Epilepsy is one of the most common neurological diseases worldwide, affecting about 50 million people. Most live in low to middle-income countries where prevention and treatment can be lacking.

Head injury, stroke, infections, and congenital abnormalities can all lead to epilepsy. The disease can diminish quality of life and cause premature death.

Epilepsy, in brief

Epilepsy is characterized by recurrent seizures, which are episodes of involuntary movement that may involve a part or all of the body and are sometimes accompanied by loss of consciousness and bowel or bladder function. Seizures can be brief or prolonged as well as frequent (several per day) or rare (one per year).

The World Health Organization reports that about 25% of epilepsy cases are preventable by reducing head injuries, controlling high blood pressure, ensuring adequate perinatal care, and avoiding infections. And if treatment is required, low-cost medications can control seizures in up to 70% of people living with epilepsy. Less than half of the global epileptic patient population has access to anti-epileptic drugs. Moreover, an estimated 15 million patients exhibit refractory epilepsy, based on their non-responsiveness to existing anti-epileptic drugs.

The lack of response to drugs and the presence of drug side effects have spurred interest in the role that the gut microbiota plays in epilepsy. There is emerging evidence that alterations in the gut microbiota are seen in epilepsy and in response to seizure interventions such as the ketogenic diet and anti-epileptic drugs.

Microbiome links to epilepsy

Three recent studies in humans report alterations in the fecal microbiota of individuals with refractory epilepsy relative to varied non-epileptic controls. Each observed increased Firmicutes relative to Bacteroides in individuals with refractory epilepsy. But the results were conflicting with regard to whether α-diversity is altered.

In addition to this correlation, dysbiosis is seen to be involved in the pathogenesis of and susceptibility to epilepsy. The gut microbiota communicates with the brain by a complex bidirectional connection known as the “microbiota-gut-brain axis”, via neuroendocrine, immunological, and direct neural mechanisms.

Pathogenesis

Dysbiosis may contribute to the onset of epileptic seizures through several mechanisms.

Gut bacteria produce cytokines, and metabolites such as short-chain fatty acids (SCFAs), γ-aminobutyric acid (GABA), and serotonin precursors. Dysbiosis can alter the excitatory-inhibitory balance in a direction that favors epileptic seizures. A reduction in short-chain fatty acids (SCFAs) alters the blood-brain barrier, allowing the entry of toxins and inflammatory cytokines, and a decrease in neurotransmitters such as GABA and serotonin favor the onset of a seizure.

Susceptibility

Susceptibility to seizures may be increased with antibiotic use, infections, and both psychological and physical stressors. These can also perturb the gut microbiota.

• Antibiotics are commonly prescribed for bacterial infections but can also cause changes in neuronal activity as well as contribute to dysbiosis. Different antibiotics affect seizure susceptibility differently; a finding that suggests further study is needed on type, dose, and route of antibiotic treatment.
• Infections from bacteria, viruses, and parasites can promote seizure propensity. Several large epidemiological and case studies associate infections with increased risk.
• Stress— physical and psychological—can alter the gut microbiota. An altered microbiota can in turn influence behavior. The microbiome may mediate stress-induced increases in seizure susceptibility. In one recent experiment, fecal contents from stressed rats were transplanted into non-stressed rats. The latter developed a greater sensitivity to epilepsy than controls.

These results implicate perturbations in the gut microbiome in the increased susceptibility to epilepsy.

Gut microbes and antiepileptic drugs

The gut microbiota can modify anti-epileptic drug metabolism and thereby impact drug efficacy and toxicity. In turn, treatment with anti-epileptic drugs may impact gut microbiota composition. In animals, studies reveal microbial changes in the offspring of mothers treated with valproic acid; for example, decreased fecal Firmicutes and increased Bacteroidetes were seen in pups of treated mothers.

These reciprocal impacts require further investigations.

Gut microbes and the ketogenic diet

When drugs fail to control seizures, a ketogenic diet is used in clinical treatment. The diet severely reduces carbohydrates, while increasing proteins and fats. Changes in both the human and mouse gut microbiome with the diet have suggested that alterations in the gut microbiome may contribute to the protective effects of the ketogenic diet against seizures.

Probiotic treatment and seizure risk

Probiotics may have beneficial effects on epileptic seizures.

A study in an animal model of epilepsy found that a combination of different probiotic strains of Lactobacillus rhamnosus (new nomenclature Lacticaseibacillus rhamnosus), Lactobacillus reuteri (new nomenclature Limosilactobacillus reuteri), and Bifidobacterium infantis reduced seizure severity and epileptic activity when compared to seizures in controls. The anti-epileptic effects of probiotic administration were accompanied by an increase in GABA levels in the brain, as well as a decrease in brain oxidative stress. Neurotransmitter metabolites such as GABA may contribute to increasing the convulsion threshold.

Two recent studies in humans examined the effects of probiotics on seizures.

• One study showed that administration of strains of probiotics Saccharomyces boulardii or Lactobacillus casei (new nomenclature Lacticaseibacillus casei) in neonates affected by rotavirus was associated with a 10-fold decreased risk for seizures as compared to non-treated infected controls.
• A small study on 45 drug-resistant symptomatic epileptic patients showed that a probiotic cocktail was associated with a >50% reduction in seizure frequency in 29% of patients and 77% of them maintained reduced seizure frequency 4 months after discontinuation.

Takeaway

Current drug therapy for epilepsy fails to control seizures for as many as 25% of patients. Other options such as surgery and the ketogenic diet have disadvantages.

