Open access peer-reviewed chapter
Logistic regression analysis of the factors associated with the stool characteristics.
Abstract
Constipation is a common gastrointestinal disorder in children with cerebral palsy, which affects up to 74%. Children with cerebral palsy are at a high risk of gut dysbiosis. Prebiotics and probiotics may modulate gut microbiota and influence brain functions. Probiotics are defined as “live organisms that, when administered in adequate amounts, confer a health benefit on the host.” Prebiotics are a substrate that is selectively utilized by host microorganisms that confer a health benefit. Both probiotics and prebiotics have been shown to improve the gut microbiota and confer an improvement in the characteristics of stools such as the history of painful defecation, the presence of fecal mass in the rectum, and stool frequency in children with cerebral palsy. A strong bidirectional communication between the central nervous system and the enteric system exists, which is known as the gut-brain axis, which regulates gastrointestinal motility, gastric secretion, blood flow, gut barrier integrity, immune response, and visceral sensations. The use of probiotics and prebiotics can modulate the production of bioactive compounds that have an impact on the gut-microbiota-brain axis and brain functions in children with cerebral palsy.
Keywords
- probiotics
- prebiotics
- synbiotics
- cerebral palsy
- constipation
- gastrointestinal dysmotility
- pediatric neurological impairment
- gut microbiota
- gut-brain axis
1. Introduction
It has been recognized that cerebral palsy (CP) is a term that encompasses etiologically diverse symptoms, which change with age. The term “cerebral palsy” was first used in the nineteenth century by the English orthopedic surgeon William Little. He observed a dystocia delivery and consequent neonatal hypoxia leading to limb spasticity and musculoskeletal deformities [1]. This disorder occurs in 2–3 out of every 1000 live births and has multiple etiologies resulting in corresponding brain lesions [2, 3].
The risk factors that can cause damage to the central nervous system (CNS) at an early stage of its development are divided into the following categories: before conception, prenatal factors; perinatal factors, and risk factors in the neonatal period and infant stage [4, 5]. In general, CP has a high prevalence of musculoskeletal, gastrointestinal, cardiovascular, and psychiatric diseases. It has been recognized that children with severe motor and intellectual deficiencies, epilepsy, and feeding difficulties have poorer survival.
1.1 Types of cerebral palsy
CP subtypes include spastic, dyskinetic, ataxic, and mixed forms. The Gross Motor Function Classification System (GMFCS) incorporates motor function and is intended to identify differences between CP subtypes in terms of individual abilities. There has been a lot of interest in investigating the function, activity limitations, severity, and quality of life that affect individuals with CP. For this reason, function-based classification groups have been created. The GMFCS is divided into five levels: Level I - ambulation without restriction; Level II - ambulation without assistive devices but with some limitations outside the home; Level III - ambulation with assistance; Level IV – ambulation with assistance with motorized devices or car; level V – little or no ambulation [6]. The mild form of CP is equivalent to levels I and II of the GMFCS, moderate involvement is equivalent to level III, and severe involvement is equivalent to levels IV and V [7]. Spastic CP is the most common form of this movement disorder and affects 80% of children diagnosed with this pathology [8]. Spastic quadriplegia is the most severe form and is often complicated by spinal deformities, speech and feeding disorders, seizures, and muscle contractures. The ataxic type is another form of CP with jerky and uncoordinated movements. This type of cerebral palsy is often associated with speech problems, eye movement dysfunction, and difficulty swallowing [8].
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2. Gastrointestinal tract disorders in children with cerebral palsy
Most children with cerebral palsy have feeding difficulties and gastrointestinal (GI) problems such as oropharyngeal dysfunction, gastroesophageal disease, and constipation [1, 9]. In addition, it is known that patients with cerebral palsy may have difficulty swallowing, gastroesophageal reflux, frequent vomiting, and encopresis. During the eating process, food must be chewed, formed into a bolus, and transported to the pharynx, driven primarily by the tongue [10, 11]. Quitadamo et al., [12] have pointed out that almost nine out of ten children with CP experience digestive system alterations, such as difficulty eating, salivation problems, dysphagia, gastroesophageal reflux, and constipation.
2.1 Feeding problems
Children with CP often have difficulty sucking. The inability of an infant to perform safe and successful oral feedings may be an early sign of central nervous system immaturity [13].
