Gut Dysbiosis and Parkinson’s Disease: 6 Surprising Connections

In recent years, the intriguing connection between gut dysbiosis and Parkinson's Disease (PD) has garnered significant attention.

This article delves into the complex interplay between the gut-brain axis and its impact on non-motor symptoms in PD, notably pain hypersensitivity.

We explore how alterations in gut microbiota not only influence the severity of PD's motor symptoms but also contribute to the heightened pain sensitivity experienced by patients.

By examining the role of neuro-immunity in this context, we aim to shed light on the underlying mechanisms that link gut health to neurodegenerative processes, offering new perspectives on managing and understanding PD.

Key Findings

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1. Prevalence and Non-Motor Symptoms in PD: Parkinson’s disease affects 1–2% of the population over 65 and is characterized by non-motor symptoms like pain and gastrointestinal issues.
2. Gut-Brain Axis Dysregulation: PD symptoms may stem from dysregulation within the gut-brain axis, affecting immunity and inflammation.
3. Link Between Gut Dysbiosis and PD: Gut dysbiosis is linked to the severity of PD's motor symptoms and to somatosensory hypersensitivities.
4. High Incidence of Pain in PD Patients: Pain is a significant non-motor symptom present in 60–85% of PD patients and can precede motor symptoms.
5. Inflammation and Immune Response in PD: Inflammation and immune response, involving both innate and adaptive immune cells, play roles in PD progression.
6. Gastrointestinal Dysfunction in PD: Up to 80% of PD patients experience gastrointestinal alterations, with symptoms like constipation potentially preceding the onset of motor symptoms by decades

Gut Dysbiosis: A Key Player in Parkinson's Disease

Parkinson's disease (PD), affecting 1-2% of those aged 65 and above, extends beyond its motor symptoms.

PD often brings pain and gut troubles.

The gut-brain axis may be the link.

Dysbiosis can disrupt immunity, inflammation, and trigger neurodegeneration.

Emerging evidence ties gut dysbiosis to PD's severity and hypersensitive sensations.

This article explores how maladaptive neuro-immune connections in the context of gut dysbiosis may contribute to PD-induced pain hypersensitivity.

Understanding Pain in Parkinson's Disease: A Complex Neurobiological Perspective

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The Complex Relationship Between Immunity and Pain: Insights into Gut Dysbiosis and Parkinson's Disease

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These insights are derived from studies on rodent models with nerve injuries or autoimmune diseases.

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Neuro-immune interactions aren't limited to the injury site.

In models involving chemotherapy or sciatic nerve ligation, immune cells infiltrate the dorsal root ganglia (DRG)

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The Connection Between Gut Microbes and Pain Sensation in Parkinson's Disease

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The Hidden Pain of Parkinson's Disease: Understanding and Managing PD-Induced Pain

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PD-induced pain usually manifests as musculoskeletal hypersensitivity in areas like the neck, arms, or paravertebral muscles.

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Unraveling the Role of Immune Responses in Parkinson's Disease Sensory Hypersensitivity

In understanding sensory hypersensitivity in Parkinson's Disease (PD), it's crucial to recognize the involvement of the immune system.

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Inflammation, involving both innate and adaptive immune cells, can occur in the peripheral or central nervous system.

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For instance, higher TNF-α levels relate to motor dysfunction, while raised IL-1β and IL-2 levels are linked to cognitive decline A Trusted Source

Williams-Gray CH, Wijeyekoon R, Yarnall AJ, Lawson RA, Breen DP, Evans JR, et al. Serum Immune Markers and Disease Progression in an Incident Parkinson's Disease Cohort (ICICLE-Pd). Mov Disord (2016) 31(7):995–1003. doi: 10.1002/mds.26563v PubMed AbstractCrossRef Full TextGoogle Scholar.

This rise in cytokines results from increased immunocyte numbers in the bloodstream.

