The Gut Microbiome and Parkinson's Disease

From MicrobeWiki, the student-edited microbiology resource
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by Rebecca Hölzel
For an introduction to Parkinson's Disease, click here: Parkinson's
For more information on the gut microbiome, visit The Gut Microbiome and Anxiety, The Human Gut Microbiome and Obesity, & The Development of the Gut Microbiome in Young Children

Abnormal Gut Microbiome

The conditions that contribute to the development of Parkinson's Disease are likely very complex. A growing body of research has indicated, however, that the gut microbiome may play a key role in disease development and progression. Parkinson's Disease is commonly associated with abnormal gut microbiomes, including increased and decreased counts of bacteria normally found in healthy individuals.[1] However, some researchers remain skeptical that the gut microbiome influences Parkinson's Disease, believing instead that the disease is what causes the abnormal gut bacteria, and not the abnormal gut bacteria that cause the disease.[2]

General Abnormalities

One research team examined the relationship between gut microbiota and Parkinson's Disease by recruiting newly diagnosed and unmedicated Parkinson's disease patients for study. Fecal samples were collected from all patients and used to extract bacterial DNA, which provided measures of bacterial diversity and relative abundance of bacterial genera. They discovered that levels of Verrucomicrobia, Verrucomicrobiaceae, and Akkermansia were twofold higher in Parkinson's Disease patients than healthy controls. Levels of Proteobacteria, Enterobacteriaceae, Christensenellaceae, Lactobacillaceae, Coriobacteriaceae, Bifidobacteriaceae, and Parabacteroides were also increased in Parkinson's Disease patients, with Roseburia showing a considerable decrease. A significant increase was also seen for Oscillospira and a significant decrease was seen for Ruminococcus.[3]

Relative numbers of various bacterial phyla can differ in the guts of Parkinson's Disease patients.[4]

Gut bacteria produce short chain fatty acids (SCFA). Some researchers hypothesize that there may be a link between Parkinson's Disease, abnormal gut microbiota, and abnormal levels of SCFA. One research team recruited 34 Parkinson's Disease patients to better clarify this link. They found that Parkinson's Disease patients showed reduced levels of many normal gut bacteria, including Bacteroides, Prevotellaceae, Faecalibacterium prausnitzii, Lactobacillaceae, and Enterococcaceae. Methanobrevibacter smithii showed reduced abundance only in younger patients. Bacterial abundance was increased for Bifidobacterium and Enterobacteriaceae. In analyzing SCFAs, researchers found significant decreases in acetate, propionate and butyrate. They hypothesized that abnormal SCFA levels may play a role in Parkinson's Disease development and progression.[4]

To better characterize the association between the gut and Parkinson's Disease, one research group decided to exclusively examine Chinese patients. Their results confirmed that Chinese Parkinson's Disease patients also have altered gut microbiota compared to healthy controls, an important finding, as other studies rarely use Chinese participants. The researchers found that levels of Clostridium IV, Aquabacterium, Holdemania, Sphingomonas, Clostridium XVIII, Butyricicoccus and Anaerotruncus were all increased in Parkinson's Disease patients. Their other findings included noting that levels of Escherichia/Shigella negatively correlated to disease progression, and levels of Dorea and Phascolarctobacterium negatively correlated to LED (levodopa equivalent doses).[5]

Idiopathic Parkinson's Disease refers to cases of Parkinson's that arise spontaneously or otherwise have no obvious cause. One research team examined whether specifically idiopathic Parkinson's Disease patients have altered compositions of gut microbiota. Unsurprisingly, they found abundance of certain gut microbes differed between the Parkinson's Disease patients and healthy controls. The largest discrepancies were found between Firmicutes and Bacteroidetes. For example, Akkermansia and Butyricimonas abundance were found to be increased in Parkinson's Disease patients.[6]

Literature surrounding the connection between Parkinson's Disease and the gut microbiome can be inconsistent. One research group attempted to clarify these inconsistences by recruiting 327 patients for study and using statistical analysis to account for potential confounding variables (20 potential confounding variables were ultimately identified, including factors like disease duration and medications). With these accounted for, the researchers confirmed that levels of Akkermansia, Lactobacillus, and Bifidobacterium were increased in Parkinson's Disease patients, while Lachnospiraceae decreased. The researchers noted that Lachnospiraceae produce SCFA.[7]