Dysphagia in CP is characterized by poor tongue function that makes it difficult to transport the bolus, delaying the start of swallowing with the risk of aspiration, reduced pharyngeal motility, and drooling due to sialorrhea. Feeding problems arise from the prolonged times of this eating process with a delay in the progression of oral feeding skills that can cause growth slowdown due to chronic food insufficiency. These eating problems can lead to dehydration, malnutrition, aspiration pneumonia, and even death [14]. During this initial phase of swallowing, closing the lips ensures the permanence of the bolus in the oral cavity, while the cyclical movements of the tongue, coordinated with the movements of the jaw, process solid food.
Speyer et al. [15] conducted a systematic review to obtain published data on drooling, swallowing, and feeding problems in people with cerebral palsy throughout life and to estimate the prevalence of drooling, swallowing, and feeding problems by meta-analysis. They obtained 42 articles on the prevalence of drooling, swallowing, and feeding problems in people with cerebral palsy. Estimates in the pediatric population from 0 to 18 years old showed a prevalence of drooling of 44.0% (95% CI 35.6–52.7), of swallowing problems of 50.4% (95% CI 36.0–64.8), and of feeding problems of 53.5. % (95% CI 40.7–65.9).
2.1.1 Feeding problems and malnutrition
Furthermore, feeding difficulties in children with CP play an important role in the pathogenesis of malnutrition and consequently increase the risk of stunting [16]. It even nearly doubled between 2002 and 2015. Minority and economically disadvantaged ethnic groups were more likely to be malnourished. Likewise, gastrointestinal disorders increase the likelihood of malnutrition in hospitalized patients. In this context, physical growth is a fundamental measure of health and well-being in children with CP [17]. However, it must be remembered that patients with CP grow at a slower rate compared to typical developmental milestones, even when medical and nutritional care are optimal. And, also there are feeding schemes that promote rapid weight gain and can cause metabolic syndrome, among other clinical disorders [18, 19, 20, 21].
Zhao et al., [22] conducted a multicenter cross-sectional study with children with CP in China. In addition to obtaining the Z score from the anthropometric measurements, they evaluated the GMFCS, the Eating and Drinking Ability Classification System (EDACS), the Subjective Global Nutritional Assessment (SGNA), and the capacity for social life, and they concluded that the degrees of malnutrition in children with CP correlate with the severity of eating and drinking dysfunction and with gross motor impairment.
2.2 Constipation in children with cerebral palsy
Intestinal dysmotility includes various disorders that are characterized by impaired muscle activity in the gastrointestinal tract (GIT) with altered peristalsis [23]. Intestinal motility disorders are common in children with cerebral palsy, which are characterized by abnormal movements of the gut and can result in symptoms such as constipation, diarrhea, reflux, and vomiting [24]. These alterations have a significant impact on the quality of life of the affected population [23]. Constipation would affect 26–74% of children with CP [12, 25]. The etiology is associated with neurological and dietary factors, lifestyle, and decreased mobility [26]. Almost all children with CP and comorbid epilepsy have a gastrointestinal dysfunction, the most troublesome being constipation, followed by abdominal distension, vomiting, and recurrent GIT bleeding [25].
It has been considered important to have a uniform definition of constipation in children with CP [27]. The definition proposed by Veugelers et al. [28], which is, “hard, slimy, scybalous, pebble-like stools in 25% of bowel movements and stool frequency less than three times per week, or large stools palpable on abdominal examination, or use of laxatives or disimpaction faeces manual,” appears to be the most comprehensive and is based on three different consensus documents dealing with this issue. Families of children with CP and constipation need to be advised for the effective management of this problem. Parental counseling is necessary for behavior change, positive mental health, problem solving, self-efficacy, and decision making [12].
Rebelo et al. [29] carried out a systematic review with the purpose of synthesizing certain results of randomized clinical trials that evaluated the effect of dietary interventions that improved gastrointestinal problems in children with CP, such as constipation. They only found two clinical trials conducted with the purpose of improving this problem and the characteristics of the stool. One of them evaluated a supplementation for 28 days with probiotics, synbiotics, or prebiotics compared to a placebo. These authors found improvement in the consistency and frequency of bowel movements [30]. In another study conducted by Hassanein et al., [31] they studied supplementation with an oral solution of magnesium sulfate for 1 month compared to a placebo. Although they also reported improvement, the authors of this review considered that both studies were at high risk of bias, and therefore their results would be inconclusive.
