorum by initiating proliferation of intestinal epithelium. Vet Res. 2020;51(1):34.
5. Ottman N et al. Pili-like proteins of Akkermansia muciniphila modulate host immune responses and gut barrier function. PLoS One. 2017;12(3):e0173004.
6. Plovier H et al. A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice. Nat Med. 2017;23(1):107-113.
7. Lopez-Siles M et al. Alterations in the abundance and co-occurrence of Akkermansia muciniphila and Faecalibacterium prausnitzii in the colonic mucosa of inflammatory bowel disease subjects. Front Cell Infect Microbiol. 2018;8:281.
8. Everard A et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci U S A. 2013;110(22):9066-9071.
9. Dao MC et al. Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology. Gut. 2016;65(3):426-436.
10. Yassour M et al. Sub-clinical detection of gut microbial biomarkers of obesity and type 2 diabetes. Genome Med. 2016;8(1):17.
11. Zhang X et al. Human gut microbiota changes reveal the progression of glucose intolerance. PLoS One. 2013;8(8):e71108.
12. Li J et al. Gut microbiota dysbiosis contributes to the development of hypertension. Microbiome. 2017;5(1):14.
13. Grander C et al. Recovery of ethanol-induced Akkermansia muciniphila depletion ameliorates alcoholic liver disease. Gut. 2018;67(5):891-901.
14. Png CW et al. Mucolytic bacteria with increased prevalence in IBD mucosa augment in vitro utilization of mucin by other bacteria. Am J Gastroenterol. 2010;105(11):2420-2428.
15. Fruge AD et al. Fecal Akkermansia muciniphila is associated with body composition and microbiota diversity in overweight and obese women with breast cancer participating in a presurgical weight loss trial. J Acad Nutr Diet. 2020;120(4):650-659.
16. Zhu L et al. Berberine treatment increases Akkermansia in the gut and improves high-fat diet-induced atherosclerosis in Apoe(-/-) mice. Atherosclerosis. 2018;268:117-126.
17. Jeong HW et al. Green tea encourages growth of Akkermansia muciniphila. J Med Food. 2020;23(8):841-851.
18. Ryan JJ et al. Short-term tolerability, safety, and gut microbial composition responses to a multi-strain probiotic supplement: an open-label study in healthy adults. Integr Med (Encinitas). 2021;20(1):24-34.
19. Hibberd AA et al. Probiotic or synbiotic alters the gut microbiota and metabolism in a randomised controlled trial of weight management in overweight adults. Benef Microbes. 2018:1-16.
20. Munukka E et al. Six-week endurance exercise alters gut metagenome that is not reflected in systemic metabolism in over-weight women. Front Microbiol. 2018;9:2323.
21. Depommier C et al. Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study. Nat Med. 2019;25(7):1096-1103.

by Noelle Patno, PhD

Introduction

Recent findings show that not only respiratory disease but also hypertension and diabetes are prevalent comorbidities associated with COVID-19 infection.1 In fact, multiple meta-analyses indicate that individuals with high blood pressure, diabetes, or cardiovascular diseases have a higher risk for the COVID-19 disease.2–4 Metabolic disease and the immune response to infections are closely tied together in the gut, from which digestion and defense originate, as the oral route into the intestine is one major way that the body encounters food and foreign substances through the intestine. Key microbial species in the intestinal microbiome have been associated with both metabolic disorders and immunological responses.

One key popular species, Akkermansia muciniphila, has been observed at higher levels in the intestinal microbiome to be associated with better metabolic health as well as being related to inflammatory and immune mechanisms for overall immune health. The species is reduced in microbiomes of the obese5,6 and those with glucose regulation impairment,7 type 2 diabetes,5,6 as well as high blood pressure.8 In addition, A. muciniphila levels are significantly lower in samples from inflammatory bowel disease (IBD) patients9,10 and are protective in preclinical models against progression of colitis,11 including the promotion of wound healing in the intestinal mucosa,12 which is needed to heal ulcerated tissue in IBD. Thus, A. muciniphila may be a key species for microbiome therapy to support intestinal metabolic and immune responses.

