Study on Gut Microbiota in Children with Cerebral Palsy and Epilepsy

*Congfu Huang and Defeng Cai*

#### **Abstract**

Compared to children with cerebral palsy (CP), children with both CP and concurrent epilepsy (CPE) have more severe gastrointestinal symptoms, such as functional constipation (FC), and are more prone to recurrent infections. Our previous study found that these children have gut microbiota (GM) disorders, which are significantly related to the gastrointestinal symptoms and immune functions. The children with CPE also has altered oral microbiota (OM), which is consistent with the change of GM. In addition, the change of OM and GM has potential impact on the occurrence of clinical diseases such as periodontitis, dental caries and malnutrition. In our previous study, it was also found that the abundance of butyric acid- and lactic acid-producing bacteria in the GM of children who have CPE with liquid food in their diet decreased significantly, while the abundance of opportunistic pathogenic bacteria increased significantly. After the butyric acid-, lactic acid-producing probiotics and dietary fibers were administered by us to treat the FC in children with CPE, the FC improved significantly, and the abundance of butyric acid- and lactic acidproducing bacteria in the intestine increased.

**Keywords:** cerebral palsy with epilepsy, gut microbiota, oral microbiota, probiotics, dietary fiber

#### **1. Introduction**

Cerebral palsy (CP) is a group of neurological disorders that are caused by damage to the developing brain in fetuses or infants, which leads to permanent impairment of cerebral motor functions and impairment of abilities to maintain balance and posture [1]. Besides impaired cognitive function development, patients with CP often have many other co-occurring cerebral neurological disorders, such as epilepsy which has an incidence of 35–62% with an average of 43% in patients with CP [2]. The onset of concurrent epilepsy (CPE) disease is usually in infancy or early childhood, with more than half of CPE first appearing before 1 year old and more than 92% of CPE first occurring before 4 years old [2–6]. The incidence of epilepsy in patients with CP is five times that of normal children without CP [7]. The main risk factors for epilepsy in children with CP include neonatal convulsions, low birth weight, intracranial

hemorrhage, gray and white matter lesions caused by brain damage, and brain structure malformations [8, 9]. The incidence of CPE is also related to the types of CP, with most of the CPE occurring in patients with spastic CP which has a younger age of onset as well [10–12]. The occurrence of epileptic seizures might increase brain damage in CPE patients, impairing cognitive and motor function development, affecting directly the treatment outcomes and prognosis in patients with CPE, and significantly decreasing the life quality of the patient's family members [3, 6, 13]. Patients with CPE have a higher incidence of paralysis in the three or four limbs, with a more severe CP (grade IV and grade V palsies) as well [14]. The cognitive, movement, and behavioral difficulties are increased in CPE patients due to the existence of epilepsy [15, 16]. The epileptic seizures can be controlled well by anti-epileptic medications in some of the children with CPE. Some patients might even develop resistance to the anti-epileptic drugs, leading to the development of intractable epilepsy [17, 18]. The incidence of obstructive sleep apnoea (OSA) is also higher in children with CPE compared to children with only CP [18]. As a result, early and sustainable control of the occurrence of epileptic seizures in CPE patients directly affects the long-term prognosis of these patients.

There are often common pathogenesis and etiology shared between epilepsy and CP. The risk factors for epilepsy and CP can be divided into three types: 1. Prenatal factors: such as consanguineous marriages, multiple pregnancies, intrauterine infections, intrauterine growth retardation, and history of use of medications in pregnant women, etc. [19]. 2. Perinatal factors: such as placenta previa, perinatal asphyxia, premature infant, placental abruption, and infant of low birth weight, etc. [20]. 3. Postnatal factors: such as neonatal hyperbilirubinemia and non-infectious or infectious diseases, etc. In recent years, with the advances in medicines and technologies, many premature infants or infants with very low birth weights can survive. But the problems of the occurrence of movement disorders, cognitive disorders, sensory disorders, cognitive abnormalities, and learning disabilities in these premature babies have gradually come into the picture [21].