2.2.1 Factors associated with constipation in children with cerebral palsy
The mechanisms that produce gut dysmotility are various, and the clinical manifestations are nonspecific [24]. Several factors can influence the stool frequency, consistency, and pH in children with cerebral palsy, such as spasticity [26]. Constipation can be related to reduced mobility, feeding difficulties, or nutritional problems, and it could be a side effect of muscle-relaxing drugs [28]. It has been identified that children with a high degree of motor alterations are the most severely affected. Some alterations such as hypotonia, muscle incoordination, bone deformities (scoliosis, hip dysplasia, etc.), and prolonged immobility exacerbate constipation [28, 32]. Spasticity promotes constipation due to lower mobility of the trunk, lower extremities, abdominal viscera and hypertonia, all these factors contribute to reduce the stool frequency [33]. Moreover, these patients have gut motility alterations, which are related to damage in the brain that affects the entire colon, particularly the proximal colon; another segment commonly affected is the rectum-sigma [26]. A study [34] showed that the production of methane gas contributes to constipation and that the excretion of CH4 increases due to the reduction of intestinal peristalsis. The normal frequency of defecation in healthy children is variable, usually three times per day to once every 2 days; however, in children with CP, it is reduced to once every seven to 10 days [26, 35]. Other factors associated with constipation in this population are the use of anticonvulsant drugs (phenytoin and valproic acid, among others) [36, 37] and low dietary intake of liquids and fiber [38]. Oral motor dysfunction exacerbates feeding problems, which occurs in more than 90% of children with CP [39]. Caramico-Favero et al., [40] showed that children with CP and constipation had a lower fiber intake compared with the non-constipated group. The study conducted by García-Contreras et al., [30] aimed to identify the association of dietetic factors, use of anticonvulsants, and family history with the stool characteristics of 51 children with cerebral palsy and chronic constipation. There was a positive correlation between stool frequency and the consumption of oilseeds (r = 0.339, p = 0.023). There was a negative correlation between hard stools and the intake of liquids (r = −0.335, p = 0.026) and between stool pH and the intake of cereals high in insoluble fiber (r = −0.339, p = 0.030), vegetables rich in soluble fiber (r = −0.308, p = 0.044), carrots (r = −0.336, p = 0.027), and potatoes (r = −0.307, p = 0.045).
In the same study, an association was identified between the use of human milk substitutes with probiotics/prebiotics with low probability of hard stools [OR = 0.214 (95%CI 0.045–0.98), p = 0.047]; likewise, they increased the probability of a more acid fecal pH [OR = 4.708 (95%CI 1.17–18.91), p = 0.029]. The anticonvulsant polytherapy was associated with hard stools [OR = 14.2 (95%CI 1.16–174), p = 0.038], while the most common polytherapy was the combination of magnesium valproate and vigabatrin (Table 1). There was no association between family history and constipation.
| Independent variables | Dependent variables | OR | CI 95% | p |
|---|---|---|---|---|
| Use of formulas with probiotics and prebiotics | Hard Stools | 0.214 | 0.045–0.98 | 0.047 |
| Acid pH | 4.708 | 1.17–18.91 | 0.029 | |
| Anticonvulsant polytherapy | Hard Stools | 14.250 | 1.16–174 | 0.038 |
| Family history of constipation | Frequency of evacuations | 0.617 | 0.11–3.41 | 0.581 |
Table 1.
Authors concluded that the low consumption of fiber, fluids, and the anticonvulsant polytherapy were associated with harder feces and less frequency of defecation, and they recommend daily intakes of fiber and fluids, especially in children with anticonvulsant polytherapy. High intake of vegetables that contain soluble and insoluble fiber are associated with an improvement in constipation.