Interestingly, disease severity is associated with reduced naïve CD4+ T cells but elevated levels of Treg, activated CD4+ T cells, TH17 cells, and monocytes A Trusted Source

Chen S, Liu Y, Niu Y, Xu Y, Zhou Q, Xu X, et al. Increased Abundance of Myeloid-Derived Suppressor Cells and Th17 Cells in Peripheral Blood of Newly-Diagnosed Parkinson's Disease Patients. Neurosci Lett (2017) 648:21–5. doi: 10.1016/j.neulet.2017.03.045 PubMed AbstractCrossRef Full TextGoogle Scholar A Trusted Source

Kustrimovic N, Comi C, Magistrelli L, Rasini E, Legnaro M, Bombelli R, et al. Parkinson's Disease Patients Have a Complex Phenotypic and Functional Th1 Bias: Cross-Sectional Studies of CD4+ Th1/Th2/T17 and Treg in Drug-Naive and Drug-Treated Patients. J Neuroinflamm (2018) 15(1):205. doi: 10.1186/s12974-018-1248-8 CrossRef Full TextGoogle Scholar.

Surprisingly, PD-isolated Treg showed reduced ability to suppress effector T cell activity in vitro A Trusted Source

. Rosenkranz D, Weyer S, Tolosa E, Gaenslen A, Berg D, Leyhe T, et al. Higher Frequency of Regulatory T Cells in the Elderly and Increased Suppressive Activity in Neurodegeneration. J Neuroimmunol (2007) 188(1-2):117–27. doi: 10.1016/j.jneuroim.2007.05.011 PubMed AbstractCrossRef Full TextGoogle Scholar A Trusted Source

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The levels of these blood cytokines correspond to increased sensory hypersensitivity.

Patients experiencing pain exhibit a lower IL-6/IL-10 ratio in CD4+ T cells and a higher TNF-α/IL-10 ratio in CD8+ T cells A Trusted Source

Santos RMS. Doença De Parkinson: Há Associação Entre Dor E Resposta Imunologica? Minas Gerais: Universidade Federal de Minas Gerais (2017). Google Scholar.

Understanding Peripheral Mechanisms of Pain in Parkinson's Disease

In Parkinson's Disease (PD), between 20% and 60% of patients experience peripheral neuropathy, impacting large and small nerve fibers, which is linked to PD severity.

Studies have revealed that α-synuclein aggregates in cutaneous sensory nerves in PD patients, leading to nerve degeneration and sensory hypersensitivity.

Interestingly, hypersensitive PD patients have lower pain thresholds to electrical stimuli A Trusted Source

Chen Y, Mao CJ, Li SJ, Wang F, Chen J, Zhang HJ, et al. Quantitative and Fiber-Selective Evaluation of Pain and Sensory Dysfunction in Patients With Parkinson's Disease. Parkinsonism Relat Disord (2015) 21(4):361–5. doi: 10.1016/j.parkreldis.2015.01.008 PubMed AbstractCrossRef Full TextGoogle Scholar.

Conversely, some research suggests PD patients may experience hyposensitivity due to the loss of nerve fibers,

leading to increased tactile and thermal thresholds A Trusted Source

Nolano M, Provitera V, Estraneo A, Selim MM, Caporaso G, Stancanelli A, et al. Sensory Deficit in Parkinson's Disease: Evidence of a Cutaneous Denervation. Brain (2008) 131(Pt 7):1903–11. doi: 10.1093/brain/awn102 PubMed AbstractCrossRef Full TextGoogle Scholar A Trusted Source

Nolano M, Provitera V, Manganelli F, Iodice R, Stancanelli A, Caporaso G, et al. Loss of Cutaneous Large and Small Fibers in Naive and L-Dopa-Treated PD Patients. Neurology (2017) 89(8):776–84. doi: 10.1212/wnl.0000000000004274 PubMed AbstractCrossRef Full TextGoogle Scholar.

CD4+ T cells reactive to α-synuclein are expanded in PD patients' blood and have been linked to nerve pathology when injected into PD mice A Trusted Source

Lodygin D, Hermann M, Schweingruber N, Flugel-Koch C, Watanabe T, Schlosser C, et al. Beta-Synuclein-Reactive T Cells Induce Autoimmune CNS Grey Matter Degeneration. Nature (2019) 566(7745):503–8. doi: 10.1038/s41586-019-0964-2 PubMed AbstractCrossRef Full TextGoogle Scholar A Trusted Source

Ferreira N, Goncalves NP, Jan A, Jensen NM, van der Laan A, Mohseni S, et al. Trans-Synaptic Spreading of Alpha-Synuclein Pathology Through Sensory Afferents Leads to Sensory Nerve Degeneration and Neuropathic Pain. Acta Neuropathol Commun (2021) 9(1):31. doi: 10.1186/s40478-021-01131-8PubMed AbstractCrossRef Full TextGoogle Scholar.