About 80–90% of patients with CP have some gastrointestinal disorders, such as constipation, dysphagia, hypersalivation, and gastroesophageal reflux, among which the incidence of functional constipation (FC) reaches 26–74% [22, 23]. The incidence of FC is even higher in patients with CPE, which might reach 100% in some studies, with a more frequent occurrence of abdominal distensions and upper gastrointestinal tract hemorrhage, etc. in CPE patients [24–26]. These gastrointestinal disorders significantly affect CPE patients physically, socially, and emotionally, decreasing the quality of life in children with CPE [27, 28]. The alteration of gut microbiota (GM), on the other hand, can affect gastrointestinal functions. Our studies have found that there is a unique composition of gastrointestinal microbiota in patients with CPE [24–26, 29].

#### **2. The characteristics of the composition of digestive tract microbiota in CPE patients**

#### **2.1 The characteristics of GM in CPE patients**

The principal component analysis (PCA) study showed that there is a separation of microorganisms in GM in the specimens from CPE patients and healthy individuals. The isolated microorganisms include *Bacteroides*, *Bifidobacterium*, *Prevotella*,

*Study on Gut Microbiota in Children with Cerebral Palsy and Epilepsy DOI: http://dx.doi.org/10.5772/intechopen.111958*

**Figure 1.** *(A) PCA of CPE patients and healthy individuals. (B) Alpha diversity of CPE patients and healthy individuals.*

*Faecalibacterium*, and *Parabacteroides* (**Figure 1A**). Besides, the diversity of microorganisms and the Shannon index in the CPE patients group are higher compared to that in the healthy individual's group (**Figure 1B**).

Compared to healthy children, there is a significant alteration in GM in CPE patients [24, 25]. The relative abundance of *Actinomycetes* significantly increases while the relative abundance of *Bacteroides* significantly decreases in the CPE patients at the phyla level. On the other hand, at the Genus level, the relative abundance of the beneficial bacteria *Bifidobacterium* significantly increases, and the relative abundance of the opportunistic bacteria such as *Parabacteroides*, *Enterococcus*, and *Streptococcus* increases as well, but the relative abundance of butyric acid-producing bacteria such as *Bacteroides*, *Faecalibacterium*, *Ruminococcus*, and *Roseburia* significantly decreases. The above changes in GM can lead to chronic inflammations in the intestines which is closely related to gastrointestinal functional disorders such as FC. After the KEGG annotation and function enrichment analysis, it can be seen that the xenobiotics metabolism, immune system diseases, and neurodegenerative diseases are increased in CPE patients. In contrast, the functional categories related to the biosynthesis of secondary metabolites are reduced. Furthermore, the increased risk of neurodegenerative diseases is mainly attributed to *Streptococcus*, while the increased risk of immune system diseases is associated with enriched *Akkermansia* in CPE patients **(Figure 2**).

#### **2.2 The association study on GM and OM in CPE patients**

There are usually many oral diseases appearing in the patients with CP, such as periodontitis, and dental caries [30, 31]. The previous studies have also shown that the abundance of *Fusobacterium nucleatum* and *Porphyromonas gingivalis* were significantly elevated in the oral cavity of CP patients [32, 33], which induces the alteration of GM through different approaches and leads to gastrointestinal functional disorders such as FC [34–36]. It was found through our surveys that 26 out of 27 (96.30%) CPE patients suffered from periodontitis, while 22 patients (81.48%) suffered from

**Figure 2.** *Composition and functional categories of GM.*

various degrees of dental caries and 11 patients (40.74%) developed intractable constipation [28]. The bacterial plaques on the gingiva in CPE patients might enter the stomach and intestines through the enteral pathway (e.g. through ingestion and swallowing) and the bloodstream route (e.g. invading the capillaries in the endodontic through the root canal). Thus, acid-tolerant bacteria might enter and colonize the stomach and intestines, which can lead to the alteration of GM and chronic intestinal inflammations. It might also induce developmental defects in the brain, neuroinflammation, and neurodegenerative diseases through the vagus nerve route (leading to neurotransmitters disorders, e.g. GABA and acetylcholine), tryptophan metabolism (e.g. quinolinic acid and kynurenic acid) and microbial metabolism disorders (e.g. SCFA and peptidoglycan), which aggravates the neurological symptoms in the CP patients [37].