2.2.2 Pharmacological treatment for constipation in children with cerebral palsy
Drugs could be necessary to help manage gut dysmotility and constipation, such as laxatives, anticholinergics and prokinetic agents [24]. Mineral oils should be avoided in children with CP since aspiration increases the risk of lipoid pneumonia [41]. Polyethylene glycol (PEG) is a non-poisonous polymer, soluble in water, with high molecular weight, and is not absorbed by GIT. It acts as an osmotic agent and retains water in the lumen of the intestine and colon, softening the stools and stimulating bowel movements by increasing water content, and it is a safe agent without significant side effects in the treatment of chronic constipation in children. It is a safe and effective treatment for constipation in neurologically impaired children [42, 43]. Motilium is a prokinetic drug and is effective in the treatment of gastroesophageal reflux with minimal effect on constipation [44].
A randomized clinical trial in 52 pediatric CP patients with chronic constipation analyzed three therapeutic interventions: (1) PEG, (2) PEG with Motilium, and (3) Motilium for 2 weeks. PEG was administered at 0.5 g/kg/dose three times daily and Motilium at 0.2 mg/kg/dose three times daily. PEG with Motilium showed the highest improvement in chronic constipation symptoms and in stool frequency.
Oral magnesium therapy is accepted as a standard treatment for constipation, and it has been reported to significantly improve spasticity and lower limb movement [45]. A double-blinded randomized control trial was carried out in 100 children with CP (level III-V of the GMCS) and chronic constipation who received oral magnesium sulfate 1 mL/kg/day daily for 1 month. After 1 month of intervention, the constipation score and stool frequency and consistency improved compared to the placebo group (p < 0.001). The proportion of painful defecation decreased in the magnesium sulfate group vs. placebo (p = 0.03). Oral magnesium sulfate is an effective therapy improving chronic constipation and pain experience in children with CP [31].
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3. Probiotics and prebiotics on constipation in children with cerebral palsy
Probiotics are commonly used for both generally healthy consumers and in clinical settings. Probiotics have been defined as “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host;” this definition was grammatically edited from a previous FAO expert consultation [46]. Probiotics contribute to human health after an adequate intake to maintain the balance of the gut microbiota. Some probiotics are capable of producing butyric acid that will maintain the integrity of the intestinal mucosa barrier [47]. In the past 20 years, a class of substances, called prebiotics, were recognized for their ability to modulate the host microbiota [48]. According to the International Scientific Association for Probiotics and Prebiotics (ISAPP) [49], a prebiotic is a ‘substrate that is selectively utilized by host microorganisms conferring a health benefit.’ This definition also includes non-carbohydrate substances. Beneficial health effects must be documented in order for a substance to be considered a prebiotic. Fructooligosaccharides (FOS) and galactooligosacharides (GOS) currently dominate the prebiotic category as evidenced by various studies [49].
3.1 Types of probiotics and prebiotics used in children with cerebral palsy and constipation
The supplementation with dietary fiber and/or probiotics based on gut microbiota characteristics can effectively improve functional constipation in children with cerebral palsy [50]. Three clinical trials have been carried out to assess the use of probiotics and prebiotics in children with cerebral palsy. Two of them were performed in Mexico and another in China.
Rodríguez-Hernández et al., [51] conducted an intervention of 49 days (7 weeks) with modern kefir on conditions associated with moderate severe spastic quadriparesis cerebral palsy. Milk kefir is a dairy product that includes several microorganisms, which contain bacteria from genera
A study with
The study conducted by Huang et al., [50] aimed to investigate the effect of dietary fiber combined with probiotics on functional constipated children with cerebral palsy with GMFCS level III or above. The average age was 13.48 ± 3.40 years. A group was treated with a general diet (n = 14) and another with a liquid diet (n = 21); all of them received a compound dietary fiber (CDF) that contained psyllium seed husk (20 g/day) for 1 month and lactic acid-producing and butyric acid-producing probiotics for 6 months. Two types of probiotics were used; one contained <1.8 × 1010 CFU/sachet of
3.2 Gut microbiota in children with cerebral palsy
The gut microbiota is a complex ecosystem of approximately 100 trillion microorganisms that interact with digestion, immune function, and metabolism [54]. The composition of gut microbiota is influenced by many factors, such as gestational age, birth mode, maternal microbiota, exposure to antibiotics, proton pump inhibitors, type of feeding, and “biotics” (probiotics, prebiotics, synbiotics, or postbiotics) [55].
Gut microbiota influences the maturation of the immune system, gut permeability, nutrient absorption, and metabolism; maintains normal GI physiological function; and contributes to cerebral palsy through the gut-brain axis [56]. Several studies have suggested that gut microbiota is associated to neurologic diseases (Autism Spectrum Disorder, Parkinson’s Disease, and Alzheimer’s Disease) [57].
