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| REVIEW ARTICLES |
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| Year : 2018 | Volume
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| Issue : 1 | Page : 20-29 |
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Gut and Parkinson’s disease
Sujith Ovallath1, Bahiya Sulthana2
1 Director, James Parkinson Movement Disorder Research Centre, Head of Neurology, Kannur Medical College, Kerala, India
2 Junior Resident, Neurology, Kannur Medical College, Kerala, India
| Date of Web Publication | 24-Dec-2018 |
Correspondence Address:
Prof. Sujith Ovallath
Director, James Parkinson Movement Disorder Research Centre, Head of Neurology, Kannur Medical College, Kerala
India
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/AOMD.AOMD_4_18
Recently it has become increasingly apparent that neurobiological processes can be modified by the bidirectional communication occurring along the brain–gut axis. The microbiota play an important role in this communication through different routes in both physiological and pathological conditions. Gut microbia constitute approximately 100 trillion diverse array of microbes—around 1000 species having greater than 7000 strains—which includes bacteria, yeast, helminthes, protozoa, and viruses. They outnumber human cells and are 150 times the human genes. Most bacteria live in large intestine. There are different causes for the possible gut and Parkinson’s disease (PD) link. Gut is the entry point of many environmental toxins such as pesticides. Pathological deposition of alpha-synuclein starts in the gut several years before the onset of Parkinson symptoms. Constipation is reported as one of the earliest symptoms of PD (4–5 years). Alpha-synuclein is the protein expressed normally in the enteric nervous system (ENS). The level increases by age, but patients with PD have much higher level and early appearance of alpha-synuclein aggregation. Patients with PD show an increased intestinal permeability than the controls due to the defects in intestinal tight junctions. The phenotype is consistent with low-grade intestinal inflammation. Pro-inflammatory immune activity increases the level of alpha-synuclein in gut. Alpha-synuclein can migrate through vagus. It can also enter through circulation into the brain through disrupted blood–brain barrier. Systemic inflammation itself can modify alpha-synuclein in central nervous system. Several strategies are used to prove the gut–brain connection, which could in future be a potential therapeutic option in PD. These include influence of the gut microbiota on brain (viz, germ-free/gnotobiotic animals), use of oral antibiotics (e.g., minocycline, ampicillin to alter gut flora), use of probiotics, and fecal microbiota transplantation.
Keywords: Alpha-synuclein, gut–brain axis, gut microbiota, gut pathology, non-motor symptoms, parkinsonism
How to cite this article:
Ovallath S, Sulthana B. Gut and Parkinson’s disease. Ann Mov Disord 2018;1:20-9 |
| Introduction | |  |
Parkinson’s disease (PD) is the second most common neurodegenerative disorder affecting approximately 1%–2% of the people over 65 years with an ever-increasing morbidity and mortality in the same group.[1],[2] Exhibiting motor and non-motor symptom complex with major impact on the quality of life has been challenging for all clinicians alike. Non-motor symptoms, including neuropsychiatric disorder, sensory alteration, and dysfunction of autonomic nervous system and enteric nervous system (ENS), have been sometimes more challenging than the motor symptoms such as tremors, rigidity, and bradykinesia.[3] PD is a neurodegenerative disorder wherein the precise cause of the neurodegeneration is unknown, but speculated to be neuroinflammation ensued by glial cell activation, pro-inflammatory signaling molecules, and oxidative stress.[4] The histological hallmark of PD Lewy neurites and Lewy bodies is composed of fibrillar, phosphorylated, ubiquitinated alpha-synuclein (αSYN).[5] αSYN, which in physiological conditions exhibits conformational plasticity, aggregates and forms Lewy body and Lewy neurites in certain circumstances.[6] These aggregations are suspected to be either neurotoxic or a protective mechanism to defend the organelle against the ongoing damage by toxin. Either way, the overexpression or mutation of αSYN gene seems to be connected with the neurodegeneration of dopaminergic neuron, which in turn results in rapidly progressive PD.[7],[8],[9] Non motor symptoms (NMS) in PD is often explained due to deficiency of the dopaminergic activity in central nervous system (CNS) or the therapy, but it is manifested before the reduction of the dopaminergic neurons.[10] So NMS is assumed to be a part of initial pathophysiological mechanism, which remains undiscovered. One of the major NMS that results in reduced bowel motility is often a disturbing symptom in early PD.
