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Cited by 203Parkinson's Disease Mechanisms and TreatmentsGastrointestinal motility and disordersGut microbiota and health

The Gut-Brain Axis in Parkinson’s Disease: Possibilities for Food-Based Therapies

Open access
Perez-Pardo, Paula, Kliest, Tessa, Dodiya, Hemraj B., Broersen, Laus M., Garssen, Johan, Keshavarzian, Ali, Kraneveld, Aletta D.·2017·European Journal of Pharmacology
DOI 10.1016/j.ejphar.2017.05.042
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Abstract

Parkinson's disease (PD) is usually characterized by cardinal motor impairments. However, a range of non-motor symptoms precede the motor-phase and are major determinants for the quality of life. To date, no disease modifying treatment is available for PD patients. The gold standard therapy of levodopa is based on restoring dopaminergic neurotransmission, thereby alleviating motor symptoms, whereas non-motor symptoms remain undertreated. One of the most common non-motor symptoms is gastrointestinal dysfunction usually associated with alpha-synuclein accumulations and low-grade mucosal inflammation in the enteric nervous system. Accumulating evidence suggest that the enteric nervous system is involved in PD pathological progression towards the central nervous system. Moreover, different components of the gut could provide a central role in the gut-brain axis, which is as a bidirectional communicational system between the gastrointestinal tract and central nervous system. Dietary components might influence the gut-brain axis by altering microbiota composition or by affecting neuronal functioning in both the ENS and the CNS. This review gives a comprehensive overview of the evidences supporting the hypothesis that PD could initiate in the gut. We also consider how food-based therapies might then have an impact on PD pathology and/or improve non-motor as well as motor symptoms in PD.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review argues that Parkinson’s disease (PD) pathology may begin in the gut/enteric nervous system and spread to the CNS, with gut microbiota and inflammation as contributors. It evaluates food-based therapies—phospholipid precursors/cofactors, probiotics, prebiotics, and synbiotics—as potential adjuncts to levodopa, but notes that human PD trials are lacking.

Key findings

  • PD prevalence is 0.3% in the general population and 1–3% over age 65; gastrointestinal dysfunction affects 70–80% of PD patients, and constipation may precede motor symptoms by over a decade, with occurrence before motor symptoms reported at 87%.
  • Evidence supports gut initiation/spread of PD pathology: alpha-synuclein accumulates in the enteric nervous system, may spread via the vagal nerve, and full truncal vagotomy was associated with decreased PD risk; rotenone mouse models reproduce gut-to-brain progression. PD microbiota shows reduced Prevotellaceae (77.6%) and lower SCFA butyrate-producing genera such as Blautia, Coprococcus, and Roseburia, while Enterobacteriaceae abundance correlated with postural instability and gait difficulty.
  • Levodopa was used by 85% of PD patients between 2001 and 2012, whereas dopamine agonists were used by 28%; levodopa does not stop disease progression or treat non-motor symptoms, and GI dysfunction contributes to levodopa response fluctuations.
  • Food-based approaches show preclinical promise: uridine, DHA, and choline plus cofactors and prebiotic fibers reduced motor/GI abnormalities and alpha-synuclein/inflammation in rotenone models; probiotics, prebiotics, and synbiotics may improve GI function and levodopa absorption. In one PD constipation study, fermented milk containing Lactobacillus casei Shirota improved stool consistency and reduced bloating and abdominal pain; a synbiotic after antibiotics yielded 93% SIBO-negative subjects versus 67% of controls.

Methods

  • Narrative review; no primary data are reported.
  • Synthesizes clinical, epidemiological, and preclinical literature on the gut-brain axis in PD and dietary interventions.
  • Main analysis is a qualitative overview; no systematic search or meta-analysis is described.

Limitations

  • Stated: it is not possible to determine whether gut microbiota changes are a cause or consequence of PD; studies on probiotics for PD are very limited; prebiotics have never been investigated in PD patients; high-quality randomized placebo-controlled trials are needed.
  • Stated: no disease-modifying treatment is available, and levodopa has no effect on non-motor symptoms.
  • Evident from the text: the review relies heavily on animal/preclinical models and associative human studies; the acknowledgements disclose that two authors are employees of Nutricia Research, indicating a potential conflict of interest.