The dysbiosis in the gut microbiota due to dysmotility of the GI tract can alter the gut-brain axis, exacerbating the neurological symptoms [58]. Moreover, this imbalance results in gastrointestinal diseases including constipation [50]. The modulation by biotics can change the composition of the microbiota and indirectly affect gut motility [24]. Insufficient consumption of dietary fiber induce gut microbiota to use mucus glycoproteins as an alternative, which causes erosion of the colonic mucus barrier, leading to colitis [59]. Also, it can stimulate the production of short-chain fatty acids (SCFAs), which will regulate the immune response of the host [60]. It also provides a nutrient source for gut microbiota contributing to the integrity of the intestinal barrier. Gut microbiota differs between children with CP that receive a liquid diet and a general diet.
The microbiota in the general diet group was higher in butyric acid-producing bacteria, which is a characteristic of healthy individuals (
The gut microbiota of children with CP has been compared with the gut microbiota of healthy children. The gut microbiota diversity is higher in the CP children than in healthy children (p < 0.001). The most abundant genera in the CP group were
A study conducted by Huang et al., [50] during 6 months with a compound dietary fiber (for 1 month) and a probiotic (for 6 months) in 35 children with cerebral palsy (aged 13.48 ± 3.40 years) and functional constipation showed a significant increase in α-diversity after 1-month and 6-month intervention periods (p = 0.0025 and p = 0.047, respectively), with higher abundance of butyric acid-producing bacteria (
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4. Gut-microbiota-brain axis: the influence of prebiotics and probiotics
4.1 Introduction to gut-microbiota-brain axis
The gut microbiota plays a crucial role in bidirectional communications with the brain, known as the gut-microbiota-brain axis (GMBA) [62]. This complex network involves various components, including the CNS, which encompasses the brain and spinal cord, as well as the autonomic nervous system, the enteric system, the neuroendocrine system, the hypothalamic-pituitary adrenal axis (HPA), and the neuro-immune system [63, 64]. The GMBA facilitates the change of signals and molecules between the gut microbiota and the brain, influencing various physiological and cognitive processes [65].
The vagus nerve (VN) serves as a crucial communication pathway between the intestine and the brain [66]. Composed by 80% of afferent and 20% efferent fibers, the VN facilitates the transmission of signal in both directions [67]. Afferent fibers carry information from the intestine to the brain, detecting nutrients, chemical or luminal content trough chemoreceptor, and responding to distention or movement trough mechanoreceptor. On the other hand, efferent fibers transmit signal from the brain to the intestine, innervating the striated muscle and forming synapses with the enteric nervous system to regulate motor functions such as motility, secretions, and sphincter relaxation [62, 68].
The gut microbiota employs several mechanisms to transmit the information to CNS [68]. One of these mechanisms involves the production of neurotransmitters and bioactive metabolites that are transported to the brain through afferent vagus nerve fibers [69]. The gut microbiota generates various neurotransmitters, including γ-aminobutyric acid (GABA), dopamine, serotonin, norepinephrine, and histamine [70]. Additionally, bioactive substances with neurological functions, such as SCFAs, amino acids (tryptophan, tyrosine, and phenylalanine), and secondary bile acid, are produced by the gut microbiota [70, 71, 72].
Neurotransmitters can be classified into excitatory and inhibitory categories based on their effect in the CNS. Glutamate, histamine, and norepinephrine are examples of excitatory neurotransmitters, while GABA, dopamine, and serotonin are inhibitory neurotransmitters [70]. These molecules play a crucial role in controlling various physiological process such as movement, emotion, memory, learning, and so on [68].
Glutamate (Glu) is the most abundant excitatory neurotransmitter in the brain and plays a crucial role in memory storage and synaptic plasticity [73]. It is released from presynaptic nerve terminals and binds to ionotropic glutamate receptors located on postsynaptic terminals, allowing for signal transmission between nerve cells [70]. Interestingly, enteroendocrine cells in the intestine can synthesize glutamate and use it to transmit signals to the brain [74].
