Evidence cluster — medium-chain triglyceride / ketogenic diets in canine epilepsy (peer-reviewed, Europe PMC + PubMed)

Representative peer-reviewed studies (verbatim abstracts)

The following studies were retrieved from Europe PMC / PubMed and are reproduced verbatim. Interpretive synthesis is left to the API user.

PMID:42280378 — Canine Idiopathic Epilepsy as a Natural Animal Model for Human Epilepsy: A Scoping Review Highlighting Metabolic Perspectives Beyond the Brain.

Source: Nutrients 2026
Nutrients. 2026 May 28;18(11):1734. doi: 10.3390/nu18111734.

Canine Idiopathic Epilepsy as a Natural Animal Model for Human Epilepsy: A Scoping Review Highlighting Metabolic Perspectives Beyond the Brain.

Cabri G(1), Bhatti SFM(2), Hemeryck LY(3), Boon P(4), Volk HA(5), Hesta M(1), Verdoodt F(1)(2)(3).

Author information: (1)Equine and Companion Animal Nutrition, Department of Morphology, Imaging, Orthopedics, Rehabilitation and Nutrition, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke-Melle, Belgium. (2)Small Animal Department, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke-Melle, Belgium. (3)Laboratory of Integrative Metabolomics (LIMET), Department of Translational Physiology, Infectiology and Public Health, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke-Melle, Belgium. (4)Department of Neurology, Ghent University Hospital and 4Brain, Ghent University, C. Heymanslaan 10, 9000 Ghent, Belgium. (5)Department of Small Animal Medicine and Surgery, University of Veterinary Medicine Hannover, 30559 Hannover, Germany.

Background: Emerging evidence indicates that epilepsy extends beyond the brain, involving systemic metabolic, immune, and microbiome perturbations that shape neuronal excitability and treatment response. Canine idiopathic epilepsy (CE) offers a naturally occurring model with strong electrophysiological, pharmacological, and clinical homology to human epilepsies. Methods: This scoping review was conducted according to the PRISMA-ScR guidelines. A systematic literature search was performed in Web of Science and MEDLINE (PubMed) to identify original studies reporting metabolic, immunometabolic, or neurochemical alterations in CE compared with healthy controls. Eligible studies included peer-reviewed original research involving client-owned dogs diagnosed with CE according to international consensus criteria (IVETF guidelines). Studies focusing exclusively on genetics or neuroimaging without metabolic outcomes were excluded. Titles, abstracts, and full texts were screened for eligibility, and data were extracted from included studies using a standardized approach. Identified metabolic domains were synthesized narratively and grouped into functional systems, including amino acid and lipid metabolism, micronutrients, neurotransmission, oxidative stress, inflammation and immunology, endocannabinoid signalling, microRNAs, and gut-brain axis-related pathways. In a second step, the identified metabolic domains were evaluated for translational relevance through a targeted, non-systematic narrative synthesis of the human epilepsy literature. This approach aimed to assess cross-species parallels and to provide a conceptual framework to guide future research, rather than to perform a comprehensive systematic review of metabolic alterations in human epilepsy. Results: Across CE studies, consistent alterations were observed in multiple interconnected functional systems, including metabolic, immune, and gut-brain axis pathways, in agreement with findings reported for human epilepsy. These data support a model of epileptogenesis involving systemic dysfunction beyond the central nervous system. Translationally, these findings suggest opportunities for biomarker development, patient stratification, and mechanism-based interventions, including dietary and metabolic approaches (e.g., medium-chain triglyceride supplementation), microbiome modulation, and immunometabolic targeting. The current evidence is limited by small and heterogeneous cohorts, potential confounding effects of antiseizure medications, variability in dietary and fasting conditions, breed-related effects, and a predominance of associative over causal relationships. Conclusions: This review positions CE as a reference framework for future research into epilepsy metabolism, integrating current evidence and its translational relevance to human disease. The findings support a shift toward a systems-level view of epileptogenesis, involving interconnected metabolic, immune, and gut-brain axis pathways beyond the brain. CE represents a valuable translational model to identify shared mechanisms, inform biomarker discovery, and guide the development of mechanism-based therapeutic strategies across veterinary and human epilepsy.