What does research suggest?
Research suggests that A. muciniphila participates in mechanisms that improve immune response related to metabolism. Higher endotoxin levels and the serum inflammatory marker high-sensitivity C-reactive protein (hs-CRP) are associated with significantly lower levels of A. muciniphila in nonalcoholic steatohepatitis patients.13 Animal models have shown how A. muciniphila affects glucose metabolism through underlying inflammatory response modulation, specifically, the immune system cytokine interferon gamma (IFN-y).14 Recently, A. muciniphila has been shown to induce the intestinal immune response specifically through T cell responses in mice.15 Glucose metabolism and inflammation become dysregulated during cancer as well, another situation in which A. muciniphila levels are relevant. Specifically, A. muciniphila increases the response against tumor growth during anti-PD-1 immunotherapy in cancer patients.16 Multiple studies now have shown that higher A. muciniphila is associated with beneficial response during cancer treatment.17

In an in vitro study with peripheral blood mononuclear cells (PBMCs), components from A. muciniphila modulated the cytokine response,18 suggesting that it could balance the gut ecosystem, which may be involved in how the host would respond to cytokine storm, an uncontrolled release of proinflammatory cytokines.19 Compared to other bacteria in the study, A. muciniphila’s induction was shown to be lower in inflammatory potential compared to other studied microbes.18 Many other in vitro and preclinical studies have demonstrated that the bacteria also induces anti- or proinflammatory responses depending on the context of the situation, and overall, A. muciniphila shows a protective role in intestinal immunity.20 One key preclinical study21 suggested that a certain threshold of A. muciniphila was likely protective for these intestinal barrier effects to support intestinal immune responses.

To therapeutically increase A. muciniphila in the intestine, dietary modifications have demonstrated some efficacy. A healthy lifestyle approach, including dietary modification and fiber increases, has been beneficial.22 Metformin treatment in diabetes has resulted in an increase in A. muciniphila.23,24  Multiple supplementary strategies have been explored in preclinical research to increase A. muciniphila.20 Use of probiotics to modulate A. muciniphila is an emerging area of research. One clinical trial showed that daily consumption of 10 billion CFU of probiotic Bifidobacterium lactis B420 resulted in higher levels of A. muciniphila in the gut in a large scale, randomized, placebo-controlled trial.25 In that same probiotic supplementation trial, probiotic B420 consumption was associated with a reduction in caloric intake, maintenance of body weight, and a reduction in waist circumference, while the placebo group gained weight during the six-month trial.26 Thus, the B. lactis B420 probiotic supplementation trial associated A. muciniphila increases with beneficial metabolic effects as well.  

Conclusion
Higher levels of A. muciniphila in stool samples are associated with better metabolic profiles as well as underlying immune mechanisms, while lower levels are associated with metabolic diseases and inflammatory bowel diseases. Thus, increasing this beneficial bacteria may be an approach to reduce the risk of negative health outcomes in diabetic, obese, and hypertensive patients who are also more susceptible to immunological insults.
Citations