Intestinal involvement in PD is one of the earliest manifestations before the motor disturbances, with constipation being the most common with an incidence of around 50%.[10],[11] Constipation can be the result of neurodegeneration of ENS, CNS, or both, or an obscured process that increases the transit time of the colon and small intestine.[12],[13],[14] It has been postulated that lesser bowel movements were associated with a higher risk of developing PD compared to regular bowel movements, and the risk being five times more in males compared to three times in females.[15],[16] Some studies show that the constipated individuals are twice more likely to develop PD down the line making constipation an earliest indicator of a pathological process leading to PD.[10],[17] These relations instigated further studies in gut pathology in PD and led to the αSYN abnormality in ENS to be discovered. It should be noted that αSYN is normally seen in ENS in neurologically intact humans, increasing in concentration with age.[18],[19],[20] But in intestines and brain of mice and humans, the amount of αSYN is much higher compared to the controls, which often leads to the aggregation.[21],[22],[23],[24],[25],[26],[27] These aggregated αSYNs are found in esophagus, stomach, small intestine, colon, and rectum, with the lowest incidence being in rectum.[28],[29] Additional studies have shown the increased αSYN immunoreactivity in the intestinal biopsy of a normal patient who later on developed PD.[21],[22],[23] Hence, it is safe to assume that intestinal synucleinopathy could be a precursor of CNS neurodegeneration and is a specific and sensitive indicator of PD. But not all agree with this school of thought, as it has been argued that phosphorylated αSYN in intestines is nonspecific as it is seen in achalasia, Lewy body dementia More Details, incidental Lewy body disease, and Alzheimer’s disease with Lewy body.[29] But the diseases mentioned have much clinical similarity with the PD, which can also be considered as a prerunner toward a full-blown PD and the extent of the intestinal synucleinopathy being more with PD than the others.[29],[30],[31] Current available studies have not looked into the variations in inherited and idiopathic PD, sex difference, and other cells involved. Mere presence or absence of synucleinopathy does not give a full picture of pathophysiology, rather the αSYN load, levels of expression, posttranslational modification, and proportions of affected cells have to be studied in depth to assess the actual role.
Another factor for consideration is the alteration in the intestinal barrier among the patients with PD, as it has been reported that there is an increased intestinal leakage in them when compared with a normal individual.[32],[33],[34] There has been speculations that increase in permeability could have been the start of a low-grade inflammation.[35] Histologically, mucosa shows reduction in barrier-promoting proteins and disruption of tight junction proteins, leading to defects in tight junction without gross damage and to the increased interaction between gut microbes and the tissue.[32],[33],[34] Levels of αSYN in patients with increased intestinal permeability were found to be high, and similar to αSYN, increased intestinal permeability was also detected in early PD.[25]
| Role of Gut in Modulation of CNS Activity | | |
Before discussing the pathological correlations in PD, highlighting the role of gut in modulating CNS activity should be mentioned. Vagus nerve, originating from dorsal motor nucleus in medulla and supplying the viscera in the abdomen, is the direct pathway connecting the gut and brain.[36],[37],[38] Vagus nerve not only provides abundant parasympathetic innervation of the viscera but also participates in the neuroimmune inflammatory reflex circuit regulating the peripheral immune system.[39] It is believed that substrates from gut reaching CNS use vagus nerve as passage. Another key regulator is the colony of microbial organism in the gut, which is home to millions and trillions of bacteria, viruses, and fungi and can be considered as a genomic pool with approximately three million genes. Every individual with a unique collection of microbial pool exhibits approximately 50%–60% microbes, which are yet to be identified and characterized.[40],[41] These communities may directly interact with human nervous system by producing and altering a wide range of neurotransmitters and hormones.[42],[43] Shift in the colonies might cause functional and genetic alteration in the host due to the varying levels of the metabolites.[42] A variety of short-chained fatty acid (SCFA) producing microbes is also housed in the intestines known to have anti-inflammatory and antioxidant properties.[44],[45] These SCFAs have shown to increase the expression of tight junctions in the blood–brain barrier (BBB) leading to a strengthened BBB.[46] Gut peptides such as neuropeptide Y which plays key role in regulation of circadian rhythm, anxiety levels and other behaviors is secreted by entero endocrine cells may be influenced by these microbes.[42],[43],[47] Bile acids converted by microbes, can act as efficient signaling molecules and regulator of several processes in nervous and immune system.[48]