DOI: 10.3390/nu18111734 PMCID: PMC13258797 PMID: 42280378 [Indexed for MEDLINE]

Conflict of interest statement: F.V. has recently finished a doctoral research project regarding the role of the gastro-intestinal microbiome and nutrition in canine idiopathic epilepsy, which was financially supported by Nestlé Purina Petcare Europe. M.H. is a Member of the Advisory Board of Nestlé Purina Petcare Europe. M.H. has been paid for several consulting services by a variety of pet food companies. The authors have no other financial or personal relationships with other people or organizations that could inappropriately influence or bias the content of the paper.

Abstract (verbatim excerpt):

JOURNAL:Nutrients 2026

Nutrients. 2026 May 28;18(11):1734. doi: 10.3390/nu18111734.

Canine Idiopathic Epilepsy as a Natural Animal Model for Human Epilepsy: A Scoping Review Highlighting Metabol

PMID:40170936 — Treatment-Refractory Epilepsy Alimentary Therapy (TREAT): A canine case study.

Source: Can Vet J 2025
Can Vet J. 2025 Apr;66(4):378-384.

Treatment-Refractory Epilepsy Alimentary Therapy (TREAT): A canine case study.

Frankel G(1), Findlay M(1), Bargen L(1).

Author information: (1)Clinical pharmacist, Southern Health, 381 Stonebridge Crossing, Steinbach, Manitoba R5G 0P8 (Frankel); Emergency veterinarian, Pembina Veterinary Hospital, 400 Pembina Hwy, Winnipeg, Manitoba R3L 2E7 (Findlay); Small-animal practice veterinarian, Pet Vet, 25 MB-52A, Steinbach, Manitoba R5G 1X6 (Bargen).

Half of all epilepsy cases in both humans and canines are identified as idiopathic. Of these cases, 30 to 40% remain treatment-refractory to antiepileptic medications. Several human and dog studies have demonstrated low-carbohydrate diets and dietary medium-chain triglyceride (MCT) supplementation are effective for seizure reduction, with some patients achieving a seizure-free status. Recent evidence suggests the gut-brain axis has an important role in the pathology of neurological disease among both humans and dogs. Altered gut microbiota may have a major role in treatment-refractory epilepsy. This case report describes a dog with treatment-refractory epilepsy experiencing cluster seizures triggered by an altered gut microbiome despite therapeutic drug concentrations of multiple agents. Consideration of an underlying gastrointestinal disorder should be investigated in patients with treatment-refractory epilepsy, despite therapeutic concentrations of several antiepileptic medications. Dietary and gastrointestinal health-promoting interventions for epilepsy should also be considered before add-on pharmacotherapy or euthanasia. For difficult epilepsy cases, we suggest exploring the role of a limited-ingredient, low-carbohydrate diet, MCT supplementation, and/or pre/probiotics to augment pharmacotherapeutic strategies. This information may be critically valuable in designing high-quality, diet-based therapies for epileptic dogs. Key clinical message: Gastrointestinal workup, dietary changes to a low-carbohydrate diet, supplementation with MCTs, and addition of pre/probiotics could be considered to augment pharmacotherapeutic strategies in treatmentrefractory epilepsy cases in dogs.

