Probiotics counteract hepatic steatosis caused by ketogenic diet and upregulate AMPK signaling in a model of infantile epilepsy

Chunlong Mu; Naghmeh Nikpoor; Thomas A Tompkins; Jong M Rho; Morris H Scantlebury; Jane Shearer

doi:10.1016/j.ebiom.2022.103838

Probiotics counteract hepatic steatosis caused by ketogenic diet and upregulate AMPK signaling in a model of infantile epilepsy

EBioMedicine. 2022 Feb:76:103838. doi: 10.1016/j.ebiom.2022.103838. Epub 2022 Feb 9.

Authors

Chunlong Mu¹, Naghmeh Nikpoor², Thomas A Tompkins², Jong M Rho³, Morris H Scantlebury⁴, Jane Shearer⁵

Affiliations

¹ Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, 2500 University Dr. NW, Calgary, AB T2N 1N4, Canada. Electronic address: chunlong.mu1@ucalgary.ca.
² Rosell Institute for Microbiome and Probiotics, Lallemand Health Solutions, Montreal, QC H4P 2R2, Canada.
³ Division of Pediatric Neurology, Rady Children's Hospital-San Diego, Department of Neurosciences, University of California, San Diego, CA 92123, USA.
⁴ Department of Pediatrics, Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada; Alberta Children's Hospital Research Institute, Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N 1N4, Canada.
⁵ Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, 2500 University Dr. NW, Calgary, AB T2N 1N4, Canada; Alberta Children's Hospital Research Institute, Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N 1N4, Canada.

Abstract

Background: Infantile spasms syndrome (IS) is a type of epilepsy affecting 1.6 to 4.5 per 10,000 children in the first year of life, often with severe lifelong neurodevelopmental consequences. Only two first-line pharmacological treatments currently exist for IS and many children are refractory to these therapies. In such cases, children are treated with the ketogenic diet (KD). While effective in reducing seizures, the diet can result in dyslipidemia over time.

Methods: Employing a neonatal Sprague-Dawley rat model of IS, we investigated how the KD affects hepatic steatosis and its modulation by a defined probiotic blend. A combination of multiple readouts, including malondialdehyde, fatty acid profiles, lipid metabolism-related enzyme mRNA expression, mitochondrial function, histone deacetylase activity, cytokines and chemokines were evaluated using liver homogenates.

Findings: The KD reduced seizures, but resulted in severe hepatic steatosis, characterized by a white liver, triglyceride accumulation, elevated malondialdehyde, polyunsaturated fatty acids and lower acyl-carnitines compared to animals fed a control diet. The KD-induced metabolic phenotype was prevented by the co-administration of a blend of Streptococcus thermophilus HA-110 and Lactococcus lactis subsp. lactis HA-136. This probiotic blend protected the liver by elevating pAMPK-mediated signaling and promoting lipid oxidation. The strains further upregulated the expression of caspase 1 and interleukin 18, which may contribute to their hepatoprotective effect in this model.

Interpretation: Our results suggest that early intervention with probiotics could be considered as an approach to reduce the risk of hepatic side effects of the KD in children who are on the diet for medically indicated reasons.

Funding: This study was funded by the Alberta Children's Hospital Research Institute and Mitacs Accelerate Program (IT16942).

Keywords: Epilepsy; Ketogenic diet; Nutrition; Pediatric; Probiotic; Steatosis.

MeSH terms

AMP-Activated Protein Kinases / metabolism
Animals
Diet, Ketogenic* / adverse effects
Epilepsy* / metabolism
Humans
Liver / metabolism
Probiotics*
Rats
Rats, Sprague-Dawley

Substances

AMP-Activated Protein Kinases