FMT as an Effective Therapeutic Agent for Epilepsy

Gupta PD and Pushkala K

Published on: 2024-10-02

Abstract

Epilepsy is a neurological disease involving the brain that makes people to have unprovoked seizures. In some, seizure alone, in others become unconscious along with symptoms. Some people stare blankly for a few seconds during a seizure. Others may repeatedly twitch their arms or legs, movements known as convulsions. This seizure disorder affects people of all ages, races and ethnic background. Treatment with medicines or sometimes surgery can control seizures. Some people require lifelong treatment. Though the development of epilepsy is idiopathic, the intestinal microbiota may play a role in the etiology of epilepsy. Manipulating the gut microbiota using FMT (faecal microbiota transplantation) technique have significant effect on the physiological, behavioral and cognitive functions of the brain operating through diverse pathways such as neuroanatomical pathways, neuroendocrine-hypothalamic-pituitary-adrenal axis, intestinal immune system, some neurotransmitters, and nerve regulators synthesized by intestinal bacteria and intestinal mucosal barrier and blood brain barrier systems. Therefore FMT is a promising alternative for the management of epilepsy.

Keywords

Unprovoked seizures; Intestinal microbiota; Neuroendocrine-Hypothalamic-Pituitary-Adrenal axis

Introduction

Approximately 50 million people worldwide suffer with Epilepsy considered as one of the most common neurological disorders. Unfortunately, even with the advent of a large number of antiepileptic drugs since the 1990s, about 36% of epilepsy patients do not respond to an appropriately pharmacological treatment and remains uncontrolled [1]. Epilepsy entails a major burden in seizure-related disability, mortality, comorbidities, stigma and costs. Surgery is still in vogue in a small subset of drug-resistant epilepsy cases [2].

At the beginning of the 20th century, that a some intestinal microorganism present in the blood of epilepsy patients was hypnotized and named “Bacillus Epilepticus,” was considered as a causal factor involved in the prognosis and maintenance of epilepsy since, their isolation and application was able to induce convulsive seizures in rabbits. However, “Bacillus Epilepticus” was never observed again, causing that epilepsy researchers abandoned the gut microbiota hypothesis for almost a century [1].

The causal factor for the predisposition of Epilepsy is anticipated to be both genetic and environmental factors involved in an individual though the exact etiology of most cases remains unknown. Many possible causes of epilepsy, including an imbalance of nerve-signalling neurotransmitters, tumours, strokes, and brain damage from illness or injury, or cumulative effect of some combination of these.

In epilepsy patients, the brain's electrical rhythms have a tendency to become imbalanced, resulting in recurrent seizures. The normal electrical pattern is disrupted by sudden and synchronized bursts of electrical energy that may briefly affect their consciousness, movements or sensations. Epilepsy is usually diagnosed after a person had at least two seizures that were not caused by some known medical condition, such as alcohol withdrawal or extremely low blood sugar. The following factors may increase the risk of seizures in people predisposed to seizures: Stress, sleep deprivation or fatigue, insufficient food intake, alcohol use or drug abuse, failure to take prescribed anticonvulsant medications [3].

Variables That Affect Microbiome Composition

Susceptibility to variation in the gut microbiota is due to multiple factors. In the early stages of development, the microbiota is not very diverse and is mainly composed of two phyla, Actinobacteria and Proteobacteria. Notably, children have less gut microbiota diversity than adults due to existence of predominantly catabolic pathways in the former and the later biosynthetic routes.

The gut microbiota has different transitions throughout the human lifespan and depends on type of delivery, nutritional preferences, exposure to medications, antibiotics or environmental pollutants, lifestyle, immune and genetic predisposition, and intestinal physiology. In addition, the sleep-wake and feeding-fasting cycles can also act as modulators of the intestinal microbiome. Diet, taking into account the “enterotype,” or clusters of bacteria, body mass index, and frequency of exercise, climate, geographical location, culture, and state of health - disease also influence the susceptibility to change the gut microbiota. Some studies conclude that alterations in the endocannabinoid system have an influence on the composition of the gastrointestinal microbiota which can generate disruptions in the integrity of the intestine and generate a chronic pro-inflammatory state.