Publisher: Thérapie alimentaire de l’épilepsie réfractaire au traitement (TREAT) : une étude de cas caninLa moitié des cas d’épilepsie chez les humains et les chiens sont identifiés comme idiopathiques. Parmi ces cas, 30 à 40 % restent réfractaires au traitement aux médicaments antiépileptiques. Plusieurs études sur les humains et les chiens ont démontré que les régimes pauvres en glucides et la supplémentation alimentaire en triglycérides à chaîne moyenne (TCM) sont efficaces pour réduire les crises, certains patients obtenant un statut sans crise. Des preuves récentes suggèrent que l’axe intestin-cerveau joue un rôle important dans la pathologie des maladies neurologiques chez les humains et les chiens. Une altération du microbiote intestinal peut jouer un rôle majeur dans l’épilepsie réfractaire au traitement. Ce rapport de cas décrit un chien souffrant d’épilepsie réfractaire au traitement présentant des crises en grappes déclenchées par un microbiome intestinal altéré malgré les concentrations thérapeutiques de plusieurs agents. La possibilité d’un trouble gastro-intestinal sous-jacent est à considérer chez les patients atteints d’épilepsie réfractaire au traitement, malgré les concentrations thérapeutiques de plusieurs médicaments antiépileptiques. Des interventions diététiques et gastro-intestinales favorisant la santé de l’épilepsie doivent également être envisagées avant une pharmacothérapie complémentaire ou l’euthanasie. Pour les cas d’épilepsie difficiles, nous suggérons d’explorer le rôle d’un régime alimentaire pauvre en glucides et à faible teneur en ingrédients, d’une supplémentation en TCM et/ou de pré/probiotiques pour renforcer les stratégies pharmacothérapeutiques. Ces informations peuvent être d’une valeur cruciale pour la conception de thérapies diététiques de haute qualité pour les chiens épileptiques.Message clinique clé :Un bilan gastro-intestinal, des changements alimentaires vers un régime pauvre en glucides, une supplémentation en TCM et l’ajout de pré/probiotiques pourraient être envisagés pour renforcer les stratégies pharmacothérapeutiques dans les cas d’épilepsie réfractaire au traitement chez les chiens.(Traduit par Dr Serge Messier).

PMCID: PMC11932361 PMID: 40170936 [Indexed for MEDLINE]

Abstract (verbatim excerpt):

JOURNAL:Can Vet J 2025

Can Vet J. 2025 Apr;66(4):378-384.

Treatment-Refractory Epilepsy Alimentary Therapy (TREAT): A canine case study.

Frankel G(1), Findlay M(1), Bargen L(1).

Author informat

PMID:40004205 — Exploring Gut Microbiota-Targeted Therapies for Canine Idiopathic Epilepsy.

Source: Int J Mol Sci 2025
Int J Mol Sci. 2025 Feb 18;26(4):1742. doi: 10.3390/ijms26041742.

Exploring Gut Microbiota-Targeted Therapies for Canine Idiopathic Epilepsy.

Blanquet L(1), Serra D(1)(2)(3), Marrinhas C(4), Almeida A(1)(2)(5).

Author information: (1)EUVG-Escola Universitária Vasco de Gama, Campus Universitário, Av. José R. Sousa Fernandes 197, 3020-210 Coimbra, Portugal. (2)CIVG-Centro de Investigação Vasco da Gama, EUVG-Escola Universitária Vasco da Gama, Campus Universitário-Bloco B, Av. José R. Sousa Fernandes 197, 3020-210 Coimbra, Portugal. (3)CNC-Centro de Neurociências e Biologia Celular, Universidade de Coimbra, 3004-531 Coimbra, Portugal. (4)Onevet Hospital Veterinário do Baixo Vouga, Estrada Nacional 1, 355, 3750-742 Águeda, Portugal. (5)CIBIT/ICNAS-Instituto de Imagem Biomédica e Investigação Translacional de Coimbra, Universidade de Coimbra, Polo 3, Azinhaga de Santa Comba, 3000-548 Coimbra, Portugal.