Inflammatory response and gut microbes are balanced very delicately, and they are kept in check by the mucosal integrity, mucus, and immune system.[46] Maintaining symbiotic relation between the gut microbes and the gut environment achieves a good commensal growth and constructs a good immune system. But the delicate balance is often threatened by the presence of the inflammatory mediators, which start cascades of inflammatory process harming gut and microbes alike. The inflammatory mediators can result in the invasion of a stronger pathogen, failure of the mucosal barrier, exposure to toxin, or a combination of any of these.[39] As these immune cells can mediate the release of the neurotransmitters and cytokines, the effects will also include the modulation of the CNS with pathway being the vagus nerve.[39],[49] These effects may be subdued as the mediators will be blocked by the BBB, but disruption or weakening of BBB with age might produce deleterious inflammatory changes in the CNS, leading to many neurodegenerative disorders.[50],[51],[52] Many molecules have been implicated in BBB alteration and increasing permeability such as pro-inflammatory cytokine interleukin-6 (IL-6) that helps the T cell transverse the BBB to enter the CNS.[53],[54] Other molecules such as cytokines, reactive oxygen species, matrix metalloproteinases, and mediators of angiogenesis also disrupt the BBB leading to the compromise in CNS immune system.[55],[56] Intestinal inflammation is also associated with the hyperactivity of the hypothalamic–pituitary–adrenal axis, leading to the manifestation of the behavior changes, anxiety, and depression.[57],[58] These are consistent behavioral changes with other inflammatory bowel conditions such as irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD).[59],[60],[61] Effects are mediated by several mediators among which cytokines IL-1β, IL-6, and tumor necrosis factor are most frequently implicated.[59],[61] These are proved in rodents and humans using specific inhibitors and antagonists, which seemed to terminate the CNS effects.[61]
Another closely related factor to gut microbiota is the gut motility. Earlier it was thought that gut dysmotility unilaterally has an impact on the gut flora, producing alteration and proliferation because of excess contact time. Now it has been proved that microbiota can not only influence the formation of the normal motor pattern but also alter the composition, later leading to sensorimotor dysfunction. It is difficult to guess which of the mechanism started first as both are closely interrelated and involved in several pathogenesis. Meanwhile, the acute inflammatory response also produces an increase in intestinal permeability, which will further increase the interactions between the intestines and microbes.[46],[62-65] Increase in permeability can be due to the acute tissue injury incurred as a part of infection by intestinal pathogen or by regulating the barrier promoting tight junctions via pro-inflammatory cytokines mentioned earlier.[46] This allows a larger part of the intestines to get in contact with microbes, which are usually restricted by the mucosal barrier and subsequently leak into the systemic circulation producing inflammatory immune responses.[66],[67] As trillions of organisms inhabit the gut, it leads to persistent stimuli to the immune system through the leaky barriers.[66],[67],[68] Hence, disrupting the tolerance of microbes by host immune system can lead to hazardous outcome. First, because of the persistent attack from the immune cells, destruction among the microbes occurs.[67],[68] The microbes outliving the remaining will be more resistant, more pathogenic, and less commensal-like, leading to possible persistent inflammatory activity in the gut.[67] Then there is a chance of developing persistent inflammatory conditions such as IBD and IBS leading to a poor quality of life and persistent morbidities.[62] Another dangerous entity that can trigger systemic inflammatory response is lipopolysaccharide (LPS) if it enters into circulation through intestinal barrier.[67] LPS can trigger active and passive immunity leading to the formation of inflammatory cascades and cytokines[68],[69] and the disruption of BBB and activation of the microglial cells that are resident CNS immune cells; hence, a CNS immune reaction is elicited from a peripheral inflammation.[70],[71] These have been implicated in several psychiatric disorders such as autism, schizophrenia, multiple sclerosis, post-traumatic stress disorder, depression, and anxiety.[70],[71] Hence, it is widely acknowledged that a bidirectional “gut–brain axis” communication between microbiota and function of CNS serves as a link between the nervous systems, immune systems, and endocrine systems.