1. Yang J et al. Prevalence of comorbidities and its effects in coronavirus disease 2019 patients: A systematic review and meta-analysis. International Journal of Infectious Diseases. 2020;94:91-95.
2. Wang B et al. Does comorbidity increase the risk of patients with COVID-19: evidence from meta-analysis. Aging (Albany NY). 2020;12(7):6049-6057.
3. Emami A et al. Prevalence of underlying diseases in hospitalized patients with COVID-19: a systematic review and meta-analysis. Arch Acad Emerg Med. 2020;8(1). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7096724/. Accessed April 27, 2020.
4. Li B et al. Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China. Clin Res Cardiol. 2020:1-8.
5. Dao MC et al. Akkermansia muciniphila and improved metabolic health during a dietary intervention in obesity: relationship with gut microbiome richness and ecology. Gut. 2016;65(3):426-436.
6. Yassour M et al. Sub-clinical detection of gut microbial biomarkers of obesity and type 2 diabetes. Genome Med. 2016;8.
7. Zhang X et al. Human gut microbiota changes reveal the progression of glucose intolerance. PLoS One. 2013;8(8):e71108.
8. Sun S et al. Gut microbiota composition and blood pressure. Hypertension. 2019;73(5):998-1006.
9. Png CW et al. Mucolytic bacteria with increased prevalence in IBD mucosa augment in vitro utilization of mucin by other bacteria. Am J Gastroenterol. 2010;105(11):2420-2428.
10. Rajilić-Stojanović M et al. Phylogenetic analysis of dysbiosis in ulcerative colitis during remission. Inflamm Bowel Dis. 2013;19(3):481-488.
11. Kang C et al. Extracellular vesicles derived from gut microbiota, especially Akkermansia muciniphila, protect the progression of dextran sulfate sodium-induced colitis. PLoS One. 2013;8(10):e76520.
12. Alam A et al. The microenvironment of injured murine gut elicits a local pro-restitutive microbiota. Nat Microbiol. 2016;1:15021.
13. Ozkul C et al. Determination of certain bacterial groups in gut microbiota and endotoxin levels in patients with nonalcoholic steatohepatitis. Turk J Gastroenterol. 2017;28(5):361-369.
14. Greer RL et al. Akkermansia muciniphila mediates negative effects of IFNγ on glucose metabolism. Nat Commun. 2016;7:13329.
15. Ansaldo E et al. Akkermansia muciniphila induces intestinal adaptive immune responses during homeostasis. Science. 2019;364(6446):1179-1184.
16. Routy B et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018;359(6371):91-97.
17. Zhang T et al. Akkermansia muciniphila is a promising probiotic. Microb Biotechnol. 2019;12(6):1109-1125.
18. Ottman N et al. Pili-like proteins of Akkermansia muciniphila modulate host immune responses and gut barrier function. PLoS One. 2017;12(3):e0173004.
19. Tisoncik JR et al. Into the eye of the cytokine storm. Microbiol Mol Biol Rev. 2012;76(1):16-32.
20. Xu Y et al. Function of Akkermansia muciniphila in obesity: Interactions with lipid metabolism, immune response and gut systems. Front Microbiol. 2020;11:219.
21. Schneeberger M et al. Akkermansia muciniphila inversely correlates with the onset of inflammation, altered adipose tissue metabolism and metabolic disorders during obesity in mice. Sci Rep. 2015;5:16643.
22. Verhoog S et al. Dietary factors and modulation of bacteria strains of Akkermansia muciniphila and Faecalibacterium prausnitzii: A systematic review. Nutrients. 2019;11(7):1565.
23. de la Cuesta-Zuluaga J et al. Metformin is associated with higher relative abundance of mucin-degrading akkermansia muciniphila and several short-chain fatty acid-producing microbiota in the gut. Diabetes Care. 2017;40(1):54-62.
24. Lee H et al. Modulation of the gut microbiota by metformin improves metabolic profiles in aged obese mice. Gut Microbes. 2018;9(2):155-165.
25. Hibberd AA et al. Probiotic or synbiotic alters the gut microbiota and metabolism in a randomised controlled trial of weight management in overweight adults. Benef Microbes. 2019;10(2):121-135.
26. Stenman LK et al. Probiotic with or without fiber controls body fat mass, associated with serum zonulin, in overweight and obese adults—randomized controlled trial. EBioMedicine. 2016;13:190-200.