Additionally, in PD animal models, alterations in ion channels and receptors associated with pain have been observed, providing a mechanistic link between these changes and non-motor PD symptoms.

Further research is needed to explore the potential of targeting these changes to alleviate PD-induced pain and delay or prevent the onset of motor symptoms.

Central Mechanisms of PD-Induced Pain

Neuronal Activity in the Brain

Positron emission tomography (PET) studies have unveiled heightened neuronal activity in specific brain regions of PD patients experiencing chronic pain.

These regions include the prefrontal cortex, primary somatosensory cortex, posterior insula, and anterior cingulate cortex A Trusted Source

Brefel-Courbon C, Payoux P, Thalamas C, Ory F, Quelven I, Chollet F, et al. Effect of Levodopa on Pain Threshold in Parkinson's Disease: A Clinical and Positron Emission Tomography Study. Mov Disord (2005) 20(12):1557–63. doi: 10.1002/mds.20629 PubMed AbstractCrossRef Full TextGoogle Scholar A Trusted Source

Brefel-Courbon C, Ory-Magne F, Thalamas C, Payoux P, Rascol O. Nociceptive Brain Activation in Patients With Neuropathic Pain Related to Parkinson's Disease. Parkinsonism Relat Disord (2013) 19(5):548–52. doi: 10.1016/j.parkreldis.2013.02.003 PubMed AbstractCrossRef Full TextGoogle Scholar.

Connectivity Changes

Resting-state magnetic resonance imaging (MRI) has shown reduced connectivity between the right nucleus accumbens

and the left hippocampus in PD patients with pain compared to those without A Trusted Source

Polli A, Weis L, Biundo R, Thacker M, Turolla A, Koutsikos K, et al. Anatomical and Functional Correlates of Persistent Pain in Parkinson's Disease. Mov Disord (2016) 31(12):1854–64. doi: 10.1002/mds.26826 PubMed AbstractCrossRef Full TextGoogle Scholar A Trusted Source

Antonini A, Tinazzi M, Abbruzzese G, Berardelli A, Chaudhuri KR, Defazio G, et al. Pain in Parkinson's Disease: Facts and Uncertainties. Eur J Neurol (2018) 25(7):917–e69. doi: 10.1111/ene.13624 PubMed AbstractCrossRef Full TextGoogle Scholar.

Early Signs of Neuropathology

Interestingly, before motor symptoms appear, early signs of PD neuropathology emerge in the locus coeruleus and raphe nuclei, both associated with pain processing A Trusted Source

Hawkes CH, Del Tredici K, Braak H. A Timeline for Parkinson's Disease. Parkinsonism Relat Disord (2010) 16(2):79–84. doi: 10.1016/j.parkreldis.2009.08.007 PubMed AbstractCrossRef Full TextGoogle Scholar.

Presence of α-syn Aggregates

Aggregates of α-syn (alpha-synuclein) protein, a hallmark of PD, are found in areas related to pain processing,

including the spinal cord's lamina I, preganglionic neurons of the vagal nerve, sympathetic preganglionic neurons, and the coeliac ganglion A Trusted Source

Braak H, Sastre M, Bohl JR, de Vos RA, Del Tredici K. Parkinson's Disease: Lesions in Dorsal Horn Layer I, Involvement of Parasympathetic and Sympathetic Pre- and Postganglionic Neurons. Acta Neuropathol (2007) 113(4):421–9. doi: 10.1007/s00401-007-0193-x PubMed AbstractCrossRef Full TextGoogle Scholar.

Immune Response

CD4+ and CD8+ T cells from PD patients respond to α-syn, triggering the production of immune molecules like IL-5 and IFN-γ.