Epilepsy stands out as one of the most prevalent chronic neurological conditions affecting companion animals. Recent research has increasingly focused on exploring the role of gut microbiota in influencing neurological conditions, like epilepsy. This influence stems from the bidirectional communication pathways between gut bacteria and the brain, which involve metabolic, neural, immunological, and endocrine mechanisms. In fact, a balanced and stable gut microbiota is essential to maintaining normal gut physiology and ensuring appropriate signaling along the gut-brain axis. Conversely, dysbiosis can have detrimental effects on gut physiology and may contribute to the development or exacerbation of neurological conditions, including epilepsy. Considering these findings, this review article aims to deepen the understanding of the mechanisms underlying the microbiota-gut-brain connection in the context of canine idiopathic epilepsy. Moreover, this review presents recent data on innovative gut-related therapeutic strategies for canine idiopathic epilepsy treatment.

DOI: 10.3390/ijms26041742 PMCID: PMC11855791 PMID: 40004205 [Indexed for MEDLINE]

Conflict of interest statement: The authors declare no conflicts of interest.

Abstract (verbatim excerpt):

JOURNAL:Int J Mol Sci 2025

Int J Mol Sci. 2025 Feb 18;26(4):1742. doi: 10.3390/ijms26041742.

Exploring Gut Microbiota-Targeted Therapies for Canine Idiopathic Epilepsy.

Blanquet L(1), Serra D(1)

PMID:42311395 — A multicenter retrospective analysis of canine idiopathic epilepsy in China.

Source: Front Vet Sci 2026
Front Vet Sci. 2026 Jun 2;13:1808718. doi: 10.3389/fvets.2026.1808718.

eCollection 2026.

A multicenter retrospective analysis of canine idiopathic epilepsy in China.

Zhang XW(1), Guan YC(2), Liu ZJ(3), Lou LS(4), Liu ZH(5), Tipold A(6), Lin YW(7).

Author information: (1)Tianhong Pet Hospital, New Ruipeng Pet Healthcare Group, Hefei, Anhui, China. (2)Ainuo Blessing Veterinary Hospital, New Ruipeng Pet Healthcare Group, Guangzhou, Guangdong, China. (3)Zhengzhou Pet Health Center Hospital, New Ruipeng Pet Healthcare Group, Zhengzhou, Henan, China. (4)Hangzhou Meilian Zhonghe Animal Hospital, New Ruipeng Pet Healthcare Group, Hangzhou, Zhejiang, China. (5)Qingdao Ainuo Central Hospital, New Ruipeng Pet Healthcare Group, Qingdao, Shandong, China. (6)Department of Small Animal Medicine and Surgery, University of Veterinary Medicine, Hannover, Germany. (7)Naughty Family Animal Hospital, New Ruipeng Pet Healthcare Group, Shanghai, China.

OBJECTIVE: Canine idiopathic epilepsy (IE) is one of the most common neurological diseases in veterinary medicine, with no comprehensive study in China. This study collected IE cases from five large referral pet hospitals and conducted a multicenter retrospective analysis in order to supplement the clinical data of canine IE in China, clarify the predisposing factors, diagnostic and therapeutic characteristics of canine IE in the China, and provide regional clinical data for cross-country comparison of canine epilepsy diagnosis and treatment. METHODS: Canine patients diagnosed with epilepsy from five pet hospitals in China between 2019 and 2023 were collected. IE cases were diagnosed based on the consensus of the International Veterinary Epilepsy Task Force (IVETF). Breed, age, body condition score (BCS), diagnosis, treatment and follow-up were included for analysis. RESULTS: A total of 211 cases with IE were included in the study. Male dogs (p < 0.05), small dogs weighing <10 kg (p < 0.05), poodles (p < 0.05) had a significantly higher risk to be diagnosed with IE. The age of first seizure episode was mainly between 1 and 5 years, with an average of 4 years. Most patients had seizure episodes with a mean duration of less than 2 min (78.9%). Generalized seizures with tonic-clonic convulsions, accompanied by autonomic signs, were the most frequently observed type. The incidence of cluster seizures (CS) was 38.9%, while status epilepticus (SE) occurred in 12.4% of cases. Phenobarbital was administered in 89.1% of cases, with 58.3% receiving monotherapy with phenobarbital; 74.8% of these cases achieved good seizure control (seizure-free or a clinically meaningful reduction in seizure frequency). The disease-related mortality rate in these cases was approximately 1%. CONCLUSION: This study reveals a significant diagnostic gap in China, with 18.7% of cases exceeding a one-year delay to diagnosis, likely due to a shortage of specialists and owner-related factors. Optimizing clinical management should prioritize reducing this delay through enhanced practitioner and owner education, while reinforcing Phenobarbital as a highly effective (93.8% success rate) first-line monotherapy. Addressing these barriers could facilitate earlier intervention and improve therapeutic outcomes for dogs with idiopathic epilepsy in this region.