By Monazza Ahmad, B.Pharm, MSc

In the fascinating world of our microbiome, there is one bacterium that has been making waves, and that is Akkermansia muciniphila. 
Among the trillions of bacteria residing in our body (yes, that's 10 times more than our own cells!), this particular species has caught the attention of researchers and health enthusiasts alike. Discovered about 20 years ago, A. muciniphila has been continuously showing promising results in promoting healthier gut lining and overall wellbeing.1*
You might wonder, don't all good bacteria do that? What sets A. muciniphila apart? Let's explore the unique attributes of this remarkable bacterium and discover how you can increase its levels to unlock its outstanding health benefits.* 

Uncovering Akkermansia muciniphila and the secret to its success
A. muciniphila is quite a unique character on the stage of the bacterial world. It thrives in areas with limited oxygen supply, making it particularly adept at flourishing even in tissues that have less oxygen supply.2

A. muciniphila does not follow the same dietary rules as its bacterial counterparts. While many bacteria rely on fiber for growth, A. muciniphila doesn't need it to survive. It can thrive on its own, without the need for any additional nutrients to reproduce.

Originating from Greek, muciniphila translates to “mucin-loving.” And true to its name, this bacterium resides in the mucus lining of our intestines, where it finds its energy source—mucin. By feasting on mucin, it encourages our epithelial cells to produce even more of it. What's so special about mucin? Mucin is a molecule that lubricates the gut lining, playing a crucial role in strengthening the walls of our gut against allergens and debris.*

Unveiling the impact of A. muciniphila on the microbial community
Here is another interesting fact about Akkermansia muciniphila: It turns mucin into something incredibly beneficial for our gut health—short-chain fatty acids (SCFAs), such as butyrate, which can be used as food by other friendly bacteria in our body. This quality makes A. muciniphila a “cross-feeder.” It makes up about 3-4% of the gut lining in healthy people, populating our gastrointestinal tract within the first year of life through breast milk but gradually decreasing as we age. Hence, it’s critical to give it lifelong care to maintain a thriving gut environment.3*

Unraveling the importance of Akkermansia in improving health
Research on the effects of A. muciniphila on human health is ongoing, but some studies have shown encouraging results, indicating that A. muciniphila may offer potential benefits for various aspects of health:

Excess weight: Overweight individuals are mostly found to have lower levels of A. muciniphila alongside other beneficial bacteria as compared to their lean counterparts. By increasing the thickness of the protective mucus layer in the intestines and enhancing gut barrier function, this microbe blocks bacteria and other substances from entering our bloodstream. The result? Our metabolic health gets a boost! From blood sugar and cholesterol to blood pressure and waist circumference, A. muciniphila helps keep them all in check.4,5*

Glucose regulation: Did you know that a thinner mucus layer is associated with health risks? This is why, if you have an adequate amount of A. muciniphila in your body, it will boost healthy gut mucus lining and improve glucose metabolism. By degrading the mucus layer in the intestines, A. municiphila can increase the production of SCFAs, which keeps the glucose regulated and produces energy in your body.6*
Therefore, supplementation with A. muciniphila can lead to reduced fat mass, improved insulin metabolism, and better blood sugar control—factors that are essential in tackling blood sugar health.7*

Cardiovascular health: There are several cardiovascular markers shown to improve with the presence of Akkermansia in the body. This bacterium works wonders helping to promote healthy arteries and healthy blood pressure. How does it support our hearts? By producing the superstar butyrate!8-13*

Understanding the difference between live vs. pasteurized forms
One more thing to consider is the live and pasteurized forms of Akkermansia. Although the difference in their effects is still inconclusive, most studies found the pasteurized form to be more effective than the live form.14,15*

Nurturing the growth of Akkermansia for optimal health
There are many ways to naturally enhance the production of this beneficial bacteria in your body.