These immune cells recognize specific peptides bound to microglia and dopaminergic neurons in the brain A Trusted Source

Sulzer D, Alcalay RN, Garretti F, Cote L, Kanter E, Agin-Liebes J, et al. T Cells From Patients With Parkinson's Disease Recognize Alpha-Synuclein Peptides. Nature (2017) 546(7660):656–61. doi: 10.1038/nature22815 PubMed AbstractCrossRef Full TextGoogle Scholar.

Inflammation and Blood-Brain Barrier (BBB)

Peripheral inflammation associated with PD increases the BBB's permeability, allowing pathogenic lymphocytes to infiltrate the central nervous system (CNS).

Infiltrated T cells may contribute to neurodegeneration by releasing cytokines that act on CNS neurons A Trusted Source

Mao X, Ou MT, Karuppagounder SS, Kam TI, Yin X, Xiong Y, et al. Pathological Alpha-Synuclein Transmission Initiated by Binding Lymphocyte-Activation Gene 3. Science (2016) 353(6307):1513–24. doi: 10.1126/science.aah3374 CrossRef Full TextGoogle Scholar.

CD8 T Cell-Mediated Neurodegeneration

CD8 cytotoxic T cells recognize mitochondrial antigens expressed by dopaminergic neurons and may contribute to their elimination, though the exact mechanism remains unclear A Trusted Source

Cebrian C, Zucca FA, Mauri P, Steinbeck JA, Studer L, Scherzer CR, et al. MHC-I Expression Renders Catecholaminergic Neurons Susceptible to T-Cell-Mediated Degeneration. Nat Commun (2014) 5:3633. doi: 10.1038/ncomms4633 PubMed AbstractCrossRef Full TextGoogle Scholar.

IL-17 and Neuronal Loss: IL-17, produced by CD3+ T cells, has been linked to the loss of midbrain dopaminergic neurons in PD A Trusted Source

Sommer A, Marxreiter F, Krach F, Fadler T, Grosch J, Maroni M, et al. Th17 Lymphocytes Induce Neuronal Cell Death in a Human iPSC-Based Model of Parkinson's Disease. Cell Stem Cell (2018) 23(1):123–31.e6. doi: 10.1016/j.stem.2018.06.015 PubMed AbstractCrossRef Full TextGoogle Scholar.

GI Dysfunction in PD-Induced Pain

Common GI Troubles

Gastrointestinal problems are remarkably prevalent in PD, affecting up to 80% of patients A Trusted Source

Stankovic I, Petrovic I, Pekmezovic T, Markovic V, Stojkovic T, Dragasevic-Miskovic N, et al. Longitudinal Assessment of Autonomic Dysfunction in Early Parkinson's Disease. Parkinsonism Relat Disord (2019) 66:74–9. doi: 10.1016/j.parkreldis.2019.07.008 PubMed AbstractCrossRef Full TextGoogle Scholar.

These issues encompass a range of symptoms, from constipation to nausea, dyspepsia, and dysphagia A Trusted Source

Martinez-Martin P. The Importance of non-Motor Disturbances to Quality of Life in Parkinson's Disease. J Neurol Sci (2011) 310(1-2):12–6. doi: 10.1016/j.jns.2011.05.006 PubMed AbstractCrossRef Full TextGoogle Scholar .

Notably, constipation can manifest many years before the motor symptoms of PD,

making it a potential early indicator of the disease A Trusted Source

Pont-Sunyer C, Hotter A, Gaig C, Seppi K, Compta Y, Katzenschlager R, et al. The Onset of Nonmotor Symptoms in Parkinson's Disease (the ONSET PD Study). Mov Disord (2015) 30(2):229–37. doi: 10.1002/mds.26077 PubMed AbstractCrossRef Full TextGoogle Scholar A Trusted Source

Abbott RD, Petrovitch H, White LR, Masaki KH, Tanner CM, Curb JD, et al. Frequency of Bowel Movements and the Future Risk of Parkinson's Disease. Neurology (2001) 57(3):456–62. doi: 10.1212/wnl.57.3.456 PubMed AbstractCrossRef Full TextGoogle Scholar .