Studies suggest a role for the gut microbiome in epilepsy, in its genesis as well as in response to seizure interventions such as the ketogenic diet and anti-epileptic drugs.

Probiotics to modulate the gut microbiota may be a novel therapy to improve outcomes. Further studies are needed to clarify the gut microbiota in epilepsy to understand biomarkers for disease and therapeutic response as well as to form novel approaches for the treatment of refractory epilepsy.

Key references

Amlerova, Jana et al. “Evidences for a Role of Gut Microbiota in Pathogenesis and Management of Epilepsy.” International journal of molecular sciences vol. 22,11 5576. 25 May. 2021, doi:10.3390/ijms22115576m

Bagheri, Samaneh et al. “Effect of probiotic supplementation on seizure activity and cognitive performance in PTZ-induced chemical kindling.” Epilepsy & behavior : E&B vol. 95 (2019): 43-50. doi:10.1016/j.yebeh.2019.03.038

Chen, Baibing et al. “Psychiatric and behavioral side effects of antiepileptic drugs in adults with epilepsy.” Epilepsy & behavior : E&B vol. 76 (2017): 24-31. doi:10.1016/j.yebeh.2017.08.039

Dahlin, Maria, and Stefanie Prast-Nielsen. “The gut microbiome and epilepsy.” EBioMedicine vol. 44 (2019): 741-746. doi:10.1016/j.ebiom.2019.05.024

Gómez-Eguílaz, M et al. “The beneficial effect of probiotics as a supplementary treatment in drug-resistant epilepsy: a pilot study.” Beneficial microbes vol. 9,6 (2018): 875-881. doi:10.3920/BM2018.0018

Holmes, Manisha et al. “Cross talk between drug-resistant epilepsy and the gut microbiome.” Epilepsia vol. 61,12 (2020): 2619-2628. doi:10.1111/epi.16744

Kitamura, S et al. “The role of mammalian intestinal bacteria in the reductive metabolism of zonisamide.” The Journal of pharmacy and pharmacology vol. 49,3 (1997): 253-6. doi:10.1111/j.2042-7158.1997.tb06790.x

Larroya, Ana et al. “Towards Tailored Gut Microbiome-Based and Dietary Interventions for Promoting the Development and Maintenance of a Healthy Brain.” Frontiers in pediatrics vol. 9 705859. 1 Jul. 2021, doi:10.3389/fped.2021.705859

Lindefeldt, Marie et al. “The ketogenic diet influences taxonomic and functional composition of the gut microbiota in children with severe epilepsy.” NPJ biofilms and microbiomes vol. 5,1 5. 23 Jan. 2019, doi:10.1038/s41522-018-0073-2

Lum, Gregory R et al. “Emerging roles for the intestinal microbiome in epilepsy.” Neurobiology of disease vol. 135 (2020): 104576. doi:10.1016/j.nbd.2019.104576

Maier, Lisa et al. “Extensive impact of non-antibiotic drugs on human gut bacteria.” Nature vol. 555,7698 (2018): 623-628. doi:10.1038/nature25979

Mattappalil, Arun, and Kari A Mergenhagen. “Neurotoxicity with antimicrobials in the elderly: a review.” Clinical therapeutics vol. 36,11 (2014): 1489-1511.e4. doi:10.1016/j.clinthera.2014.09.020

Medel-Matus, Jesús-Servando et al. “Facilitation of kindling epileptogenesis by chronic stress may be mediated by intestinal microbiome.” Epilepsia open vol. 3,2 290-294. 9 Apr. 2018, doi:10.1002/epi4.12114

Peng, Anjiao et al. “Altered composition of the gut microbiome in patients with drug-resistant epilepsy.” Epilepsy research vol. 147 (2018): 102-107. doi:10.1016/j.eplepsyres.2018.09.013

Sgritta, Martina et al. “Mechanisms Underlying Microbial-Mediated Changes in Social Behavior in Mouse Models of Autism Spectrum Disorder.” Neuron vol. 101,2 (2019): 246-259.e6. doi:10.1016/j.neuron.2018.11.018

Sheng, Jiyao et al. “Drug-Resistant Epilepsy and Surgery.” Current neuropharmacology vol. 16,1 (2018): 17-28. doi:10.2174/1570159X15666170504123316

Strandwitz, Philip. “Neurotransmitter modulation by the gut microbiota.” Brain research vol. 1693,Pt B (2018): 128-133. doi:10.1016/j.brainres.2018.03.015

Vuong, Helen E et al. “The Microbiome and Host Behavior.” Annual review of neuroscience vol. 40 (2017): 21-49. doi:10.1146/annurev-neuro-072116-031347

Xie, Gan et al. “Ketogenic diet poses a significant effect on imbalanced gut microbiota in infants with refractory epilepsy.” World journal of gastroenterology vol. 23,33 (2017): 6164-6171. doi:10.3748/wjg.v23.i33.6164

Yeom, Jung Sook et al. “Neonatal seizures and white matter injury: Role of rotavirus infection and probiotics.” Brain & development vol. 41,1 (2019): 19-28. doi:10.1016/j.braindev.2018.07.001

Yue, Qiang et al. “The Microbiota-Gut-Brain Axis and Epilepsy.” Cellular and molecular neurobiology, 10.1007/s10571-021-01130-2. 19 Jul. 2021, doi:10.1007/s10571-021-01130-2

Esiobu, Nwadiuto, and Naseema Hoosein. “An assessment of the in vitro antimicrobial effects of two antiepileptic drugs–sodium valproate and phenytoin.” Antonie van Leeuwenhoek vol. 83,1 (2003): 63-8. doi:10.1023/a:1022992224594