D-glutamate, a component of the peptidoglycan structure in bacterial cell walls, is produced by glutamate racemase, an enzyme that is present in bacteria. Several bacterial species have been identified to possess the ability to convert L-Glu to D-Glu. These bacteria include
Dopamine, a neurotransmitter, is primarily produced in the substantia nigra, central tegmental area, and hypothalamus. It is released into the nucleus accumbens and prefrontal cortex. Dopamine synthesis occurs in dopaminergic nerve cells and is dependent on the availability of the amino acid tyrosine. Tyrosine, which is obtained from the diet, can be transported across the blood-brain barrier (BBB) to reach the brain [68, 70]. Its synthesis begins with the hydroxylation of tyrosine to L-dihydroxyphenylalanine (L-DOPA), followed by the decarboxylation of L-DOPA to dopamine [77]. The production of dopamine is not exclusive for the brain. Certain bacteria such as
Serotonin also known as 5-hidroxytryptamine (5-HT) is synthesized by serotonergic neurons in the raphe nuclei of the brain [78]. However, it is important to note that a substantial proportion of serotonin, approximately 90%, is produced in the gut by the enterochromaffin cells. This neurotransmitter plays a vital role in regulating sleep, behavior, and various other functions within the CNS and GIT [63, 78]. The production of serotonin in the gut can be influenced by microbial metabolites, including SCFAs, secondary bile acids, a-tocopherol, p-aminobenzoate, and tyramine [62]. Several bacteria have been identified as participants in the production of serotonin. These include
Histamine plays a crucial role in various homeostatic functions, promoting wakefulness and regulating feeding and motivational behavior [75]. Histamine can also be produced by certain bacteria in the gut, which can activate histamine receptor [79]. A variety of bacterial species are implicated in the synthesis of histamine, comprising
Norepinephrine (NE) is a catecholamine that serves as a neurotransmitter in both central and peripheral nervous systems. It is produced by neurons in the locus coeruleus, where the precursor molecule tyrosine is converted into dopamine and subsequently into norepinephrine [81]. Bacteria such as
It is important to note that certain neurotransmitters, such as GABA, dopamine, and serotonin, do not penetrate the BBB [74]. Therefore, they must be synthesized within the brain local pools of neurotransmitter precursors [82]. However, the gut microbiota also contributes to the production of these molecules, which in turn can modulate other processes, for example, the enteric nervous system (ENS) [65].
Multiple brain disorders, such as Alzheimer’s disease, Parkinson’s disease, depression, anxiety, and cerebral palsy, are associated with the dysregulation of the gut microbiota, which can impact neurotransmitter production and disrupt the GMBA [62, 83]. Modulating the gut microbiota through the use of prebiotics and probiotics has emerged as a promising therapeutic approach to improve the GMBA and potentially treat these conditions [67]. However, further research is needed to fully understand the underlying mechanisms involved in the regulation of the GMBA by the gut microbiota.
4.2 Prebiotics and probiotics in the gut-microbiota-brain Axis
The gut microbiota is influenced by various factors including age, antibiotic therapy, diet, and gut microbiology, among others [84]. Diet plays a significant role in modulating the bacterial community and promoting changes in the alpha and beta diversity of the microbial ecosystem [85]. Prebiotics are utilized to selectively increase the abundance of specific beneficial bacteria, such as
Ongoing research aims to elucidate the mechanisms through which prebiotics and probiotics modulate the GMBA. Prebiotics, such as FOS, GOS and pectin, are a type of dietary fibers that are utilized by the gut microbiota to produce SCFAs [87]. The production of SCFAs has been implicated in the modulation of GMBA through various mechanisms, including the production of neurotransmitters, modulation of the BBB, development and regulation of the immune system, and modulation of inflammation in both the brain and GIT [71].
The concentration of SCFAs in the cerebrospinal fluid ranges from 0 to 171 uM for acetate, 0–5 uM for propionate, and 0–2.8 uM for butyrate. In the human brain tissue, the reported concentrations are 17 pmol/mg for butyrate and 18.8 pmol/mg for propionate. These concentrations highlight the close relationship between the GIT and brain through GMBA. Furthermore, they indicate that SCFAs have the ability to cross BBB and influence brain function [63].