The Presence of α-syn

α-synuclein (α-syn), a protein closely associated with PD, isn't confined to the central nervous system (CNS); it also resides in the colon, the neurons of the enteric nervous system (ENS), and the vagus nerve A Trusted Source

Braak H, de Vos RA, Bohl J, Del Tredici K. Gastric Alpha-Synuclein Immunoreactive Inclusions in Meissner's and Auerbach's Plexuses in Cases Staged for Parkinson's Disease-Related Brain Pathology. Neurosci Lett (2006) 396(1):67–72. doi: 10.1016/j.neulet.2005.11.012 PubMed AbstractCrossRef Full TextGoogle Scholar .

This intriguing finding is mirrored in animal models of PD, where aggregates of α-syn have been detected in the GI tract A Trusted Source

Hallett PJ, McLean JR, Kartunen A, Langston JW, Isacson O. Alpha-Synuclein Overexpressing Transgenic Mice Show Internal Organ Pathology and Autonomic Deficits. Neurobiol Dis (2012) 47(2):258–67. doi: 10.1016/j.nbd.2012.04.009 PubMed AbstractCrossRef Full TextGoogle Scholar .

This discovery has led researchers to propose that PD might originate in the gut and subsequently spread to the CNS through the vagus nerve.

This theory gains support from animal studies revealing that externally introduced α-syn into the gut wall can journey to the brain via the vagus nerve,

covering a distance estimated at 5–10 mm per day in rats A Trusted Source

Holmqvist S, Chutna O, Bousset L, Aldrin-Kirk P, Li W, Bjorklund T, et al. Direct Evidence of Parkinson Pathology Spread From the Gastrointestinal Tract to the Brain in Rats. Acta Neuropathol (2014) 128(6):805–20. doi: 10.1007/s00401-014-1343-6 PubMed AbstractCrossRef Full TextGoogle Scholar ).

Additionally, a patient who underwent a surgical truncal vagotomy showed a reduced risk of developing PD later in life A Trusted Source

Svensson E, Horvath-Puho E, Thomsen RW, Djurhuus JC, Pedersen L, Borghammer P, et al. Vagotomy and Subsequent Risk of Parkinson's Disease. Ann Neurol (2015) 78(4):522–9. doi: 10.1002/ana.24448 PubMed AbstractCrossRef Full TextGoogle Scholar A Trusted Source

Hui KY, Fernandez-Hernandez H, Hu J, Schaffner A, Pankratz N, Hsu NY, et al. Functional Variants in the LRRK2 Gene Confer Shared Effects on Risk for Crohn's Disease and Parkinson's Disease. Sci Transl Med (2018) 10(423). doi: 10.1126/scitranslmed.aai7795 PubMed AbstractCrossRef Full TextGoogle Scholar .

Auto-Immune Reactions and PD

The exact cause and role of these gut disruptions in PD remain unclear, but the presence of α-syn in the ENS alone is sufficient to induce irregular colonic motility in the gastrointestinal tract,

which aligns with the severity of motor impairment observed in some animal models A Trusted Source

Paumier KL, Luk KC, Manfredsson FP, Kanaan NM, Lipton JW, Collier TJ, et al. Intrastriatal Injection of Pre-Formed Mouse Alpha-Synuclein Fibrils Into Rats Triggers Alpha-Synuclein Pathology and Bilateral Nigrostriatal Degeneration. Neurobiol Dis (2015) 82:185–99. doi: 10.1016/j.nbd.2015.06.003 PubMed AbstractCrossRef Full TextGoogle Scholar .

PD patients experiencing constipation exhibit increased infiltration of CD4+ T cells into the colonic mucosa, along with elevated circulating TH17 and Treg cells A Trusted Source

Chen Y, Yu M, Liu X, Qu H, Chen Q, Qian W, et al. Clinical Characteristics and Peripheral T Cell Subsets in Parkinson's Disease Patients With Constipation. Int J Clin Exp Pathol (2015) 8(3):2495–504. PubMed AbstractGoogle Scholar .

Furthermore, mice lacking PINK1 or Parkin genes, when exposed to bacterial intestinal infections, demonstrate increased permeability of the blood-brain barrier (BBB).