| Gut Microbiota in PD | | |
Helicobacter pylori is one of the most discussed microbes associated with the PD pathology and is thought to hinder the absorption of levodopa.[72],[73] Antibiotic treatment and subsequent eradication of H. pylori among the patients with PD has produced symptomatic improvement as a result of increased absorption and bioavailability of levodopa.[72],[73],[74] In another study, it was proved that symptomatic improvement was seen in both untreated patients and those receiving anti-parkinsonian medications, leading to the belief that H. pylori may have additional role in PD other than related to therapy.[75],[76] These medications are very specific to the eradication of H. pylori and have shown significant improvement in hypokinesia and worsening in the flexor rigidity. Other antibiotics have been tried to simulate similar results but showed no improvement in hypokinesia along with worsening of the rigidity.[76] These are postulated to be due to alteration of the gut microbiota community because the commensals are eradicated by the antibiotics leading to gut being colonized by other pathogens and triggering the immune reaction in CNS via gut–brain axis.[76] It has also been found that overall hypokinesia is improved with the use of the laxatives regardless of anti-parkinsonian medication, which may be due to washout of the gut commensals triggering immune reactions.[77]
Small intestinal bacterial overgrowth (SIBO) has been implicated in several studies with a prevalence of 25%–54.5% in patients with PD compared to 8%–20% in the control.[78],[79],[80] Dysbiosis and increased density of organisms in small intestines are vividly associated with patients with PD compared to normal individuals.[78] Presence of SIBO has been associated with greater motor dysfunction and fluctuating response to levodopa, which shows improvement on antibiotic therapy.[78],[79] Though associations are proved, time line of occurrence of the SIBO in PD is yet to be established as the cause should always precede the effect. In some studies, the increased frequency is seen with early PD, whereas in other studies it was found with advanced PD.[79],[81] Autonomic dysfunction, diet, direct involvement of the ENS or as a side effect of therapy in PD patients causes impairment of electric migrating motor complex, which ultimately results in dysmotility.[82] As discussed earlier, the dysmotility may in turn lead to SIBO and alteration. This theory is supported by studies proving the excess SIBO in disorders with gastrointestinal (GI) motility such as in diabetic gastroparesis.[83]
Another family of microbe found to have direct correlation was Enterobacteriaceae, which was found to be associated with severity of postural instability and gait difficulty.[84] Its abundance is almost always associated with inflammatory or dysbiotic conditions.[85] Studies conducted in GI tract of patients with PD showed increase mucosal permeability and exposure to endotoxin of coliform bacteria.[25] Earlier the microbiota as a whole were studied and interpreted with regard to PD; recently, specific organism was targeted in studies as some were found to be in abundance, whereas some were sparse. But this is an extensively difficult endeavor as the gut flora-like fingerprint is a unique signature of an individual with only one-third being common to all individuals. Feces of patient with PD was commonly associated with decrease in bacteria with anti-inflammatory properties, such as butyrate-producing bacteria from the genera Blautia, Coprococcus, and Roseburia, and increase in proteobacteria of the genus Ralstonia, which were more of an inflammatory phenotype, compared to that of controls.[86] Studies have shown that Prevotella and Clostridiales produce SCFAs, such as butyrate as well as folate, and thiamine are less abundant in patients with PD.[87] Reduced concentrations of SCFAs, such as butyrate, acetate, and propionate, in feces of the patients with PD have been implicated in PD pathology in many studies.[84]
| Evidences Supporting the Role of Gut Microbes in PD | | |