In epilepsy patients, the anticonvulsant effect of the endocannabinoid system has been demonstrated, being a promising target in the therapeutic field. One can achieve homeostasis only by maintaining a stable, balanced, and healthy intestinal microbiota to full fills digestive, immunostimulatory, anti-inflammatory, and structural functions that contribute to the integrity of the epithelium integrity, protection against pathogens and metabolism of nutrients and xenobiotics [1].

Management Of Epilepsy

Antibiotics

Intestinal microbiome seems to be altered in several neuropathological diseases including epilepsy. Antibiotics has been shown to reduce the gut microbiota community for several weeks strongly showing beneficial results on physiopathology. A recent controversy emerged concerning to the use of antibiotics in epilepsy as some antibiotics promote seizures in both epilepsy patients and animal models, particularly the beta-lactam antibiotics.

Cellular mechanisms by which antibiotics induce seizures relies on the reduction of GABAergic neurotransmission, as some antibiotics block GABAA receptors and inhibit GABA synthesis, and on the upregulation of excitatory neurotransmission. Although evidences are available to point out that antibiotics have a crucial role on seizure control, lack of direct link between both variables still wants to confirm or rule out the causal mechanisms linking specific antibiotics to gut microbiota disequilibrium and its influence on seizure/epilepsy susceptibility [1].

Probiotic Supplementation

Gómez-Eguílaz and his colleagues [4] reported to have treated a cohort of 43 Spanish drug-resistant epilepsy patients with probiotic supplementation. In their study probiotic supplementation reduced up to 50% of the seizure frequency in 28.9% of patients. However, 48.9% of patients did not respond to probiotic supplementation. The beneficial effects of probiotic supplementation on seizures were also reported by other studies performed in a considerable population of Korean neonates with Rotavirus and seizures. In the same study, Yeom et al., [5] treated with probiotic supplementation containing Saccharomyces boulardii and Lactobacillus case within the 24 hours of birth, decreased the risk of seizures in rotavirus-positive neonates 10-fold [5:6].

The Ketogenic Diet (KD) and Its Benefits on Epilepsy

The ketogenic diet (KD) is commonly used as a complementary alternative to treat drug-resistant epilepsy. Replacing carbohydrates with a high proportion of fat can induce a metabolic state of liver ketosis, a condition similar to fasting or intense exercise. Using mitochondrial beta-oxidation, Short-chain fatty acids (SCFAs) are transformed into acetyl-CoA, and then metabolized into the three main ketone bodies: acetoacetate, 3-beta-hydroxybutyrate, and acetone which reaches the blood-brain barrier and consequently supply the energy requirements to brain. Scientific evidences are available from clinical and experimental studies to prove that KD has a favorable effect on seizures though the mechanism of operation is still an enigma. The dysbiotic gut microbiome has emerged as a key promotor of chronic inflammation and seizure susceptibility and so the efficacy of KD on seizure may arise from gut microbiota modulation [1].

Xie and colleagues [7], analyzed the taxonomical gut microbiota changes in Chinese pediatric drug-resistant epilepsy patients treated with KD Using a 16S rRNA sequencing approach, for a week. They observed that KD increased the relative expression of particular phyla, including Bacteroidetes and Provotella, while reducing the relative expression of Cronobacter, Erysipelatoclostridium, Streptococcus, Alistipes, Ruminiclostridium, Barnesiella, and Enterococcus. These alterations could be the reason for the seizure reduction induced by KD, as 21% of patients were seizure-free and 43% had up to 50% seizure reduction confirmed from subsequent studies. Zhang and colleagues [8] also explained from their studies from Chinese pediatric drug-resistant epilepsy patients treated with KD that after six months of KD treatment, beta-diversity differentiates from baseline levels [8]. Increment in the relative abundance of Bacteroidetes and a significant lower proportion of Firmicutes and Actinobacteria was observed after KD. 10% of patients were seizure-free and 40% reduced seizure frequency to up to 50% during KD treatment. Interestingly, a higher relative abundance of Clostridiales, Clostridia, Ruminococcaceae, Lachnospiraceae, Alistipes, and Rikenellaceae was seen in the remaining 50% who responded less to KD.