This facilitates the entry of pro-inflammatory cytotoxic CD8 T cells into the central nervous system (CNS).

These immune cells target the host's mitochondrial antigens, potentially leading to the elimination of dopaminergic neurons in the striatum and subsequent motor impairments A Trusted Source

Matheoud D, Cannon T, Voisin A, Penttinen AM, Ramet L, Fahmy AM, et al. Intestinal Infection Triggers Parkinson's Disease-Like Symptoms in Pink1(-/-) Mice. Nature (2019) 571(7766):565–9. doi: 10.1038/s41586-019-1405-y PubMed AbstractCrossRef Full TextGoogle Scholar ).

Inflammatory Markers

Histological data indicates increased immunoreactivity of the astrocytic marker GFAP in the colon of PD patients, along with elevated levels of inflammatory mediators such as TNF-α, IFN-γ, IL-6, and IL-1β A Trusted Source

Devos D, Lebouvier T, Lardeux B, Biraud M, Rouaud T, Pouclet H, et al. Colonic Inflammation in Parkinson's Disease. Neurobiol Dis (2013) 50:42–8. doi: 10.1016/j.nbd.2012.09.007 PubMed AbstractCrossRef Full TextGoogle Scholar .

Notably, these mediators are elevated in the early stages of the disease and are inversely correlated with disease duration.

Since both enteric and central glial cells respond to IL-6 and IL-1β, their upregulation could influence pain transmission in both the gut and the CNS A Trusted Source

Morales-Soto W, Gulbransen BD. Enteric Glia: A New Player in Abdominal Pain. Cell Mol Gastroenterol Hepatol (2019) 7(2):433–45. doi: 10.1016/j.jcmgh.2018.11.005 PubMed AbstractCrossRef Full TextGoogle Scholar .

Dysbiosis in PD-Induced Pain

Gut Barrier Permeability and PD

Gut dysbiosis might play a crucial role in the progression of PD by influencing the permeability of both the blood-gut barrier and the blood-brain barrier (BBB).

This can facilitate the transport of α-syn (alpha-synuclein), a protein associated with PD, from the gut to the brain.

Additionally, gut dysbiosis can activate sensory neurons, contributing to pain hypersensitivity.

These effects may occur directly or indirectly through the release of cytokines by immune cells A Trusted Source

Qi J, Buzas K, Fan H, Cohen JI, Wang K, Mont E, et al. Painful Pathways Induced by TLR Stimulation of Dorsal Root Ganglion Neurons. J Immunol (2011) 186(11):6417–26. doi: 10.4049/jimmunol.1001241PubMed AbstractCrossRef Full TextGoogle Scholar A Trusted Source

Liu T, Gao YJ, Ji RR. Emerging Role of Toll-Like Receptors in the Control of Pain and Itch. Neurosci Bull (2012) 28(2):131–44. doi: 10.1007/s12264-012-1219-5 PubMed AbstractCrossRef Full TextGoogle Scholar.

Characteristics of Dysbiosis

Dysbiosis in PD is characterized by increased levels of Enterobacteriaceae, Akkermansia spp., Catabacter spp., and Akkermansiaceae, alongside decreased levels of Roseburia spp., Faecalibacterium spp., and Lachnospiraceae A Trusted Source

Nishiwaki H, Ito M, Ishida T, Hamaguchi T, Maeda T, Kashihara K, et al. Meta-Analysis of Gut Dysbiosis in Parkinson's Disease. Mov Disord (2020) 35(9):1626–35. doi: 10.1002/mds.28119 PubMed AbstractCrossRef Full TextGoogle Scholar A Trusted Source

Lin CH, Chen CC, Chiang HL, Liou JM, Chang CM, Lu TP, et al. Altered Gut Microbiota and Inflammatory Cytokine Responses in Patients With Parkinson's Disease. J Neuroinflamm (2019) 16(1):129. doi: 10.1186/s12974-019-1528-y CrossRef Full TextGoogle Scholar.