DOI: 10.3389/fvets.2026.1808718 PMCID: PMC13269065 PMID: 42311395

Conflict of interest statement: The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor PM declared a past co-authorship with one of the author AT.

Abstract (verbatim excerpt):

JOURNAL:Front Vet Sci 2026

Front Vet Sci. 2026 Jun 2;13:1808718. doi: 10.3389/fvets.2026.1808718.

eCollection 2026.

A multicenter retrospective analysis of canine idiopathic epilepsy in China.

PMID:38783265 — Re-evaluating the placebo response in recent canine dietary epilepsy trials.

Source: BMC Vet Res 2024
BMC Vet Res. 2024 May 24;20(1):224. doi: 10.1186/s12917-024-04066-z.

Re-evaluating the placebo response in recent canine dietary epilepsy trials.

Schmidt T(1)(2), Meyerhoff N(1), Meller S(1), Twele F(1), Charalambous M(1), Berk BA(3)(4), Law TH(4), Packer RMA(4), Zanghi B(5), Pan Y(5), Fischer A(6), Volk HA(7)(8).

Author information: (1)Department of Small Animal Medicine and Surgery, University of Veterinary Medicine Hannover, Hannover, Germany. (2)Centre for Systems Neuroscience, University of Veterinary Medicine Hannover, Hannover, Germany. (3)BrainCheck.Pet® - Tierärztliche Praxis für Epilepsie, Mannheim, Germany. (4)Department of Clinical Science and Services, Royal Veterinary College, Hatfield, UK. (5)Research and Development, Nestlé Purina PetCare, St. Louis, MO, USA. (6)Centre for Clinical Veterinary Medicine, Ludwig-Maximilians-Universität München, Munich, Germany. (7)Department of Small Animal Medicine and Surgery, University of Veterinary Medicine Hannover, Hannover, Germany. Holger.Volk@tiho-hannover.de. (8)Centre for Systems Neuroscience, University of Veterinary Medicine Hannover, Hannover, Germany. Holger.Volk@tiho-hannover.de.

The placebo response is a common phenomenon. Limited evidence is available about its magnitude in canine epilepsy trials, even though it can significantly influence the efficacy evaluation of new treatments. It was hypothesised that the placebo response is diminished when epilepsy trials are conducted in a prospective crossover design. Seizure data spanning six months from three previous multicenter epilepsy studies were analysed. The monthly seizure frequency of 60 dogs diagnosed with idiopathic epilepsy was calculated, comparing baseline data with placebo treatment. Furthermore, differentiation was made between dogs randomised to the placebo group early (Phase 1: first 3 months) or later during the study (Phase 2: second 3 months).The analysis did not reveal any placebo response in terms of monthly seizure frequency. Instead, an increase was noted during the placebo treatment period, with a mean of 2.95 seizures per month compared to 2.30 seizures per month before study entry (p = 0.0378). Additionally, a notable phase effect was observed. Dogs receiving the placebo in the second study phase exhibited a significant increase in monthly seizure frequency compared to baseline (p = 0.0036). Conversely, no significant difference from baseline was observed for dogs receiving the placebo in the first study phase. These findings underscore the considerable variability in placebo responses observed in trials for canine epilepsy, contrasting with previous limited data. The identified phase effect should be carefully considered in the design and evaluation of canine epilepsy trials to ensure a more accurate assessment of efficacy for new treatments.