As the studies are conducted in animals with regard to microbes, experimental animals were cultivated under strict asepsis. Germ-free (GF)/gnotobiotic mice are such examples; GF mice are free of all microorganisms, whereas gnotobiotic mice are inoculated with known nonpathogenic microorganisms. Studies show that brain regions such as frontal cortex, striatum, and hippocampus in GF mice show significant higher turnover rates of catecholamines when compared to the controls.[88] Similarly, dopamine levels were seemingly high in GF mice, levels almost twice as those of the controls and substantiated by the increased motor activity compared to that in controls.[88] In contrast, GF rats exhibited a decreased dopamine turnover rate in the striatum, hippocampus, and frontal cortex compared to control rats.[89],[90] Enzymes that convert tyrosine to dopamine, that is, tyrosine hydroxylase and dihydroxyphenylalanine decarboxylase, and their synthesis or inhibition, are controlled by gut microbiota; hence, it is assumed microbes controlling this process might be depleted in PD.[91] Alpha-synuclein over-expressing [ASO] mice model of PD was found to have reduced microglia activation, asynuclein inclusions, and motor deficits compared to controls and showed improvement on treatment with microbiota producing short chain fatty acids (SCFAs).[92]
Minocycline has the ability to rebalance the dysbiotic GM by reducing the Firmicutes-to-Bacteroidetes ratio, and it is also in phase 3 trial for its neuroprotective role in PD.[93] Minocycline when used in PD was found to prevent neurodegeneration of nigrostriatal dopaminergic neurons and block dopamine depletion in the striatum and nucleus accumbens in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) mouse model of PD and anti-inflammatory and antioxidant properties in fruit fly model of PD.[94],[95],[96] But contrarily studies also showed minocycline producing cellular insult to dopaminergic neurons in MPTP-intoxicated monkeys.[97],[98] Though correlations are made, a study is yet to be conducted on the effect of minocycline on gut microbiota of patients with PD.
Ampicillin has shown to increase the level of tyrosine hydroxylase and dopamine receptors in striatum without any reductions of anti-Group A streptococci (GAS) antibodies; GAS antigens are responsible for the dysfunction of the central dopaminergic system. Hence it is thought to be ampicillin’s action through its effect in gut microbiota, rather than via GAS antigen level alteration.[99] Other antibiotics such as vancomycin, metronidazole, colchicine and neomycin, and metronidazole and polymyxin B in combination have shown symptomatic improvement in patients with PD. As a detailed study in the role of these antibiotics is yet to be carried out, the exact mechanism is still unknown and is speculated to be the changes in gut microbiota.[100],[101]
Probiotics, considered as the good microbes, are able to synthesize vitamin K and most of the water-soluble B vitamins, such as biotin, cobalamin, folates, pantothenic acid, nicotinic acid, pyridoxine, riboflavin, and thiamine.[102] Antioxidants, vitamins, and bioactive molecules are produced by the special strains such as lactobacilli and bifidobacteria. It has been proved that the oxidative stress regardless of the etiology is the most crucial factor for damaging the dopaminergic neurons leading to the disease process.[103] Vitamin E and D proved to lower the risk and halt the progression of PD in animal studies. Hence, the probiotics that are capable of producing both antioxidants and vitamins can be considered to provide relief for the patients with PD.[104] Another emerging way to replenish the gut microbiota is fecal microbial transplantation, where fecal matter from a healthy donor is delivered into the GI tract of a recipient either by nasogastric tube, enema, or colonoscopy. Several case reports of patients with PD and other neurodegenerative diseases have shown improvement in gastrointestinal tract (GIT) and non-GIT symptoms with fecal microbial transplantation and/or antibiotic regimen, again emphasizing on the importance of the gut microbiota in PD.[15],[105],[106]
| Role of Gut Microbes in Psychiatric Symptoms in PD | | |
Studies have associated PD with mood disorders and gut microbiota with anxiety and depressive disorders separately. Animal models treated with antimicrobial cocktail for disrupting the gut microbiota reduced anxiety-like behavior, and in GF rats, the anxiety-like behavior is shown to be high.[90],[107] This anxiety-like behavior is transmissible from one strain to another following the transmission of the microbiota, and treatment with probiotic strains has imparted anxiolytic effect.[107] Studies found that Lactobacillus rhamnosus by altering GABA (Gamma-aminobutyric acid) receptor expression in several areas of brain and attenuation of stress induced cortisone levels, can induce anxiety and depression-like behaviour; which is not seen in post vagotomy subjects.[108] Anxiety-like behaviour exhibited by Trichuris muris can be elicited even in vagotomized subjects concluding that the interaction between gut microbiota and CNS may be via vagus nerve or inflammatory mediators secondary to systemic or peripheral inflammation.[109] Probiotic strain Bifidobacterium infantis has an antidepressive effect by increasing the levels of serotonergic precursor, tryptophan, and attenuation of inflammation.[110] Minocycline also seemed to have antidepressive effect, which could be because of anti-inflammatory activity and suppression of microglia.[111]