Gut Inflammation

Intestinal inflammation, common to Parkinson's Disease, has been linked to abnormal gut microbiota through characterization of bacteria as either pro-inflammatory or anti-inflammatory. One research group found that healthy controls possessed far more colonic mucosal bacteria from Coprobacillaceae, Dorea, and Faecalibacterium than Parkinson's Disease patients. Notably, Faecalibacterium have anti-inflammatory properties. Parkinson's Disease patients also had more pro-inflammatory bacteria, including bacteria from the family Oxalobacteraceae. Fecal samples also showed higher levels of pro-inflammatory bacteria, including Akkermansia, Oscillospira, and Bacteroides. Levels of pro-inflammatory and anti-inflammatory bacteria correlate to Parkinson's Disease duration.[8]

Similar research was conducted with 63 Parkinson's Disease patients and 137 healthy controls. Researchers identified "eight characteristic genera" associated with Parkinson's Disease progression: Parabacteroides, Akkermansia, Coprococcus, Bilophila, Collinsella, Methanobrevibacter, Eggerthella, and Adlercreutzia. Each genera has previously been associated with inflammation or Parkinson's Disease. For example, Coprococcus was previously found to worsen neurodegeneration in a Parkinson's Disease rat model. Adlercreutzia, however, has anti-inflammatory properties, leading researchers to hypothesize its increased numbers were attempts to compensate for Parkinson's Disease related inflammation.[9]

Levels of pro-inflammatory and anti-inflammatory bacteria in the gut correlate to Parkinson's Disease duration. Panels A-B represent data for pro-inflammatory bacteria (positive correlation). Panels C-F represent anti-inflammatory bacteria (negative correlation).[8]

Phenotypes

One research team attempted to connect abnormal gut microbiota with common Parkinson's Disease phenotypes (tremor, abnormal gait, poor balance). From fecal samples, they discovered that the mean abundance of Prevotellaceae was 77.6% lower in Parkinson's Disease patients than in healthy controls. By applying generalized linear modeling, the team demonstrated that this difference could not be explained by differences in constipation levels, comorbidities, or medications. Interestingly, their models revealed that increased levels of Ruminococcaceae in Parkinson's Disease patients could be explained by the decrease in Prevotellaceae; that is, Ruminococcaceae increased because Prevotellaceae decreased. When the researchers attempted to link gut microbiota with phenotype, they discovered that Enterobacteriaceae were more abundant in patients who dominantly displayed abnormal gait/poor balance than patients who dominantly displayed tremors. They speculated that increased levels of Enterobacteriaceae may explain why patients who do not express the tremor phenotype have faster disease progression and worse prognosis.[10]

Another team discovered that Parkinson's Disease patients with higher abundance of Christensenellaceae had worse nonmotor symptoms. Increased Lactobacillaceae and decreased Lachnospiraceae also correlated with worse cases of intellectual impairment, nonmotor symptoms, gait instability, and posture problems.[3]

Parkinson's Disease phenotypes can be characterized as tremor dominant (TD), akinetic rigid (AR), or dyskinetic (D). One research group found correlations between each of these phenotypes and abnormal gut microbiota in Parkinson's Disease patients. Between the AR and TD phenotypes, AR phenotype patients showed unique reductions in Brevibacteriaceae and Lachnospiraceae, as well as Brevibacterium, Blautia, Coprococcus and Lachnospira. The AR phenotype also showed increases in Enterobacteriaceae, Serratia, and Sedimentibacter compared to the TD phenotype.[11]
Between the D and TD phenotypes, the D phenotype showed unique reductions in Brevibacteriaceae, Eubacteriaceae, Gemellaceae, Lachnospiraceae, and Peptococcaceae, as well as Brevibacterium, Acetobacterium, Gemella, Blautia, Coprococcus, Lachnospira, and Sedimentibacter. There were also increases in Escherichia and Serratia.[11]
There were no significant differences between the D and AR phenotypes.[11]