In a separate pilot study, Lindefeldt and colleagues [9] demonstrated the modulatory effect of KD on beta-diversity in a Swedish cohort of pediatric drug-resistant epilepsy patients. A decline in the relative abundances of Eubacterium rectale Dialister, and Bifidobacterium phyla, which are involved in the production of butyrate and contribute to the final conversion of non-digestible carbohydrates into other SCFAs. But KD promoted the proliferation of Escherichia coli, which has been attributed to neuroinflammation. All these vital observation substantiate the hypothesis that modulating the gut microbiota through KD administration could play a therapeutic role in people affected with epilepsy.

Faecal Microbiota Transplantation (FMT)

In recent past, due to advancement in identifying the gut microbiota as well as understanding their modulatory role in pathologies in many human diseases from clinical and experimental studies, emphasized to look out for an alternate approach in therapeutics using FMT. Very few literatures reported the clinical use of microbiota or bacteria for brain diseases in spite of knowing that the most effective strategy for reconstruction of gut microbiota should be faecal microbiota transplantation (FMT). Based on the scientific evidence on role of gut microbiota in epilepsy, targeting the gut microbiota could serve as a diagnostic or prognostic research tool. Translating microbial molecular mechanisms to medical settings could fill the gaps related to alternative therapies for patients with epilepsy, mainly in cases with refractory phenotypes.

In 60% of cases intestinal microbiota may play a role in the etiology of epilepsy though the development of this disease is idiopathic in Epilepsy [10]. Manipulating the gut microbiome using metabolomics and faecal microbiota transplantation through new approaches, have highlighted the tremendous capacity that microbes have on neuroinflammation, metabolic, and neuroendocrine signalling pathways since, epilepsy patients exhibit altered gut microbiota composition.

Mechanism of Action by Gut Microbiota in the Brain

Microbial-associated metabolites are small molecules produced from the host diet or derive naturally from the metabolism of endogenous compounds from the host and its commensal or pathogenic micro biota. Chemical effects of these bioproducts influence not only the host-microbe bidirectional interface but also microbe-microbe behavioral and physical communication between communities residing on the gut has been demonstrated earlier. Only a few studies have aimed to characterize the metabolic profile in patients with epilepsy which could connect the intestinal and peripheral small molecules with the brain.

Short-Chain Fatty Acids (Scfas)

SCFAs are the predominant end product from microbial fermentation of undigested carbohydrates and other endogenous sources such as amino acids (valine, leucine, and isoleucine), pyruvate, and long-chain fatty acids. In rodent models, the regulatory properties that SCFAs exert on the host has been confirmed. SCFAs modulate diverse receptors, including ubiquitous and pleiotropic G protein-coupled receptors (GPR) present not only on intestinal epithelial cells (IECs) but also in hematopoietic and brain tissue. Aryl hydrocarbon receptor (AHR) is another critical receptor implicated in mucosal homeostasis and xenobiotics transformation. For example, species of Lactobacilli spp use dietary tryptophan to promote AHR ligands, TH17, and IL-22 production and consequently controlling the bacterial load and pathogen colonization of the gut. These findings outline the significance of maintaining a healthy bowel and blood-brain barrier (BBB) in avoiding the translocation of microbes and their toxins to distant organs such as the CNS, thus, protecting it from chronic inflammation.