SCFAs have been found to promote the maturation of glial cells and astrocytes [62]. Butyrate, synthesized by gut microbiota, stimulates memory and synaptic plasticity by inhibiting histone deacetylase [88]. Also, it influences the release of the neurotransmitter serotonin from intestinal enterochromaffin cells. Propionate, on the other hand, has a protective effect on the BBB by mitigating oxidative stress [89]. Acetate can cross the BBB and can be incorporated into the GABA metabolic cycle in the hypothalamus [74]. Additionally, acetate can activate the HPA axis, sending signals to the enteroendocrine cells. SCFAs also can modulate the stress response and mood suppressing the HPA axis, also known as the “stress axis.” [69] Furthermore, SCFAs can influence neuroinflammation by modulating the production and recruitment of immune cells such as T cells, neutrophils, and inflammatory cytokines [71, 89]. Propionate and butyrate possess the capability to activate cell signaling systems by modulating potassium levels and regulating key enzymes involved in neurotransmitter synthesis. These SCFAs have been demonstrated to specifically impact the levels of tryptophan 5-hydroxylase 1, an enzyme implicated in the production of serotonin, as well as tyrosine hydroxylase, an enzyme implicated in the synthesis of dopamine, adrenaline, and noradrenaline [63, 71]. These effects highlight the ampliated impact of SCFAs on neurotransmitter regulation and cellular signaling [67].
The use of probiotics modulates the production of bioactive compounds and the GMBA [90].
The utilization of prebiotics and probiotics has emerged as a strategy to potentially modulate brain functions and behavior in psychiatric diseases such as anxiety and depression, as well as in neurological conditions that may affect brain physiology, such as cerebral palsy [94, 95]. In the following paragraphs, we will explore the potential mechanisms through which prebiotics and probiotics may exert their effects on cerebral palsy.
4.2.1 Role of the gut-microbiota-brain axis in cerebral palsy
The investigation of the GMBA through the modification using prebiotics and probiotics in CP has not been extensively explored. However, a comparative study examined the role of GMBA in CP and epilepsy (CPE). The study evaluates the abundance of gut microbiota and the principal metabolites in children with CP, with and without epilepsy [96]. In children with non-epileptic cerebral palsy (NECP), a reduction in
Metabolomic analysis demonstrated a higher concentration of kynurenic acid, 2-oxindole, dopamine, hydroxyphenyalanie, and 3–4-dihydroxyphenylglycol (3–4-DHPG) in CPE patients. Besides, children with DRE had higher concentrations of indole compared to those with DSE. Notably, a negative correlation was found between
4.2.2 Influence of prebiotics and probiotics on the brain and CNS in children with CP
The investigation about prebiotics and probiotics in GMBA in CP is still limited, with only one study exploring the use of
Furthermore, the administration of
The levels of proinflammatory cytokine such as IL-6 and TNF-alfa were evaluated, and it was found that the administration of
Finally, the analysis of gut microbiome showed that the alfa and beta diversity were not significantly different between the groups. However, when the circus diagram is performed, the distribution ratio shows dominant species for each group. At the genus level, the CP+
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5. Conclusion
Gastrointestinal disorders are common in children with CP such as constipation, which can alter the gut microbiota through the gut-microbiota-brain axis. Therapy with probiotics, prebiotics, and synbiotics can alleviate clinical symptoms and can modulate the gut microbiota. Probiotics that have been studied in children with CP are
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Abbreviations
3–4-dihydroxyphenylglycol | |
5-hidroxytryptamine | |
adrenocorticotropic hormone | |
blood-brain barrier | |
compound dietary fiber | |
colon-forming unit | |
central nervous system | |
cerebral palsy | |
cerebral palsy and epilepsy | |
drug resistant epilepsy | |
drug-sensitive epilepsy | |
eating and Drinking Ability Classification System | |
enteric nervous system | |
fructooligosacharides | |
γ-aminobutyric acid | |
gastrointestinal | |
gastrointestinal tract | |
glutamate | |
gut-microbiota-brain axis | |
gross Motor Function Classification System | |
galactooligosacharides | |
hypothalamic-pituitary adrenal axis | |
International Scientific Association for Probiotics and Prebiotics | |
L-dihydroxyphenylalanine | |
non-epileptic cerebral palsy | |
norepinephrine | |
polyethylene glycol | |
short-chain fatty acids | |
subjective Global Nutritional Assessment | |
vagus nerve |
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