Bacterial Overgrowth

Parkinson's Disease has been associated with general overgrowth of bacteria in the small intestine (SIBO, small intestinal bacterial overgrowth). One study tested for SIBO in 48 Parkinson's Disease patients compared to 36 healthy controls. All participants were tested using a hydrogen glucose breath test. The researchers found a significant number of Parkinson's Disease patients (26/48 participants) had SIBO compared to the controls (3/36 participants). Furthermore, Parkinson's Disease patients with SIBO were more likely to report GI symptoms such as bloating and flatulence. Disease duration and severity also correlated with a diagnosis of SIBO.[12]

These results were supported by another research team that correlated SIBO with Parkinson's Disease GI symptoms. Their study focused on 182 Chinese Parkinson's Disease patients, 55 of whom tested positive for SIBO via glucose breath test (compared to 19/200 positives for the control group). A number of factors were found to correlate with SIBO, including the presence of motor fluctuations, longer disease duration, higher scores on UPDRS-III and IV (Unified PD Rating Scale), and higher scores on NMSS (non-motor symptoms severity scale). SIBO was also significantly associated with gas and bloating.[13]

However, another study that tested for SIBO in 103 Parkinson's Disease patients claimed to find no association with GI symptoms. 26 patients ultimately tested positive for SIBO via lactulose-hydrogen breath testing. SIBO was associated with worse scores on UPDRS Part III (Unified PD Rating Scale), worse scores on Pegboard tests (which test motor dexterity and coordination), and longer times to complete gait tests. However, the authors noted that Parkinson's Disease duration was a stronger predictor of these outcomes than SIBO, and SIBO, furthermore, had no association with worse GI symptoms. Ultimately, they concluded that SIBO may be a good predictor of motor symptom severity in Parkinson's Disease patients, but not GI symptoms.[14]

Despite these results, some researchers have found instead that SIBO has no correlation at all to GI symptoms or motor symptoms. Although one team found that 19/39 Parkinson's Disease patients tested positive for SIBO via lactulose breath test, they could ultimately find no correlation to Parkinson's Disease symptoms. However, the researchers did find SIBO-positive patients had lower serum triglyceride levels, leading them to hypothesize there may be a connection between the two.[15]

Intestinal methanogen overgrowth (IMO) is a condition related to SIBO. Researchers that tested 19 Parkinson's Disease patients discovered that 10 of them had IMO. This result was significant when compared to only 23/158 control patients who also had IMO. Additionally, only 6 of the 19 Parkinson's Disease patients had SIBO. Notably, the researchers discovered that symptoms of constipation correlated with IMO, but not SIBO.[16]

Drug Interactions

Enterococcus faecalis metabolizes L-dopa into dopamine, preventing it from reaching the brain. Researchers demonstrated that knockout of protein TyrDC prevented L-dopa metabolism, confirming the important role of TyrDC in this process.[17]

L-Dopa

Levodopa (L-dopa) is widely used in the treatment of Parkinson's Disease. Despite its efficacy, up to 56% of administered L-dopa fails to reach the brain because it is metabolized in other pathways. Gut bacteria are suspected to play a large role in loss of L-dopa function; as such, identifying any microbes responsible for metabolizing L-dopa is crucial.[17]

Genome mining was used to identify a protein, tyrosine decarboxylase (TyrDC), in human gut Enterococcus faecalis capable of decarboxylating L-dopa and producing dopamine. TyrDC's role was confirmed by experiments that found knockout of the TyrDC gene drastically reduced Enterococcus faecalis dopamine production. Furthermore, enzyme assays with TyrDC using both L-dopa and the preferred substrate tyrosine showed that TyrDC was capable of decarboxylating both substrates simultaneously, indicating that substrate competition would not hinder TyrDC's affinity for L-dopa.[17]

It has also been proposed that Helicobacter pylori may decrease L-dopa bioavailability. Experiments have demonstrated that laboratory Helicobacter pylori can grow quickly on L-dopa, suggesting that they may consume L-dopa when present in the gut.[18]

One research group performed a literature search to pool any data that correlated L-dopa, Helicobacter pylori, and Parkinson's Disease. They found consistent results that indicated Helicobacter pylori infected patients took higher daily doses of L-dopa (levodopa equivalent daily dose, LEDD) than patients without Helicobacter pylori infection. Infected patients also tended to present with worse motor symptoms, although the authors cautioned that these patients may take more L-dopa because they have worse motor symptoms and that this relationship may not necessarily be related to Helicobacter pylori.[19]




Treatment Options

Parkinson's Disease patients who received fecal transplants showed significantly decreased scores on various symptom scales. (PSQI = Pittsburgh sleep quality index; HAMD = Hamilton depression scale; HAMA = Hamilton anxiety scale; PDQ-39 = quality of life survey; NMSQ = non-motor symptoms score; UPDRS = Unified PD rating scale III) [20]

The potential link between Parkinson's Disease and gut microbiota opens the possibility of related treatments.