Mejía-Granados DM. et al., [1] found some genes involved in the acetyl-CoA pathway of butyrate production, such as acetyl-CoA acetyltransferase, β-hydroxybutyric-CoA dehydrogenase, and crotonase, reduced in Epilepsy patients suggesting that the production of SCFA is reduced in epilepsy patients, thus promoting a systemic inflammatory state.

Human studies to explore the linkage between an altered microbial composition and epilepsy, intestinal profiles at a functional level have remained scarce [12]. Still few evidences from clinical as well as animal model studies, gives a clue that intestinal microbiota has a significant effect on the physiological, behavioural and cognitive functions of the brain operating through diverse pathways such as neuroanatomical pathways, neuroendocrine-hypothalamic-pituitary-adrenal axis, intestinal immune system, some neurotransmitters, and nerve regulators synthesized by intestinal bacteria and intestinal mucosal barrier and BBB [10].

According to the very recent first report, the existence of a difference in gut microbiota profiles among drug?sensitive, drug?resistant patients with epilepsy and healthy controls was observed and confirmed subsequently. Peng et al. [13] have demonstrated a significantly increased α?diversity, an elevated relative abundance of Firmicutes and Proteobacteria and rare enriched microbes (i.e., Verrucomicrobia) in 42 drug resistant patients as compared with other groups, matched to age, sex, and treatments. Further investigations is wanting to confirm a possible bidirectional correlation between drug?resistant mechanisms and gut microbiota since, drug sensitive patients have a microbiota composition that did not statistically overlap different from healthy controls [13].

He et al. [14] reported the first case of a complicated case of epilepsy with Crohn’s disease in a 17-year-old patient who after three rounds of FMT showed improvements in neurological and intestinal symptoms. Antiepileptic therapy was discontinued after 20 months, and no seizures charecterstic of epilepsy were observed. This finding was a landmark to highlight the efficacy of FMT, a novel successful treatment for epilepsy through remodelling gut microbiota [14].

Interestingly, drug-resistant epilepsy patients harbour higher levels of rare microbial genera, including Firmicutes phylum and decreased levels of Bacteroidetes (Table1). The level of blood lipid of the patient returned to the almost normal level after FMT. He et al., [14] reported earlier similar results, showing that the gut microbiota could affect host lipid metabolism. These evidence suggested that FMT may be one of the therapeutic options for metabolic diseases [14]. Presence of Bifidobacteria and Lactobacillus were correlated with four or less number of seizures per year. In addition the ketogenic diet associated with an altered gut microbiota composition and function reduced the number of seizures [15].

Table 1: Microbiol (types of bacterial species) contents in Healthy, Epilepsy Patient and Patient after FMT.

Name of the disese	Gut biome of the patient	After FMT	REF
Epilepsy	Increase		[1]. Mejía-Granados DM, et al. [10]. ?afak B, et al. [13]. Peng A, et al. [14]. He Z, et al. [17]. Ding M, et al. [18]. Gong X, et al. [19]. Xu HM, et al.
	α-diversity (drug resistant group) [17].	The alpha-diversity was higher in DS (Drug sensitive) and HC groups [17].
	Actinobacteria (Phylum) [17] Akkermansia, Atopobium, Bifidobacterium [17] Bifidobacterium Clostridium XVIII, Blautia [17] Clostridium, Coprobacillus, Coprococcus, Cronobacter, Delftia, Dorea, Firmicutes.	Bacteroidetes predominant healthy controls (HC) group, followed by Firmicutes [17].
	Fusobacterium, Gemmiger, Holdemania, Lactobacillus Methanobrevibacter, Neisseria, Neisseria, Phascolarctobacterium, [17] Roseburia, Proteobacteria, Ruminococcus, Saccharibacteria, Spirochaetes Verrucomicrobia [17] In the DR (drug resistant) group, Firmicutes was the largest group, followed by Bacteroidetes [17]
	Decrease
	Proteobacteria (Phylum) [17] Actinobacteria Cerrucomicrobiota, Actinobacteria, Bacteroidetes, Bifidobacterium Euryarchaeota, Firmicutes, Furvacheota, Prevotella.	Phylum level, DS and HC had Bacteroidetes as the largest phylum and Firmicutes as the second [17].