Notably, Roseburia spp. and Faecalibacterium spp. are known for their anti-inflammatory properties and their ability to promote the release of anti-inflammatory cytokines A Trusted Source

Zhu J, Paul WE. CD4 T Cells: Fates, Functions, and Faults. Blood (2008) 112(5):1557–69. doi: 10.1182/blood-2008-05-078154 PubMed AbstractCrossRef Full TextGoogle Scholar A Trusted Source

Shen Z, Zhu C, Quan Y, Yang J, Yuan W, Yang Z, et al. Insights Into Roseburia Intestinalis Which Alleviates Experimental Colitis Pathology by Inducing Anti-Inflammatory Responses. J Gastroenterol Hepatol (2018) 33(10):1751–60. doi: 10.1111/jgh.14144 PubMed AbstractCrossRef Full TextGoogle Scholar.

Role of Roseburia spp. and Faecalibacterium spp.

Reduced levels of Roseburia spp. and Faecalibacterium spp. may exacerbate TH17 (T-helper 17) activity and limit the action of Treg (regulatory T) cells, potentially contributing to PD-induced pain A Trusted Source

Clos-Garcia M, Andres-Marin N, Fernandez-Eulate G, Abecia L, Lavin JL, van Liempd S, et al. Gut Microbiome and Serum Metabolome Analyses Identify Molecular Biomarkers and Altered Glutamate Metabolism in Fibromyalgia. EBioMedicine (2019) 46:499–511. doi: 10.1016/j.ebiom.2019.07.031 PubMed AbstractCrossRef Full TextGoogle Scholar A Trusted Source

Dekker Nitert M, Mousa A, Barrett HL, Naderpoor N, de Courten B. Altered Gut Microbiota Composition Is Associated With Back Pain in Overweight and Obese Individuals. Front Endocrinol (Lausanne) (2020) 11:605. doi: 10.3389/fendo.2020.00605 PubMed AbstractCrossRef Full TextGoogle Scholar.

Enterobacteriaceae and PD Symptoms

Higher levels of Enterobacteriaceae in the stools of PD patients are associated with motor symptoms and are linked to increased levels of lipopolysaccharide (LPS) and α-syn fibril formation A Trusted Source

Lin CH, Chen CC, Chiang HL, Liou JM, Chang CM, Lu TP, et al. Altered Gut Microbiota and Inflammatory Cytokine Responses in Patients With Parkinson's Disease. J Neuroinflamm (2019) 16(1):129. doi: 10.1186/s12974-019-1528-y CrossRef Full TextGoogle Scholar A Trusted Source

Bhattacharyya D, Mohite GM, Krishnamoorthy J, Gayen N, Mehra S, Navalkar A, et al. Lipopolysaccharide From Gut Microbiota Modulates Alpha-Synuclein Aggregation and Alters Its Biological Function. ACS Chem Neurosci (2019) 10(5):2229–36. doi: 10.1021/acschemneuro.8b00733 PubMed AbstractCrossRef Full TextGoogle Scholar.

While the direct link between Enterobacteriaceae and PD-induced pain is not established,

LPS is known to activate nociceptor neurons, possibly leading to heightened sensitivity in gut-innervating nociceptors A Trusted Source

Diogenes A, Ferraz CC, Akopian AN, Henry MA, Hargreaves KM. LPS Sensitizes TRPV1 via Activation of TLR4 in Trigeminal Sensory Neurons. J Dent Res (2011) 90(6):759–64. doi: 10.1177/0022034511400225 PubMed AbstractCrossRef Full TextGoogle Scholar A Trusted Source

Boonen B, Alpizar YA, Sanchez A, Lopez-Requena A, Voets T, Talavera K. Differential Effects of Lipopolysaccharide on Mouse Sensory TRP Channels. Cell Calcium (2018) 73:72–81. doi: 10.1016/j.ceca.2018.04.004 PubMed AbstractCrossRef Full TextGoogle Scholar.

Short-Chain Fatty Acids (SCFAs) and Pain

Bacteria in the gut produce SCFAs, including acetate, propionate, butyrate, and valeric acid.