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Registry

Crossref · 10.1016/j.ejphar.2017.05.042

Cites

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Statistics

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Claims the paper makes

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  • Premisecitation

    Non-motor symptoms in Parkinson's disease may precede the classical motor symptoms by several years.

    “Some of these symptoms may precede the classical motor symptoms by several years (Abbott et al., 2001;Chen et al., 2015;Gao et al., 2011)”
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  • Interpretationreasoning

    The early involvement of the gastrointestinal tract in Parkinson's disease supports the hypothesis that environmental factors could exert influence on Parkinson's disease development and progression via the gut.

    “The early involvement of the GI tract in PD supports the hypothesis that environmental factors could exert its influence on PD development and progression via the gut.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Environmental factors likely play a key role in the initiation of the pathophysiological cascade in Parkinson's disease.

    “However, it is likely that environmental factors play a key role (Kieburtz and Wunderle, 2013;Wirdefeldt et al., 2011).”
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  • Premisecitation

    Occurrence of non-motor symptoms in otherwise healthy people is associated with an increased risk of developing Parkinson's disease.

    “their occurrence in otherwise healthy people has been associated with an increased risk of developing PD (Abbott et al., 2001;Ponsen et al., 2009).”
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    Alpha-synuclein is transmitted via endocytosis to neighboring neurons in vitro and in vivo.

    “Others have shown in vitro and in vivo that alpha-synuclein is transmitted via endocytosis to neighboring neurons (Angot et al., 2012;Desplats et al., 2009).”
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    Interpretationcitation

    Alpha-synuclein deposition in neurons might begin in the enteric nervous system and/or in the olfactory bulbs.

    “new evidence suggests that alpha-synuclein deposition in neurons might begin in the ENS and/or in the OB”
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    Premisecitation

    The vagal nerve might provide a path for the spread of alpha-synuclein pathology from the enteric nervous system to the brain through the brainstem, midbrain, basal forebrain, and cortical areas.

    “The vagal nerve might provide a path for the spread of alpha-synuclein pathology from the ENS to the brain through the brainstem, midbrain, basal forebrain and finally the cortical areas (Braak et al., 2003;Hawkes et al., 2007)”
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    Premisecitation

    Levodopa therapy has several side effects, does not prevent dopaminergic neuron degeneration, and has no effects on non-motor symptoms.

    “This therapy has several side effects (Schrag and Quinn, 2000), it does not prevent dopaminergic neuron degeneration, and has no effects on non-motor symptoms (Lee and Koh, 2015).”
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    Premisecitation

    Constipation is the most prominent gastrointestinal dysfunction in Parkinson's disease and might precede motor symptoms by over a decade.

    “Among them, constipation is the most prominent and it might precede motor symptoms by over a decade (Fasano et al., 2015;Pfeiffer, 2011).”
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    Premisecitation

    Gastrointestinal dysfunction is one of the most common non-motor symptoms in Parkinson's disease, with a prevalence of 70-80%.

    “One of the most common non-motor symptoms in PD are GI dysfunction, with a prevalence of 70-80% (Martinez-Martin, 2011).”
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    Premisecitation

    Braak and colleagues hypothesized that alpha-synuclein pathology might start in the olfactory bulbs and/or enteric nervous system by an unknown pathogen and/or environmental toxin and then progress to the substantia nigra and further areas of the central nervous system.

    “Braak and colleagues hypothesized that alpha-synuclein pathology might start in either the OB and/or in the ENS possibly by an unknown pathogen and/or environmental toxin and then progresses towards the SN and further areas in the CNS.”
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    Interpretationcitation

    Environmental factors such as microorganisms, including nasal/gut microbiota, and toxins like pesticides might start a pathological process at the olfactory bulbs and enteric nerve cell plexus, causing mucosal inflammation and oxidative stress and thereby initiating alpha-synuclein accumulation.