We also discovered that the first three dominant bacteria in oral microbiota (OM) in CPE patients are *Prevotella*, *Fusobacterium*, and *Neisseria*, which are potentially linked to dental caries, periodontitis, and malnutritions in CPE patients [29]. In addition, there is a positive correlation between the disorders' frequency and the levels of *Solobacterium*, *Lachnoanaerobaculum*, *Corynebacterium*, and *Veillonella* in the OM in the CPE patients. On the contrary, the levels of *Actinomyces*, *Corynebacterium*, *Leptotrichia*, and *Veillonella* correlated negatively with the spasm frequency. As for GM, the frequency of disorders is associated positively with *Alloprevotella* and *Blautia*, but negatively with *Alistipes* and *Clostridium\_XVIII*. In addition, the spasm frequency is in positive association with *Senegalimassilia*, *Staphylococcus*, *Actinomyces*, and *Bacillus*, but in a negative association with *Sutterella* and *Victivallis*. Overall,

*Study on Gut Microbiota in Children with Cerebral Palsy and Epilepsy DOI: http://dx.doi.org/10.5772/intechopen.111958*

**Figure 3.** *Association between OM/GM and clinical manifestations.*

these findings suggest that there is a significant association between the frequency of disorders and spasms and OM and GM. However, the mechanisms behind this should still be further explored (**Figure 3**).

Given the significant correlation between disorder/spasm frequency and oral/ GM, we further conducted another association analysis for OM and GM. Based on the statistical analysis using Spearman's coefficient (*P* < 0.05), it was shown that there is a positive correlation between oral *Capnocytophaga* and intestinal *Christensenella*, Clostridium-IV. A positive correlation is also identified between oral *Campylobacter* and intestinal *Lachnospiracea-incertaesedis*, between oral *Actinomyces* and intestinal *Phascolarctobacterium* and *Alistipes*, as well as between oral *Treponema* and intestinal *Clostridium-XlVa*, *Parabacteroides* and *Alistipes* (**Figure 4**).

#### **2.3 The diet and GM in CPE patients**

Diet is an important factor that affects the composition and function of GM. As we know, GM plays a key role in maintaining the normal functions of the gastrointestinal tract, and the alteration of GM is involved in the development and pathogenesis of functional gastrointestinal disorders. It was also found that most of the CPE patients who ingested liquid food in their diet suffered from FC. The intestinal tract of these patients was enriched with opportunistic pathogenic bacteria such as *Collinsella*, *Alistipes*, and *Eggerthella*. In addition, the abundance of *Bifidobacterium* was significantly increased in the patients fed with dairy products. Meanwhile, the intestinal tract in patients fed with a regular diet was enriched with the butyric acid-producing bacteria which are also found in the healthy population, such as the *Lachnoclostridium*, *Dorea*, *Ruminococcus*, *Faecalibacterium*, *Roseburia*, and *Coprococcus*, while the abundance of *Prevotella* for carbohydrate degradation was significantly increased in this group of patients as well [26] (**Table 1**). The above results suggest that the barrier of intestinal mucosa was damaged in the CPE patients who had a liquid diet, resulting in a significantly higher incidence of gastrointestinal disorders such as FC.