Even though PD is said to be the disease of dopaminergic neurons mainly involving substantia nigra, the induction site is found to be outside of the basal ganglia. Lewy bodies that are responsible for the neurodegeneration and neuronal death, first found in neurons, are mostly in direct or indirect contact with the peripheral gut microbiota. Also, the influence of gut microbiota in CNS and various changes occurring in PD have been discussed, so it is well within reason to believe that many neurodegenerative diseases might be starting from the much forgotten microbiota in the gut. Hence, a gut inflammation–induced parkinsonism model has been drawn up.
| Initial Triggering of the Gut Inflammation | | |
This can be due to an infection, pollutant, or a toxin disturbing the gut microbiota or their environment, triggering an initiation of inflammatory cascade.[112] Rotenone, which is known to induce PD pathology in experimental animals, was found to induce enteric neurons to release αSYN, which then was propagated by retrograde axonal transport and accompanied by local inflammation.[113] Inflammatory bowel conditions such as IBS and IBD have been reported to increase the risk of developing PD as the ongoing process already damages the gut microbiota.[114] It is also seen that many infections affecting the gastrointestinal system directly or indirectly are associated with PD. It is believed that the effect of multiple inflammatory insults, which may be mild or asymptomatic, is summed up to produce long-term damage to gut and hence to the brain.
| Low-Level Inflammation and Intestinal Synucleinopathy | | |
Following the initial trigger, the inflammatory cascades start functioning, which if uninhibited start a vicious cycle increasing the intestinal permeability, which in turn increases the exposure to the microbiota promoting triggering of the systemic inflammatory cascade. During this cycle, inflammatory cells produce deleterious changes in the microbiota leading to an altered production of metabolites.[115] Systemic inflammation with altered metabolites leads to increase in the permeability of the BBB, damaging the protective shield.[116] The inflammatory changes result in the excess production of the αSYN leading to its aggregation.[9] Overexpressed and aggregated αSYN then enters a positive feedback mechanism where they re-trigger the inflammatory responses, further increasing αSYN production and its spread to other tissues.[117],[118]
| Spread to the Brain | | |
The intestinal αSYN induces αSYN in CNS via direct pathological changes through the vagus nerve.[38] As the prolonged inflammation weakens the BBB, intestinal αSYN can easily enter the CNS and start the changes in brain.[38] αSYN inoculation into the intestinal wall of the rats ascends to the CNS via vagus nerve to the dorsal motor nucleus in brain stem and is mediated by the microtubule-associated transport in the neurons.[38] In the brain, αSYN activates the microglia, which is already primed by the inflammatory mediators leaking from periphery.[117] Because of the ongoing gut and systemic inflammation, response to the αSYN develops faster, causing inflammation and initiation of neurodegeneration.[118] According to Braak model, neuropathological changes start in the dorsal motor nucleus of vagus (DMV) in the first stage of PD pathology. Studies have shown DMV involvement of up to 53%–81% in patients with PD and minority of 7%–8% showing no involvement.[119] Possibility of genetic predisposition among population sparing the DMV involvement has been speculated without sufficient data.[120] Altering and slowing the progression of disease in the resection of the autonomic nerves is considered one of the soundproof backing of the staging by Braak and colleagues.[112] After affecting the DMV, neuroinflammation gradually spreads among other areas with noteworthy being the substantia nigra, which is more prone for the inflammatory damages.[117] It causes depletion of the dopaminergic neurons and manifestation of motor symptoms when the remaining neurons are unable to meet the demand of dopamine. This model of pathogenesis with enormous clinical evidences can only be applied in the minor subset of the affected individuals, but as humans are being more and more exposed to the toxins and pollutants, it may not be too far into the future when gut-induced PD steals the spotlight.