    “Environmental factors such as microorganisms, including nasal/gut microbiota, and toxins like pesticides might start a pathological process at two sites, in the OB and within enteric nerve cell plexus (Hawkes et al., 2009b), causing mucosal inflammation and oxidative stress and thereby initiating alpha-synuclein accumulation (Hawkes et al., 2010).”
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    Premisecitation

    Alpha-synuclein accumulations are associated with damage in enteric neurons and possibly underlie gastrointestinal dysfunction.

    “Alpha-synuclein accumulations are associated with damage in the enteric neurons and possibly underlie GI dysfunction (Gold et al., 2013;Sánchez-Ferro et al., 2015).”
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    Premisecitation

    Alpha-synuclein could act like a prion protein during Parkinson's disease pathogenesis, spreading pathology by templating misfolding of nearby alpha-synuclein.

    “It has been suggested that alpha-synuclein could act like a prion protein during PD pathogenesis.In this theory pathologic, misfolded alpha-synuclein is an 'infectious' protein spreading pathology by forming a template that seeds misfolding for nearby alpha-synuclein protein, turning the previously healthy protein into a pathogenic protein (Jucker and Walker, 2013;Visanji et al., 2013).”
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    Interpretationcitation

    The local effect of pesticides on the enteric nervous system might be sufficient to induce Parkinson's disease-like progression and to reproduce the neuroanatomical and neurochemical features of Parkinson's disease staging from the enteric nervous system to the central nervous system.

    “The local effect of pesticides on the ENS might be sufficient to induce PD-like progression and to reproduce the neuroanatomical and neurochemical features of PD staging, from the ENS to the CNS.”
    Quote in the paperSubstantial claim

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    Interpretationcitation

    Abnormalities of gastrointestinal motility might increase the occurrence of small intestinal bacterial overgrowth, which is highly prevalent in Parkinson's disease patients, even in recently diagnosed patients.

    “Abnormalities of GI motility might increase the occurrence of SIBO which is highly prevalent in PD patients (Brown et al., 2011;Sánchez-Ferro et al., 2015), even in recently diagnosed PD patients (Tan et al., 2014).”
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    Interpretationcitation

    Under-representation of Prevotellaceae diminishes levels of health-promoting neuroactive short chain fatty acids and the capacity for biosynthesis of thiamine and folate, in line with decreased levels of these vitamins in Parkinson's disease patients.

    “The under-representation of Prevotellaceae diminishes the levels of health-promoting neuroactive short chain fatty acids (SCFA) and the capacity for biosynthesis of thiamine and folate (Arumugam et al., 2011), which is in line with decreased levels of these vitamins in PD patients (dos Santos et al., 2009;Luong and Nguyễn, 2013).”
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    Interpretationcitation

    A decrease in Prevotella might be related with a reduction in mucin synthesis which is associated with increased gut permeability, intensifying the translocation of bacterial antigens.

    “The authors further indicate that a decrease in Prevotella might be related with a reduction in mucin synthesis which is associated with increased gut permeability (Brown et al., 2011;Forsyth et al., 2011) intensifying the translocation of bacterial antigens.”
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    Interpretationcitation

    Small intestinal bacterial overgrowth might cause changes in intestinal permeability and contribute to an increase in bacterial translocation and therefore induce an inflammatory response.

    “SIBO might cause changes in intestinal permeability and contribute to an increase in bacterial translocation and therefore induce an inflammatory response (Chen and Quigley, 2014).”
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    Interpretationreasoning

    Parkinson's disease pathogenesis may be caused or exacerbated by dysbiotic microbiota-induced inflammatory responses that could promote alpha-synuclein pathology in the intestine and the brain or by rostral to caudal cell-to-cell transfer of alpha-synuclein pathology caused by increased oxidative stress.

    “We concluded that PD pathogenesis may be caused or exacerbated by dysbiotic microbiota-induced inflammatory responses that could promote alpha-synuclein pathology in the intestine and the brain or by rostral to caudal cell-to-cell transfer of alpha-synuclein pathology caused by increased oxidative stress (due to an increase in pro-inflammatory bacteria).”
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    Premisecitation

    Short chain fatty acid butyrate has anti-inflammatory properties thought to be owing to an epigenetic mechanism or to activation of short chain fatty acid receptors leading to anti-inflammatory effects, anti-microbial effects, and decreased intestinal barrier leakiness.