Fecal Transplants

A 71 year old male Parkinson's Disease patient experienced symptom relief after a fecal transplant. Prior to the transplant, the patient suffered extreme constipation not relieved by laxatives, in addition to symptoms of tremor and bradykinesia (slow movements). Due to the severity of symptoms, the patient agreed to undergo three days of fecal transplantation using stool from a healthy 26-year-old male. A week after the treatment, the patient reported complete disappearance of leg tremors. Although the tremors returned after two months, the severity was greatly decreased. The constipation was also greatly relieved, although the patient reported no change in face or neck stiffness.[21]
Researchers sampled the patient's stool to characterize his gut microbiota both before and after the fecal transplants. After one week, the patient's gut microbiota were similar to the stool donor's gut microbiota, with increases in Firmicutes and decreases in Proteobacteria and Bacteroidetes. There were also increases in Lachnoclostridium, Dialister, Alistipes, and Unidentified-Ruminococcaceae. After one month, there was an increase in Megamonas and after 3 months, Akkermansia and Faecalibacterium increased.[21]

Another team recruited 11 Parkinson's Disease patients to further study the possibility of fecal transplant as a treatment option. Symptoms, as well as gut microbiota composition, were assessed prior to treatment, 6 weeks after treatment, and 12 weeks after treatment. One of the parameters of the study included rating patients on the Wexner constipation scale. After 6 weeks, patients reported significantly lower constipation scores, although these scores had increased again by the 12-week mark. Patients also reported improvements in posture and gait.[22]
After fecal transplant, the abundance of Blautia and Lachnospiraceae increased for the Parkinson's Disease patients. Compared to healthy controls, there was an increased abundance of Bacteroides and decreased abundance of Faecalibacterium in Parkinson's Disease patients, both before and after the fecal transplant. There was also an increased abundance of Enterobacteriaceae in Parkinson's Disease patients compared to the healthy controls, but this abundance decreased after fecal transplant.[22]

Notably, fecal transplants performed via colonoscopy seem to treat Parkinson's Disease better than fecal transplants performed via nasal-jejunal tube. Researchers recruited 15 Parkinson's Disease patients for fecal transplant, 10 of which received the transplant by colonoscopy. One month after fecal transplant, these patients reported improvements in motor and non-motor symptoms, as measured by scales such as PSQI (Pittsburgh sleep quality) and HAMD (Hamilton depression scale). These symptoms had further improved 3 months after fecal transplant.[20]
Patients that received the fecal transplant via nasal-jejunal tube did not report significant improvement of symptoms, although their UPDRS-III (Unified PD rating scale III) scores slightly decreased. Furthermore, all nasal-jejunal patients reported they were not satisfied with the fecal transplant 3 months afterwards. This is in contrast to the colonoscopy patients, 2 of whom reported they were still satisfied with the results 24 months later.[20]

Probiotics

Parkinson's Disease patients that took antibiotics to eradicate Helicobacter pylori infections experienced an increase in "on" time per day and a decrease in "off" time per day. "On" and "off" time refers to motor impairment as quantified by a neurologist and movement disorder specialist.[23]

In one study, Parkinson's Disease patients who consumed fermented milk with probiotics and prebiotics reported greater relief from constipation symptoms compared to a placebo group.[24]

In another study, researchers evaluated the effectiveness of probiotics in relieving Parkinson's Disease-related GI symptoms compared to trimebutine (a drug commonly used in GI disorders, such as irritable bowel syndrome, to relax the muscles of the intestines). Patients that received trimebutine reported improvements in abdominal pain, bloating, and constipation. Patients that received probiotics reported statistically significant improvements in only abdominal pain and bloating. However, researchers found it promising that probiotics could treat Parkinson's Disease symptoms nearly as well as trimebutine.[25]