#### **2.4 Intervention of FC in CPE patients with probiotics and dietary fibers**


Dietary fibers are carbohydrates that can not be digested by humans, which are also the fermentation substrate for the intestinal normal microbiota [38]. Therefore, the dietary fibers can promote the proliferation of probiotics, especially

#### **Table 1.**

*The first 15 dominant bacteria in the regular diet group and the liquid diet group.*

#### *Study on Gut Microbiota in Children with Cerebral Palsy and Epilepsy DOI: http://dx.doi.org/10.5772/intechopen.111958*

the *Lactobacillus* and *Bifidobacterium* [39], and inhibit the growth of opportunistic pathogenic bacteria or harmful bacteria [40]. Probiotics have a similar effect with dietary fibers. For example, the lactic acid-producing probiotics bacteria can produce some metabolites (e.g. short chain fatty acids, SCFAs) which can promote the intestinal peristalsis and the secretions from the intestinal mucosa, lowering the intestinal pH, acidifying the intestinal tract environment, thus improving constipation. Also, the propionic acid and the butyric acid in the SCFAs can induce the secretions of sIgA from the plasma cells in the lamina propria in the intestinal mucosa, and also induce the development and differentiation of Treg cells, and decrease the occurrence of mucosal inflammations, and promote the expression of tight-junction proteins, and maintain the barrier of intestinal mucosa [41].

Compound dietary fiber powders (contain psyllium cylindrical shell powder, resistant dextrin, apple pectin, Konjac powder, and 20 g of dietary fiber complex is contained in each pack), lactic acid-producing complex probiotics (contain *Lactobacillus rhamnosus*, *Lactobacillus acidophilus*, *Lactobacillus paracei*, *Lactobacillus plantarum*, *Bifidobacterium lactis*, sorbitol, fructooligosaccharide, xylooligosaccharides, and viable bacteria ≥18 billion CFUs per pack) and butyric acid-producing probiotics (each pack contains viable *Clostridium butyricum* bacteria ≥1.0 × 107 CFUs/g, viable *Bifidobacterium* bacteria ≥1.0 × 106 CFUs/g) were administered for the intervention of FC in the CPE patients, with 1-month administration of compound dietary fiber powders and 6 months administration of lactic acid-producing complex probiotics and butyric acid-producing probiotics [42]. FC was relieved in all of the CPE patients after the intervention course, with improved abdominal distensions and nutritional conditions and increased body weight in some of the CPE patients (**Figure 5**).

#### **Figure 5.**

*Comparison before and after treatment in a child with CPE (2019.10.09 vs. 2020.03.26. Their body weights were 9.8 and 11.5 kg, respectively). Week 1: Open plug dew seven capsules/week (exhaust), defecation seven times/ week (forming hard stool), serious abdominal distension; Week 2: Open plug dew zero capsules/week, defecation seven times/week (forming hard stool), abdominal distension significantly reduced; Week 3: Open plug dew zero capsules/week, defecation seven times/week (forming hard stool), slight abdominal distension; Week 4: Open plug dew zero capsules/week, defecation seven times/week (forming soft stool), abdominal distension disappeared; Week 24: Open plug dew zero capsules/week, defecation seven times/week (forming soft stool), abdominal distension disappeared. Note: The above pictures of children have been authorized and approved by the guardian of Longgang district Social Welfare Center.*

**Figure 6.** *Changes in the levels and abundance of bacterial genus before and after the intervention.*

The abundance of dominant GM in the Genus level has changed before and after the intervention. The abundance of some bacterial genus continued to drop after the intervention, such as the *Prevotella*, *Collinsella*, *Sutterella* and *Megamonas*. The abundance of some bacterial genus was increased after the intervention for 1 month, but was decreased after the intervention for 6 months, such as the *Bacteroides*, *Faecalibacterium* and *Lachnospiracea-incertaesedis*. The abundance of some bacterial genus was decreased after the intervention for 1 month, but was raised after the intervention for 6 months, such as the *Bifidobacterium*, *Oscillibacter* and *Parabacteroides* (**Figure 6**). The above results suggest that both the compound dietary fiber powders and the probiotics products should be administered for 6 months, which should exert a more sustaining effect in restoring the composition of GM.