    “Moreover, SCFA butyrate has anti-inflammatory properties thought to be owing to an epigenetic mechanism or to the activation of SCFA receptors leading to anti-inflammatory effects, anti-microbial effects, and to a decreased intestinal barrier leakiness (Forsythe and Kunze, 2013;Ganapathy et al., 2013;Maslowski and Mackay, 2011;Singh et al., 2014).”
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    Premisecitation

    Prolonged use of levodopa induces severe side effects such as dyskinesia and motor fluctuation, and as the disease progresses patients might eventually develop levodopa-resistance.

    “The prolonged use of levodopa induces severe side effects such as dyskinesia and motor fluctuation (Schrag and Quinn, 2000) and as the disease progresses patients might eventually develop levodopa-resistance (Lebouvier et al., 2010;Lee and Koh, 2015).”
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    Premisecitation

    Biopsies of colonic tissue from Parkinson's disease patients revealed increased expression of proinflammatory cytokines TNF-alpha, IFN-gamma, IL-6 and IL-1 beta as well as increased activation of enteric glial cells.

    “In support of this hypothesis, biopsies of colonic tissue retrieved from PD patients revealed an increased expression in the levels of proinflammatory cytokines, such as TNF-alpha, IFN-gamma, IL-6 and IL-1 beta as well as an increased activation of enteric glial cells (Devos et al., 2013).”
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    Premisecitation

    Parkinson's disease-like neuropathology was mimicked by gastric administration of pesticide rotenone in mice and occurred in the absence of detectable levels of rotenone in the brain and blood.

    “Another study showed that PD-like neuropathology was mimicked by gastric administration of pesticide rotenone in mice and occurred in the absence of detectable levels of rotenone in the brain and blood (Pan-Montojo et al., 2010).”
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    Premisecitation

    Patients positively tested for small intestinal bacterial overgrowth treated with antibiotics followed by synbiotic supplementation containing Bacillus coagulans and FOS showed a better response than patients on the same regimen without synbiotic supplementation; 93% of subjects treated with the synbiotic tested negative for small intestinal bacterial overgrowth compared to 67% of controls.

    “Interestingly, patients positively tested for SIBO treated with antibiotics followed by synbiotic supplementation, containing Bacillus coagulans and FOS, showed a better response than patients on the same regimen without synbiotic supplementation.93% of the subjects treated with the synbiotic tested negative for SIBO compared to 67% of the controls.”
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    Premisecitation

    A clinical study showed that the probiotic Lactobacillus salivarius decreased inflammatory markers in healthy subjects, and its effect when combined with FOS was more pronounced.

    “A clinical study showed that the probiotic Lactobacillus salivarius decreased inflammatory markers in healthy subjects, and its effect when combined with FOS was more pronounced (Rajkumar et al., 2015).”
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    Interpretationcitation

    Improving gastrointestinal function by probiotics might also improve levodopa absorption and reduce behavioral and cognitive deficits such as anxiety, depression and memory problems, which are common in Parkinson's disease patients.

    “Improving GI function by supplementation with probiotics might not solely lead to a better functionality and/or protection of the intestine, but might also improve levodopa absorption and reduce behavioral and cognitive deficits such as anxiety, depression and memory problems (Liang et al., 2015;Maes et al., 2008), which are common in PD patients.”
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    Interpretationcitation

    Prebiotic fibers added to the diet might explain its better effects on gastrointestinal function and motor function via beneficial effects on immune function, bowel motility, and microbiota composition that can alter the enteric immune and nervous system and subsequently the central nervous system.

    “Prebiotic fibers added to the diet might explain its better effects on GI-function since GOS and FOS have shown to have beneficial effects on immune function (de Kivit et al., 2011), bowel motility (Meksawan et al., 2014;Scholtens et al., 2014), but they might also contribute to its better efficacy on motor-function since the prebiotic fibers might positively affect microbiota composition that in”
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    Interpretationcitation

    Dietary interventions might influence the gut-brain axis by altering microbiota composition and therefore altering Parkinson's disease pathogenesis, or by affecting neuronal functioning in both the enteric nervous system and the central nervous system.