Parkinson's Disease patients that took probiotics containing Lactobacillus acidophilus, Bifidobacterium bifidum, Lactobacillus reuteri, and Lactobacillus fermentum for 12 weeks had decreased MDS-UPDRS (Movement Disorders Society-Unified Parkinson's Disease Rating Scale) scores. They also had decreased hs-CRP (high-sensitivity C-reactive protein) values, which indicate acute inflammation in the body. Other notable results from this study included decreased insulin levels and decreased triglyceride levels.[26]

Lactobacillus salivarius, Lactobacillus plantarum, Lactobacillus acidophilus, Lactobacillus rhamnosus, Bifidobacterium animalis, and Bifidobacterium breve may also have beneficial effects. 40 Parkinson's Disease patients that received these strains as probiotics saw significant reductions in their levels of pro-inflammatory cytokines and increases in levels of anti-inflammatory cytokines. There were also reductions in reactive oxygen species (ROS) production. Importantly, the probiotic strains also demonstrated ability to inhibit the growth of E. coli and K. pneumoniae, both of which are commonly found in septic Parkinson's Disease patients. The researchers who worked on this study concluded that probiotics are excellent tools for countering the harmful immune system responses found in Parkinson's Disease patients.[27]

Antibiotics

Antibiotics may improve the symptoms of Parkinson's Disease. One study treated Helicobacter pylori infected Parkinson's Disease patients with either antibiotics or antioxidants. The Parkinson's Disease patients that received antibiotics (complete eradication of Helicobacter pylori) showed a significant increase in L-dopa absorbance, compared to the patients that just received antioxidants. As a result, patients reported improvements in disability and GI symptoms.[28]

These results have been confirmed by follow-up studies. One research team enrolled 22 Parkinson's Disease patients also suffering from Helicobacter pylori infection. After two weeks of treatment with amoxicillin, clarithromycin, and omeprazole, 17 of the patients experienced complete eradication of Helicobacter pylori. They reported statistically significant increases in total "on" time per day and decreases in "off" time per day, as well improvements in tremor, mood, and GI symptoms. "On" and "off" times refer to the duration of involuntary motor movements. Patients who did not experience complete eradication reported no improvements and an increase in "off" time per day.[23]

Antibiotics may also be useful to treat general bacterial overgrowth (SIBO). Of 18 Parkinson's Disease patients with SIBO that took rifaximin (400 mg, 3 times a day for 1 week), 14 were cured of SIBO and only 6 redeveloped SIBO after 6 months. Those that were cured of SIBO reported improvements in motor fluctuations, specifically improvements in daily "off" time, as well as improvements in delayed "on" time.[29]

Sometimes, antibiotic usage can have unintentional effects. This was the case for an 86-year-old man who had been suffering from Parkinson's Disease for 21 years. He had been taking medications, including L-dopa, but found little relief. After an unrelated injury to his leg, the man developed suspected bacterial osteomyelitis (bone inflammation) and was prescribed ciprofloxacin and dicloxacillin. Remarkably, after finishing the course of antibiotics, the man reported that all his motor symptoms were completely cured. Almost 10 years later, he remained symptom free. Although it is unknown whether the antibiotics truly cured the man's Parkinson's Disease, the results are compelling and may be used in the future to link antibiotic usage to the gut microbiome.[30]