DOI: 10.1186/s12917-024-04066-z PMCID: PMC11119301 PMID: 38783265 [Indexed for MEDLINE]

Conflict of interest statement: BB was employed by company BrainCheck.Pet® and BZ and YP were employed by company Nestlé Purina PetCare®. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The funders of the former epilepsy trials had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Abstract (verbatim excerpt):

JOURNAL:BMC Vet Res 2024

BMC Vet Res. 2024 May 24;20(1):224. doi: 10.1186/s12917-024-04066-z.

Re-evaluating the placebo response in recent canine dietary epilepsy trials.

Schmidt T(1)(2), Meyerh

PMID:42410958 — Different Roles of Canine Cytochrome P450 2C and 3A Enzymes Involved in the Oxidative Metabolism of Phenobarbital, a Key Anticonvulsant for Dogs: Comparison With Human P450 Enzymes.

Source: J Vet Pharmacol Ther 2026
J Vet Pharmacol Ther. 2026 Jul 6. doi: 10.1111/jvp.70094. Online ahead of

print.

Different Roles of Canine Cytochrome P450 2C and 3A Enzymes Involved in the Oxidative Metabolism of Phenobarbital, a Key Anticonvulsant for Dogs: Comparison With Human P450 Enzymes.

Uno Y(1), Fukunaga K(2), Murayama N(3), Mushiroda T(2), Shimizu M(3), Yamazaki H(3).

Author information: (1)Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima, Japan. (2)RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. (3)Showa Pharmaceutical University, Tokyo, Japan.

Phenobarbital is a key anticonvulsant used in dogs. Cytochrome P450 (P450) 2C19 is reportedly involved in the oxidative metabolism of phenobarbital in humans; however, the hepatic P450 enzymes responsible for phenobarbital p-hydroxylation in dogs have not yet been identified. In the present study, we investigated the roles of a range of dog P450 enzymes in phenobarbital p-hydroxylation activity using dog liver microsomes and recombinant proteins. Recombinant dog P450 2C21, 2C41, 3A12, and 3A98 enzymes and four liver microsomal preparations from four different dogs were used to investigate the biphasic P450-dependent phenobarbital p-hydroxylation activity. Human P450 2C19 is the predominant enzyme for the p-hydroxylation of phenobarbital, but not exclusively, and a similar process was anticipated in dogs. Phenobarbital p-hydroxylation activities in four dog liver microsomal preparations at substrate concentrations of 5.0 and 50 μM were significantly correlated with P450 2C immunochemical band intensities, but activities were not correlated at a substrate concentration of 500 μM. Liver microsomes from dog 3 had a monophasic capacity (Vmax, 0.35 pmol/min/mg protein) for phenobarbital p-hydroxylation (Km, 4.9 μM), whereas liver microsomes from dog 6 had biphasic low (Vmax1, 0.11 pmol/min/mg protein) and high (Vmax2, 0.22 pmol/min/mg protein) capacities with high (Km1, 1.6 μM) and low (Km2, 72 μM) affinities, respectively. The primary P450 2C21-dependent and secondary P450 3A12-dependent phenobarbital p-hydroxylation activities of dog liver microsomes showed approximately two-fold differences among the four individual dogs. This information could help develop an individualized approach for controlling epilepsy in dogs treated with phenobarbital.

DOI: 10.1111/jvp.70094 PMID: 42410958

Abstract (verbatim excerpt):

JOURNAL:J Vet Pharmacol Ther 2026

J Vet Pharmacol Ther. 2026 Jul 6. doi: 10.1111/jvp.70094. Online ahead of