    “Dietary interventions might influence the gut-brain axis by altering microbiota composition (and therefore altering PD pathogenesis) (Clemente et al., 2012;Cryan and Dinan, 2012;Maslowski and Mackay, 2011) or by affecting neuronal functioning in both the ENS and the CNS (Fig. 2).”
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    Interpretationreasoning

    Nutrition-based interventions including phospholipid membrane precursors and/or microbiota-directed therapy like prebiotics and probiotics might provide opportunities to complement traditional Parkinson's disease therapies and overcome some of their shortcomings including lack of efficacy for gastrointestinal symptoms/dysfunction.

    “Nutrition based interventions including phospholipid membrane precursors and/or microbiota-directed therapy like prebiotics and probiotics might provide opportunities to complement the traditional PD therapies and overcome some of their shortcoming including lack of efficacy for GI symptoms/dysfunction.”
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    Interpretationcitation

    A specific nutrient combination containing neuronal precursors and cofactors may counteract synaptic loss and reduce membrane-related pathology in the central nervous system and enteric nervous system of Parkinson's disease patients.

    “Specific nutrient combination containing neuronal precursors and cofactors may counteract synaptic loss and reduce membrane-related pathology in the CNS and the ENS of PD patients.”
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    • cites Perez-Pardo et al., 2017a

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    Premisecitation

    Synbiotics have shown to have beneficial effects on immune function, dysbiosis and bowel function, which are very relevant for Parkinson's disease patients.

    “Synbiotics have shown to have beneficial effects on immune function, dysbiosis and bowel function, very relevant for PD patients.”
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    Premisecitation

    In a double blind placebo controlled trial, Lactobacillus reuteri supplementation improved bowel movement frequency in adults with chronic functional constipation, but did not show an effect on stool consistency.

    “In a double blind placebo controlled trial, Lactobacillus reuteri supplementation improved bowel movement frequency in adults with chronic functional constipations, but did not show to have an effect on stool consistency (Ojetti et al., 2014).”
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    Interpretationreasoning

    Probiotics might be a powerful tool to alter Parkinson's disease-associated microbiota composition and improve gastrointestinal function and therefore reduce gut leakiness, bacterial translocation and associated neuro-inflammation in the enteric nervous system.

    “Probiotics might be a powerful tool in order to alter PD-associated microbiota composition and improve GI function and therefore reduce gut leakiness, bacterial translocation and the associated neuro-inflammation in the ENS.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Small intestinal bacterial overgrowth is highly prevalent in Parkinson's disease and patients that tested positive for it are predisposed to worse motor-dysfunction.

    “As mentioned before, SIBO is highly prevalent in PD (Andrews et al., 2009;Brown et al., 2011) and PD patients that tested positive for SIBO are predisposed to worse motordysfunction (Tan et al., 2014).”
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    Premisecitation

    A preventive dietary intervention containing uridine, docosahexaenoic acid and choline was effective for mitochondrial dysfunction-induced motor symptoms and reduced alpha-synuclein accumulation and inflammation in the colon in the unilateral rotenone model for Parkinson's disease.

    “The preventive dietary intervention was not only effective for the mitochondrial dysfunctioninduced motor symptoms but also reduced alpha-synuclein accumulation and inflammation in the colon (Perez-Pardo et al., 2017b).”
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    Interpretationcitation

    The fecal microbial community of Parkinson's disease showed a lower abundance of short chain fatty acid butyrate-producing bacteria that could be corrected by the use of prebiotic fibers.

    “Moreover, as mentioned above, the fecal microbial community of PD showed a lower abundance of SCFA butyrate-producing bacteria (Keshavarzian et al., 2015;Unger et al., 2016) that could be corrected by the use of prebiotic fibers.”
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    Premisecitation

    Various studies have reported beneficial effects of probiotics by enhancing intestinal epithelial integrity, protecting from barrier disruption, stimulating a healthy homeostasis of the mucosal immune system and suppressing pathogenic bacterial growth.