References

  1. ↑ Sampson, Timothy. (2020). "The Impact of Indigenous Microbes on Parkinson's Disease." Neurobiology of Disease, vol. 135. https://doi.org/10.1016/j.nbd.2019.03.014
  2. ↑ Quigley, Eamonn. (2017). "Gut microbiome as a clinical tool in gastrointestinal disease management: are we there yet?" Nature Reviews Gastroenterology & Hepatology, vol. 14, 315-320. https://doi.org/10.1038/nrgastro.2017.29
  3. ↑ 3.0 3.1 Barichella, M., Severgnini, M., Cilia, R., Cassani, E., Bolliri, C., Caronni, S., Ferri, V., Cancello, R., Ceccarani, C., Faierman, S., Pinelli, G., De Bellis, G., Zecca, L., Cereda, E., Consolandi, C. and Pezzoli, G. (2019). "Unraveling Gut Microbiota in Parkinson's Disease and Atypical Parkinsonism. Movement Disorders, vol. 34, 396-405. https://doi.org/10.1002/mds.27581
  4. ↑ 4.0 4.1 Unger, Marcus M., Jörg Spiegel, Klaus-Ulrich Dillmann, David Grundmann, Hannah Philippeit, Jan Bürmann, Klaus Faßbender, Andreas Schwiertz, & Karl-Herbert Schäfer. (2016). "Short chain fatty acids and gut microbiota differ between patients with Parkinson's disease and age-matched controls." Parkinsonism & Related Disorders, vol. 32, 66-72. https://doi.org/10.1016/j.parkreldis.2016.08.019
  5. ↑ Qian, Yiwei, Xiaodong Yang, Shaoqing Xu, Chunyan Wu, Yanyan Song, Nan Qin, Sheng-Di Chen, Qin Xiao. (2018). "Alteration of the fecal microbiota in Chinese patients with Parkinson’s disease." Brain, Behavior, and Immunity, vol. 70, 194-202. https://doi.org/10.1016/j.bbi.2018.02.016
  6. ↑ Li Y, Li RX, Du YT, Xu XJ, Xue Y, Gao D, Gao T, Sheng Z, Zhang LY, & Tuo HZ. (2020). "Features of gut microbiota in patients with idiopathic Parkinson's disease." Zhonghua Yi Xue Za Zhi, vol. 100(13), 1017-1022. 10.3760/cma.j.cn112137-20190702-01480
  7. ↑ Hill-Burns, Erin M., Justine W. Debelius, James T. Morton, William T. Wissemann, Matthew R. Lewis, Zachary D. Wallen, Shyamal D. Peddada, Stewart A. Factor, Eric Molho, Cyrus P. Zabetian, Rob Knight, Haydeh Payami. (2017). "Parkinson's disease and Parkinson's disease medications have distinct signatures of the gut microbiome." Movement Disorders, vol. 32(5), 739-749. https://doi.org/10.1002/mds.26942
  8. ↑ 8.0 8.1 Keshavarzian,Ali, Stefan J. Green, Phillip A. Engen, Robin M. Voigt, Ankur Naqib, Christopher B. Forsyth, Ece Mutlu, Kathleen M. Shannon. (2015). "Colonic bacterial composition in Parkinson's disease." Movement Disorders, vol. 30(10), 1351-1360. https://doi.org/10.1002/mds.26307
  9. ↑ Zhang, Fan, Liya Yue, Xing Fang, Gengchao Wang, Cuidan Li, Xiaodong Sun, Xinmiao Jia, Jingjing Yang, Jinhui Song, Yu Zhang, Chongye Guo, Guannan Ma, Ming Sang, Fei Chen, Puqing Wang. (2020). "Altered gut microbiota in Parkinson's disease patients/healthy spouses and its association with clinical features." Parkinsonism & Related Disorders, vol. 81, 84-88. https://doi.org/10.1016/j.parkreldis.2020.10.034
  10. ↑ Scheperjans, Filip, Velma Aho, Pedro A. B. Pereira, Kaisa Koskinen, Lars Paulin, Eero Pekkonen, Elena Haapaniemi, Seppo Kaakkola, Johanna Eerola-Rautio, Marjatta Pohja, Esko Kinnunen, Kari Murros, Petri Auvinen. (2014). "Gut microbiota are related to Parkinson's disease and clinical phenotype." Movement Disorders, vol. 30(3), 350-358. https://doi.org/10.1002/mds.26069
