The first 15 dominant bacteria in the regular diet group and the liquid diet group.
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 acid-producing 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, 3, 4, 5, 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, 11, 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, 25, 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, 25, 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
Compared to healthy children, there is a significant alteration in GM in CPE patients [24, 25]. The relative abundance of
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
We also discovered that the first three dominant bacteria in oral microbiota (OM) in CPE patients are
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 (
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
Regular diet group | Liquid diet group | ||||
---|---|---|---|---|---|
The first 15 dominant bacteria | Mean value (%) | SD (%) | The first 15 dominant bacteria | Mean value (%) | SD (%) |
25.85 | 26.11 | 24.93 | 15.60 | ||
12.95 | 17.04 | 12.13 | 11.31 | ||
8.45 | 8.91 | 6.15 | 16.59 | ||
3.92 | 7.47 | 5.13 | 4.92 | ||
2.79 | 3.24 | 4.51 | 3.96 | ||
2.32 | 2.19 | 3.61 | 7.38 | ||
2.15 | 4.05 | 2.71 | 3.65 | ||
1.68 | 1.94 | 2.02 | 2.51 | ||
1.35 | 3.95 | 1.79 | 3.10 | ||
1.35 | 1.78 | 1.48 | 2.79 | ||
1.33 | 3.87 | 1.45 | 2.29 | ||
1.32 | 1.82 | 1.40 | 4.45 | ||
1.13 | 2.78 | 1.16 | 2.24 | ||
1.02 | 1.71 | 0.87 | 1.97 | ||
1.02 | 3.13 | 1.68 | 1.94 |
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 the
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
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
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
Before intervention | After intervention for 1 month | After intervention for 6 months | P value (0 vs. 1) | P value (0 vs. 6) | |
---|---|---|---|---|---|
5.7130 ± 3.9603 | 4.1067 ± 1.6176 | 4.4595 ± 1.7363 | 0.377 | 0.596 | |
1.5597 ± 1.0576 | 3.5114 ± 1.1483 | 2.6450 ± 1.4694 | 0.005 | 0.185 | |
0.3380 ± 0.4398 | 0.5299 ± 0.2232 | 0.6509 ± 0.5816 | 0.077 | 0.093 | |
0.1593 ± 0.1655 | 0.1817 ± 0.1269 | 0.1598 ± 0.0903 | 0.377 | 0.536 | |
0.1558 ± 0.1678 | 0.4053 ± 0.2265 | 0.3298 ± 0.6121 | 0.017 | 0.659 |
Before intervention | After intervention for 1 month | After intervention for 6 months | P value (0 vs. 1) | P value (0 vs. 6) | |
---|---|---|---|---|---|
2.2163 ± 2.3703 | 2.6537 ± 1.2842 | 2.9365 ± 1.1905 | 0.137 | 0.085 | |
0.5072 ± 0.8519 | 1.5424 ± 1.6814 | 0.4944 ± 0.4986 | 0.001 | 0.152 | |
1.5749 ± 1.1317 | 2.1135 ± 0.9210 | 1.6305 ± 0.5925 | 0.080 | 0.381 | |
0.1267 ± 0.1927 | 0.1195 ± 0.0870 | 0.1324 ± 0.0822 | 0.199 | 0.085 | |
0.0722 ± 0.1143 | 0.2047 ± 0.1683 | 0.0747 ± 0.0525 | 0.000 | 0.090 |
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.
Acknowledgments
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.
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