Foods that help16,17

• Dietary fiber: Adopt a diet rich in fiber from fruits, vegetables, whole grains, legumes, and nuts, such as a Mediterranean diet, that encourages the growth of A. muciniphila.*
• Prebiotics: Incorporate prebiotic-rich foods into your diet. Prebiotics are nondigestible fibers that support the growth and activity of beneficial gut bacteria.* Foods like onions, garlic, leeks, asparagus, yacon root, and bananas are good sources of prebiotics.
• Polyphenol-rich foods: Foods rich in polyphenols, such as berries (especially cranberries), cocoa, green tea, and red wine (in moderation), may have a positive impact on your gut health and promote the growth of A. muciniphila.*
• Probiotics and fermented foods: While A. muciniphila itself is not commonly available as a probiotic supplement, consuming other probiotics and fermented foods (e.g., yogurt, kefir, sauerkraut, kimchi) may help create a gut environment that supports A. muciniphila growth.*
• Omega-3 fatty acids: Fatty fish such as salmon, mackerel, sardines, etc. as well as flaxseeds and chia seeds are a good source of fish oils to boost Akkermansia production.*

Lifestyle that helps6,16

• Avoid high-fat diets and alcohol: High-fat diets, especially those rich in unhealthy fats, as well as alcohol may negatively impact the gut microbiome. Strive for a balanced diet with healthy fats, stay away from fast food, and limit alcohol consumption.16

• Regular exercise: Regular physical activity has been associated with a more diverse and beneficial gut microbiome, which may also promote the growth of A. muciniphila.18

• Stress management: Chronic stress can negatively affect gut health. Engaging in stress-reducing activities such as meditation, yoga, or spending time in nature may be beneficial.19

Remember that individual responses to dietary and lifestyle changes can vary, and it's important to make these adjustments as part of an overall healthy lifestyle. So don’t forget to consult with your healthcare provider before making significant changes to your diet or lifestyle!

Navigating the caveats: potential risks of overabundance of Akkermansia
Just like anything out of balance in life, the overabundance of this bacteria may bring some risks as well. For example, excess Akkermansia in the body may upset the intestinal barrier due to overconsumption of mucin that makes up the epithelial lining to prevent the passage of bacteria.20*

There are other emerging studies on the possible association of the abundance of A. muciniphila with certain health parameters. Whether it’s detrimental or supportive is yet to be concluded.21-24

Remember, moderation is the key! Just like any other supplements, make sure to avoid overconsumption and always consult with your healthcare practitioner before starting supplementation. 

​References:
1. Zitong L et al. Front Microbiol. 2022;13:1037708.
2. Rodrigues CF et al. Front Immunol. 2022;13:934695.
3. Zhang T et al. Microb Biotechnol. 2019;12(6):1109-1125.
4. Mayorga-Ramos A et al. Front Nutr. 2022(9).
5. Xu Y et al. Front Micriobiol. 2020;11:219.
6. Suriano F et al. Front Immunol. 2022;13:953196.
7. Hasani A et al. J Med Microbiol. 2021;70(10).
8. Li J et al. Circulation. 2016;133(24:2434-2446.
9. Wassenaar TM et al. Eur J Microbiol (Bp). 2018;8(3):64-69.
10. Mohammad S et al. Front Immunol. 2020;11:594150.
11. Luo X et al. Int J Mol Sci. 2023;24(5):4955.
12. Tilves C et al. JAHA. 2022;11(13).
13. Yan J et al. Gut Microbes. 2021;13(1):1984104.
14. Choi Y et al. Microorganisms. 2021;9(10):2039.
15. Ashrafian F et al. Scientific Reports. 2021;11:17898.
16. Zhou K. J Funct Foods. 2017;33:194-201.
17. Anonye BO. Front Immunol. 2017;8.
18. Hintikka JE et al. Scientific Reports. 2023;13:11228. 
19. Madison A et al. Curr Opin Behav Sci. 2019;28:105-110.
20. Qu S et al. Front Microbiol. 2023;14:1111911.
21. Wang K et al. Front Microbiol. 2022;13:932047. 
22. Nishiwaki H et al. NPJ Parkinsons Dis. 2022;8:65.
23. Fang X et al. Curr Med Sci. 2021;41(6):1172-1177.
24. Floch N. Science Direct. 2017.