  11. ↑ 11.0 11.1 11.2 Vascellari, Sarah, Marta Melis, Vanessa Palmas, Silvia Pisanu, Alessandra Serra, Daniela Perra, Maria L. Santoru, Valentina Oppo, Roberto Cusano, Paolo Uva, Luigi Atzori, Micaela Morelli, Giovanni Cossu, and Aldo Manzin. (2021). "Clinical Phenotypes of Parkinson’s Disease Associate with Distinct Gut Microbiota and Metabolome Enterotypes." Biomolecules, vol. 11(2), 144. https://doi.org/10.3390/biom11020144
  12. ↑ Gabrielli, Maurizio, Patrizia Bonazzi, Emidio Scarpellini, Emanuele Bendia, Ernesto C. Lauritano, Alfonso Fasano, Maria G. Ceravolo, Marianna Capecci, Anna Rita Bentivoglio, Leandro Provinciali, Pietro A. Tonali, Antonio Gasbarrini. (2011). "Prevalence of Small Intestinal Bacterial Overgrowth in Parkinson's Disease." Movement Disorders, vol. 26(5), 889-892. https://doi.org/10.1002/mds.2356
  13. ↑ Niu, Xiao-Lu, Li Liu, Zhi-Xiu Song, Qing Li, Zhi-Hua Wang, Jian-Long Zhang & He-Hua Li. (2016). "Prevalence of small intestinal bacterial overgrowth in Chinese patients with Parkinson’s disease." Neurology and Preclinical Neurological Studies, vol. 123, 1381–1386. https://doi.org/10.1007/s00702-016-1612-8
  14. ↑ Tan, Ai Huey, Sanjiv Mahadeva, Abdul Malik Thalha, Peter R. Gibson, Chiun Khang Kiew, Chia Ming Yeat, Sheang Wen Ng, Sheau Phing Ang, Siew Kian Chow, Chong Tin Tan, Hoi Sen Yong, Connie Marras, Susan H. Fox, & Shen-Yang Li. (2014). "Small intestinal bacterial overgrowth in Parkinson's disease." Parkinsonism & Related Disorders, vol. 20(5), 535-540. https://doi.org/10.1016/j.parkreldis.2014.02.019
  15. ↑ Hasuike, Y., T. Endo, M. Koroyasu, M. Matsui, C. Mori, M. Yamadera, H. Fujimura, & S. Sakoda. (2017). "Clinical features of Parkinson’s disease patients with small intestinal bacterial overgrowth." Science Direct, vol. 381, 230. https://doi.org/10.1016/j.jns.2017.08.658
  16. ↑ Sharma, Amol; Yan, Yun; Karunaratne, Tennekoon; Herekar, Anam A.; Kurek, Julie; Morgan, John; & Rao, Satish S. (2020). "Intestinal Methanogen Overgrowth (IMO) in Parkinson's Disease: High Prevalence and Correlation With Constipation." The American Journal of Gastroenterology, vol. 115, S249-S250. 10.14309/01.ajg.0000704048.99013.18
  17. ↑ 17.0 17.1 17.2 Rekdal, Vayu, Elizabeth Bess, Jordan Bisanz, Peter Turnbaugh, & Emily Balskus. (2019). "Discovery and inhibition of an interspecies gut bacterial pathway for Levodopa metabolism." Science, vol. 364(6445). 10.1126/science.aau6323
  18. ↑ Lyte, Mark. (2010). "Microbial endocrinology as a basis for improved l-DOPA bioavailability in Parkinson’s patients treated for Helicobacter pylori." Medical Hypotheses, vol. 74(5), 895-897. https://doi.org/10.1016/j.mehy.2009.11.001
  19. ↑ Zhong, Rui, Qingling Chen, Xinyue Zhang, Mengmeng Li & Weihong Lin. (2022). "Helicobacter pylori infection is associated with a poor response to levodopa in patients with Parkinson’s disease: a systematic review and meta-analysis." Journal of Neurology, vol. 269, 703-711. https://doi.org/10.1007/s00415-021-10473-1
  20. ↑ 20.0 20.1 20.2 Xue, Liu-Jun; Yang, Xiao-Zhong; Tong, Qiang; Shen, Peng; Ma, Shi-Jie; Wu, Shang-Nong; Zheng, Jin-Long; & Wang, Hong-Gang. (2020). "Fecal microbiota transplantation therapy for Parkinson's disease." Medicine, vol. 99(35). 10.1097/MD.0000000000022035
  21. ↑ 21.0 21.1 Huang, Hongli, Haoming Xu, Qingling Luo, Jie He, Mengyan Li, Huiting Chen, Wenjuan Tang, Yuqiang Nie, & Yongjian Zhou. (2019). "Fecal microbiota transplantation to treat Parkinson's disease with constipation." Medicine (Baltimore), vol. 98(26). 10.1097/MD.0000000000016163