Considering the diet being the most significant factor affecting the composition of GM, which also causes the largest interference on the outcomes of therapeutic interventions. In this study, the composition of GM in the CPE patients with different diets in different diet groups varied significantly. Therefore, a stratified statistical analysis was also conducted. The results showed that the abundance of intestinal *Lactobacillus* and *Clostridium* displayed an increasing trend in the CPE patients with regular diet after the intervention, but the increase is not statistically significant. The abundance of *Bifidobacterium* was decreased after the 1-month intervention and was increased again after the 6-month intervention in the CPE patients with regular diet (**Table 2**). The abundance of the above three bacteria all changed statistically significantly in the CPE patients with liquid diet after the intervention: the abundance of intestinal *Lactobacillus* and *Clostridium* showed a statistically significant increase after the intervention. The abundance of *Bifidobacterium* was decreased after the 1-month intervention and was increased statistically significantly after the 6-month intervention in the CPE patients with liquid diet (**Table 3**). The above results suggest that the supplementation of probiotics products can help in raising the abundance of relevant intestinal microflora bacteria in the CPE patients, while the CPE patients in the liquid


 *Changes in the abundance of probiotics bacteria in feces before and after the intervention in the CPE patients in the regular diet group (mean ± SD, %).*

#### *Study on Gut Microbiota in Children with Cerebral Palsy and Epilepsy DOI: http://dx.doi.org/10.5772/intechopen.111958*


 *Changes in the abundance of probiotics bacteria in feces before and after the intervention in the CPE patients in the liquid diet group (mean ± SD, %).* diet group showed a sustaining response to the therapeutic intervention and showed a better response compared to the CPE patients in the regular diet group.

#### **3. Conclusion**

CPE patients often have concurrent functional gastrointestinal disorders, especially FC, which have a unique composition of digestive tract microbiota as well. The altered OM can then enter the gastrointestinal tract through different routes, leading to disordered GM which produces metabolites that can cause damage to the barrier function of the intestinal mucosa, resulting in chronic intestinal inflammations that are able to induce or aggravate FC. This can also affect brain functions through the gut-brain axis (GBA). Based on the therapeutic target of GM in CPE patients, the administration of specific probiotics bacteria and dietary fiber products was able to improve FC, restoring some of the composition and function of GM (e.g. the abundance of the butyric acid-producing and lactic acid-producing bacteria showed an increase). This approach to interventions could also improve the quality of sleep and improve the absorption of nutrients and metabolic conditions in CPE patients. However, whether the mental and neurological symptoms can be improved through the effects of GBA in CPE patients still needs to be further studied in the future.

#### **Acknowledgements**

We are thankful for the large amount of work done by the staff at the Longgang District Social Welfare Centre of Shenzhen City and the Longgang District Maternity and Child Healthcare Hospital of Shenzhen City. We also appreciate the funds and support from the Science and Technology Innovation Bureau of Longgang District of Shenzhen City. We also want to thank the BGI Nutrition Precision Co., Ltd. (Shenzhen) for the provision of therapeutic intervention products.

#### **Conflict of interest**

All the pictures and tables are original works from the author. We declared that there are no conflicts of interest.

#### **Author details**

Congfu Huang1 \* and Defeng Cai<sup>2</sup>

1 Department of Pediatrics, Longgang District Maternity and Child Healthcare Hospital, Shenzhen, China

2 Clinical Laboratory (Pathology) Center, South China Hospital of Shenzhen University, Shenzhen, China

\*Address all correspondence to: 78333755@qq.com

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Study on Gut Microbiota in Children with Cerebral Palsy and Epilepsy DOI: http://dx.doi.org/10.5772/intechopen.111958*

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#### **Chapter 3**