    “Various studies have reported the beneficial effects of probiotics by enhancing intestinal epithelial integrity, protecting from barrier disruption, stimulating a healthy homeostasis of the mucosal immune system and suppressing pathogenic bacterial growth (Ait-Belgnaoui et al., 2012;Corridoni et al., 2012;Patel et al., 2012;Sartor, 2005;Zareie et al., 2006).”
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  • May combine two claims.

    Interpretationreasoning

    Probiotics, prebiotics and/or synbiotics might impact gut microbiota composition and possibly enhance intestinal epithelial integrity and reduce the pro-inflammatory response, impacting initiation or progression of the neurodegenerative process.

    “Probiotics, prebiotics and/or synbiotics might impact the gut microbiota composition and possibly enhance intestinal epithelial integrity and reduce the pro-inflammatory response, impacting initiation or progression of the neurodegenerative process.”
    Quote in the paperSubstantial claim

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    Interpretationnone given

    Dietary membrane precursors and cofactors can increase neuronal membrane formation and function, and reduce inflammation, affecting both the enteric nervous system and central nervous system and reducing motor and non-motor abnormalities in Parkinson's disease.

    “Dietary membrane precursors and cofactors can increase neuronal membrane formation and function, and reduce inflammation, affecting both the ENS and CNS and reducing motor and non-motor abnormalities in PD.”
    Quote in the paperSubstantial claim

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    Interpretationreasoning

    Food-based therapies have shown beneficial effects on gastrointestinal dysfunction and when combined with levodopa treatment they might increase levodopa uptake and availability, allowing a reduction in the doses of levodopa given to patients and reducing the negative secondary effects produced by the drug.

    “Moreover, these therapies have shown to have beneficial effects on GI dysfunction and when combined with levodopa treatment they might increase levodopa uptake and availability, allowing a reduction in the doses of levodopa given to patients and reducing the negative secondary effects produced by the drug.”
    Quote in the paperSubstantial claim

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    Interpretationreasoning

    Bacterial translocation could also induce a pro-inflammatory environment that could signal to specific parts of the brain systemically and through dysfunctional blood brain barrier structures.

    “Bacterial translocation could also induce a pro-inflammatory environment that could signal to specific parts of the brain systemically and through dysfunctional blood brain barrier structures.”
    Quote in the paperNot a substantial claim
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  • The paper relies on this without support.

    Findings from preclinical animal models of Parkinson's disease predict clinical benefit in Parkinson's disease patients.

    “It might confer clinical benefits to patients suffering from PD since they are able to reduce motor and non-motor abnormalities in preclinical studies.”
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Research works printed but not linked: 5

  1. Bazan, 2012, NIH Public Access, 321
  2. Hawkes, 2009, Parkinson's disease: the dual hit theory revisited, Ann. N. Y. Acad. Sci., 1170, 615, 10.1111/j.1749-6632.2009.04365.x · DOI · Paper page
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Authors
Perez-Pardo, P., Kliest, T., Dodiya, H. B., Broersen, L. M., Garssen, J., Keshavarzian, A., & Kraneveld, A. D.
Affiliations
  • Utrecht University (NL)
  • Rush University Medical Center (US)
Corresponding author
Kraneveld, Aletta D.
ORCID
Venue
European Journal of Pharmacology
Publisher
Elsevier BV
Published
2017-12
Volume
817
Pages
86-95
ISSN
0014-2999 (ISSN-L)
DOI
10.1016/j.ejphar.2017.05.042
OpenAlex
W2619485173
Semantic Scholar
71a5d182d95e15cca7e5e0fda83418a331c54a0b
Cited by
203
References
165
Citations by year
2026: 7 · 2025: 16 · 2024: 23 · 2023: 20 · 2022: 29 · 2021: 35 · 2020: 30 · 2019: 27 · 2018: 11 · 2017: 5
FWCI
13.78
Type
journal article
Language
en
Open access
Licence
Locations
  • European Journal of Pharmacology (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
Keywords
Parkinson's disease, gut-brain axis, non-motor symptoms, gastrointestinal dysfunction, enteric nervous system, alpha-synuclein, gut microbiota, mucosal inflammation, levodopa, dopamine signaling, food components
MeSH terms
Animals, Brain, Food, Humans, Parkinson Disease, Enteric Nervous System, Gastrointestinal Tract

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

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