Epilepsy has a close link to autoimmune diseases and the fact that the cause of epilepsy is idiopathic in 60% of cases, suggest that intestinal microbiota may play a role in the etiology of epilepsy [10]. In this study, they analyzed and compared the intestinal microbiota composition 16s ribosomal DNA sequencing as a tool of patients with idiopathic focal epilepsy (n=30) and healthy volunteer group (n=10). Proteobacteria (phylum) and genera of Campylobacter, Delftia, Haemophilus, Lautropia, and Neisseria among Proteobacteria phylum were found to be significantly higher statistically in patients with epilepsy than in healthy volunteers (Table). The healthy volunteer group harboured less of Fusobacteria phylum (10.6%) compared to the patients represented by Leptotrichia and Fusobacterium. ?afak, et al., [10] correlated taxonomic drift and significant differences in the intestinal microbiota of patients with epilepsy as a causal factor operating autoimmune mechanisms and inflammation in the etiology of epilepsy [10]. Lee et al., [16] observed that 17 and 18 species of bacteria strongly related to epilepsy and the (healthy controls) HC group respectively. This group also suggested that Enterococcus faecium, Bifidobacterium longum, and Eggerthella lenta could be considered as strongest potential biomarkers in epilepsy [16].

Bacterial function analysis showed that glucose- and lipid-associated metabolic pathways were all down regulated in the epileptic group and ABC (ATP-binding cassette) transporter-associated metabolic pathways elevated in the drug resistant (DR) group compared to drug-sensitive DS group [16].

Clinical trials in humans provide enough evidence that FMT reduces the severity of the disease probably by altering the production of microbial metabolites such as serotonin, SCFA or GABA receptor agonists. The reduction of proinflammatory gut bacteria may decrease cerebral oxidative stress and neuro and systemic inflammation.

Conclusion

A growing body of evidence are produced for the pivot role played by gut microbiota as a modulator of immunity, metabolism, and neuroendocrine signaling pathways.

Most of the studies fail to focus, on the genetic potential of host and microbial metabolites, maybe due to the elevated cost and the complexity in data analysis coming from this technology.

Since most of the studies discussed focus only on methods that assess the taxonomic composition of the gut, the genetic potential of host and microbial metabolites are usually underestimated, maybe due to the elevated cost and the complexity in data analysis coming from this technology.

Therefore, continued efforts are needed to adopt a multi-omic approach, i.e., whole-genome and metabolomics analysis, to integrate multiple biological mechanisms, microorganisms, and particular metabolites involved in epilepsy. Major challenges faced in therapeutics to translation FMT as a diagnostic tool includes:

Sandardization of large cohorts to ensure a wide variability of microbiome profiles among patients.
Reduction of confounding factors, such as nutritional preferences, exposure to medications and antibiotics, lifestyle, immunological factors, genetic influences, environment, intestinal physiology;

Systematic microbial sampling that integrates multi-omic approaches.

Stratification of the etiology and type of epilepsy. Safety of this modality, potential benefits of FMT should be carefully weighed since, risks involved in choosing donors (all healthy donors or only few with certain gut microbiota are suitable is still unknown).

Underestimation of these suggestions may lead to a fuzzy concept of “normal” and “pathological” and, identifying the specific context in which microbes become harmful would help in personalized treatments for epilepsy patients. Though gut bacteria may be one factor, they aren’t the sole “man behind the curtain” in the susceptibility and prognosis of epilepsy. Much more results from well-designed large double-blinded trialsin human patients are needed to elucidate the significance of FMT in treating neurological disorders.

International Journal of Womens Health and Gynecology