  22. ↑ 22.0 22.1 Kuai, Xiao-yi, Xiao-han Yao, Li-juan Xu, Yu-qing Zhou, Li-ping Zhang, Yi Liu, Shao-fang Pei & Chun-li Zhou. (2021). "Evaluation of fecal microbiota transplantation in Parkinson's disease patients with constipation." Microbial Cell Factories, vol. 20(98). https://doi.org/10.1186/s12934-021-01589-0
  23. ↑ 23.0 23.1 Lolekha, Praween, Thanakarn Sriphanom, & Ratha-Korn Vilaichone. (2021). Helicobacter pylori eradication improves motor fluctuations in advanced Parkinson’s disease patients: A prospective cohort study (HP-PD trial)." PLoS ONE. https://doi.org/10.1371/journal.pone.0251042
  24. ↑ Barichella, Michela, Claudio Pacchetti, Carlotta Bolliri, Erica Cassani, Laura Iorio, Chiara Pusani, Giovanna Pinelli, Giulia Privitera, Ilaria Cesari, Samanta Andrea Faierman, Riccardo Caccialanza, Gianni Pezzoli, & Emanuele Cereda. (2016). "Probiotics and prebiotic fiber for constipation associated with Parkinson disease." Neurology, vol. 87(12). https://doi.org/10.1212/WNL.0000000000003127
  25. ↑ Georgescu, Doina, Oana Elena Ancusa, Liviu Andrei Georgescu, Ioana Ionita, & Daniela Reisz. (2016). "Nonmotor gastrointestinal disorders in older patients with Parkinson’s disease: is there hope?" Clinical Interventions in Aging, vol. 11, 1601–1608. 10.2147/CIA.S106284
  26. ↑ Omid Reza Tamtaji, Mohsen Taghizadeh, Reza Daneshvar Kakhaki, Ebrahim Kouchakia, Fereshteh Bahmani, Shokoofeh Borzabadi, Shahrbanoo Oryan, Alireza Mafi, & Zatollah Asemi. (2019). "Clinical and metabolic response to probiotic administration in people with Parkinson's disease: A randomized, double-blind, placebo-controlled trial." Clinical Nutrition, vol. 38(3), 1031-1035. https://doi.org/10.1016/j.clnu.2018.05.018
  27. ↑ Magistrelli, Luca; Amoruso, Angela; Mogna, Luca; Graziano, Teresa; Cantello, Roberto; Pane, Marco; & Comi, Cristoforo. (2019). "Probiotics May Have Beneficial Effects in Parkinson's Disease: In vitro Evidence." Frontiers in Immunology, vol. 10. 10.3389/fimmu.2019.00969
  28. ↑ Pierantozzi, M., A. Pietroiusti, L. Brusa, S. Galati, A. Stefani, G. Lunardi, E. Fedele, G. Sancesario, G. Bernardi, A. Bergamaschi, A. Magrini, P. Stanzione, & A. Galante. (2006). "Helicobacter pylori eradication and l-dopa absorption in patients with PD and motor fluctuations." Neurology, vol. 66(12), 1824-1829. https://doi.org/10.1212/01.wnl.0000221672.01272.ba
  29. ↑ Fasano, Alfonso, Francesco Bove, Maurizio Gabrielli, Martina Petracca, Maria Assunta Zocco, Enzo Ragazzoni, Federico Barbaro, Carla Piano, Serena Fortuna, Annalisa Tortora, Raffaella Di Giacopo, Mariachiara Campanale, Giovanni Gigante, Ernesto Cristiano Lauritano, Pierluigi Navarra, Stefano Marconi, Antonio Gasbarrini, & Anna Rita Bentivoglio. (2013). "The role of small intestinal bacterial overgrowth in Parkinson's disease." Movement Disorders, vol. 28(9), 1241-1249. https://doi.org/10.1002/mds.25522
  30. ↑ Leheste JR, Gottlieb SF, Biegel CA, Ramos RL, Torres G, & Saggio G. (2018). "Parkinson’s Disease: A Case Report of Motor Symptoms Resolution Following Antibiotic Treatment for Suspected Bacterial Osteomyelitis." Journal of Molecular and Genetic Medicine, vol. 12(1), 10.4172/1747-0862.1000328



Authored for BIOL 238 Microbiology, taught by Joan Slonczewski, 2022, Kenyon College

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