These SCFAs can influence pain by driving microglia polarization, the release of inflammatory cytokines, and microglia activation A Trusted Source

Zhou F, Wang X, Han B, Tang X, Liu R, Ji Q, et al. Short-Chain Fatty Acids Contribute to Neuropathic Pain via Regulating Microglia Activation and Polarization. Mol Pain (2021) 17:1744806921996520. doi: 10.1177/1744806921996520 PubMed AbstractCrossRef Full TextGoogle Scholar A Trusted Source

Sampson TR, Debelius JW, Thron T, Janssen S, Shastri GG, Ilhan ZE, et al. Gut Microbiota Regulate Motor Deficits and Neuroinflammation in a Model of Parkinson's Disease. Cell (2016) 167(6):1469–80.e12. doi: 10.1016/j.cell.2016.11.018 PubMed AbstractCrossRef Full TextGoogle Scholar.

Additionally, SCFAs can affect the immune response by inhibiting Treg cells, increasing T cell density, and modulating leukocyte activity A Trusted Source

Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly YM, et al. The Microbial Metabolites, Short-Chain Fatty Acids, Regulate Colonic Treg Cell Homeostasis. Science (2013) 341(6145):569–73. doi: 10.1126/science.1241165 PubMed AbstractCrossRef Full TextGoogle Scholar A Trusted Source

Vinolo MA, Rodrigues HG, Nachbar RT, Curi R. Regulation of Inflammation by Short Chain Fatty Acids. Nutrients (2011) 3(10):858–76. doi: 10.3390/nu3100858 PubMed AbstractCrossRef Full TextGoogle Scholar.

Sodium butyrate, an HDAC inhibitor, has been shown to reduce pain, suggesting a potential role of gut SCFAs in promoting sensory hypersensitivity A Trusted Source

Kukkar A, Singh N, Jaggi AS. Attenuation of Neuropathic Pain by Sodium Butyrate in an Experimental Model of Chronic Constriction Injury in Rats. J Formos Med Assoc (2014) 113(12):921–8. doi: 10.1016/j.jfma.2013.05.013 PubMed AbstractCrossRef Full TextGoogle Scholar.

Fecal Microbiota Transplantation (FMT) and PD: FMT has shown promise in restoring a healthy microbiome, decreasing SCFA levels,

alleviating physical impairment, and reducing neuroinflammation in PD animal models A Trusted Source

Sun MF, Zhu YL, Zhou ZL, Jia XB, Xu YD, Yang Q, et al. Neuroprotective Effects of Fecal Microbiota Transplantation on MPTP-Induced Parkinson's Disease Mice: Gut Microbiota, Glial Reaction and TLR4/TNF-Alpha Signaling Pathway. Brain Behav Immun (2018) 70:48–60. doi: 10.1016/j.bbi.2018.02.005 PubMed AbstractCrossRef Full TextGoogle Scholar.

In PD patients, FMT has led to improvements in constipation and certain motor and non-motor symptoms, as well as enhanced mental well-being A Trusted Source

Vendrik KEW, Ooijevaar RE, de Jong PRC, Laman JD, van Oosten BW, van Hilten JJ, et al. Fecal Microbiota Transplantation in Neurological Disorders. Front Cell Infect Microbiol (2020) 10:98. doi: 10.3389/fcimb.2020.00098 PubMed AbstractCrossRef Full TextGoogle Scholar A Trusted Source

Huang H, Xu H, Luo Q, He J, Li M, Chen H, et al. Fecal Microbiota Transplantation to Treat Parkinson's Disease With Constipation: A Case Report. Med (Baltimore) (2019) 98(26):e16163. doi: 10.1097/MD.0000000000016163 CrossRef Full TextGoogle Scholar.

There is growing interest in exploring how FMT could potentially improve PD-induced pain and delay the onset of motor symptoms A Trusted Source

Roman P, Abalo R, Marco EM, Cardona D. Probiotics in Digestive, Emotional, and Pain-Related Disorders. Behav Pharmacol (2018) 29(2 and 3-Spec Issue):103–19. doi: 10.1097/FBP.0000000000000385 PubMed AbstractCrossRef Full TextGoogle Scholar A Trusted Source

Pusceddu MM, Gareau MG. Visceral Pain: Gut Microbiota, a New Hope? J BioMed Sci (2018) 25(1):73. doi: 10.1186/s12929-018-0476-7 PubMed AbstractCrossRef Full TextGoogle Scholar.

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