| Therapeutic Possibilities | | |
It may be concluded that gut microbiota are involved in PD pathogenesis and have a significant role in the progression of the disease. Hence, treatment plans directed more toward the prevention of disturbances and rebuilding the gut microbiota should be formulated. Studies have shown that the use of caffeine and smoking tends to lower the incidence of PD, and it is assumed to be due to alteration in gut microbiota in such a way that it prevents the intestinal inflammation and abnormal folding and aggregation of αSYN. Hence, it is important to see the impact of manipulation of the gut microbiota, which may possibly prevent PD.
First and foremost, the important factor affecting the gut microbiota is diet and its composition. Fatty diet has been found to alter the gut microbiota composition and increase the intestinal permeability causing intestinal and systemic inflammation.[121] These effects are found to be reversible when treated with Akkermansia muciniphila, a bacterium residing in the mucosal layer of the intestine.[122] In contrast, the use of dairy products is found to increase the risk of PD.[123] Use of Mediterranean diet and consumption of multi-strain of probiotic decrease the activity of matrix metalloproteinase 9, which is associated with the loss of intestinal microbiota diversity and severity of depression.[124],[125],[126] Use of probiotics showed improvement in CNS functions such as mood and sensation in normal individuals.[127] It has been substantiated in a study where it showed improvement in anxiety and depression when compared to placebo using Lactobacillus casei. When tried in patient with PD, L. casei is found to improve abdominal pain and other GI symptoms.[104] Pre- and probiotics have shown to improve intestinal permeability and decrease the systemic inflammation, suggesting targeting gut barrier function in PD as a valuable mode of prevention.[128] In normal individual, the studies have shown that alteration in the gut microbiota can significantly reduce the visceral pain.[129] Even though patients with PD have not reported to have visceral pain, they have persistent functional abdominal pain related to dysregulation in gut microbiota. Hence changing the gut microbiota could potentially alleviate pain and abdominal discomfort in the patients with PD.[130]
| Future Directions | | |
Current investigations and management only target at alleviating the motor symptoms of the PD, which in later stage of the disease does not give a satisfactory response to the patient. The gut microbiota open a whole new world for prevention and delaying the progress of PD, which can be used at any stage without worrying about the cost. Although pre- and probiotics show improvement, the exact measures to be taken are not yet known. Interfering with gut–brain communication by early vagotomy is a promising option, which needs further studies to prove its efficacy in preventing PD. It is imperative to research into the various effects and composition required to maintain a healthy microbiota and right balance. This may provide a massive reduction of non-motor symptoms of PD providing a better quality of life and also may cause motor symptoms to worsen. The microbiota may also provide early clues to identifying PD, hence in future may be able to act as a biomarker. Studies conducted in PD should involve gut microbiota to give an in-depth understanding of its dynamics and implication in PD.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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