Probiotics and Prebiotics Effect on Brain Development

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Probiotic, prebiotic and brain development

Abstract: During the last years, a number of studies have demonstrated that there are extensive bi-directional interactions between the central nervous system (CNS) and the enteric nervous system (ENS), linking emotional and cognitive centres of the brain with peripheral intestinal functions. Thus, the use of bacteria as therapeutics has attracted much interest. The bacterial commensals of the gut can signal to the brain through a variety of mechanisms to influence processes such neurotransmission, neurogenesis, and behaviour. Data derived from both, in vitro experiments and in vivo clinical trials have supported some of these new health implications, while recent molecular advancement has provided strong indications to support and justify the role of the gut microbiota on gut-brain axis. However, it is still not clear whether or not gut manipulations through probiotics and prebiotics administration can correct or treat neurological problems. The understanding of the gut microbiota and its activities is essential for the generation of future personalized healthcare strategies. Our goal was to explore and summarize the potential beneficial effects of probiotics and prebiotics in the neurodevelopmental process and in the prevention and treatment of certain neurological human diseases, highlighting current and future perspectives in this topic.

Introduction

The microorganisms that inhabit within the human gastrointestinal tract (GI) have been implicated in the development and functioning of a number of basic physiological processes, such as digestion, immunity and the maintenance of homeostasis. The GI microbiota may also play a role in multiple diseases, ranging from inflammation to obesity[1,2]. Recently, many studies have shown that gut microbiota plays a very important role in the development and function of the central nervous system (CNS) through specific channels such as metabolic, neuroendocrine and immune pathways[3]. In particular, these researchers have found a bi-directional communication, between the brain and the gut microbiota denominated the microbiota-gut-brain axis[4-6].

Although the mechanisms by which the gut microbiota communicates with the brain are not yet clear, the link between both components is currently associative by immune signals and vagus nerve. On one hand, components associated to gut microbiota like lipopolysaccharide (LPS), peptidoglycan, flagellin or other structural components are recognized by pattern-recognition receptors (PRRs), such as Toll-like receptors (TLRs), NOD-like receptors (NLRs) or RIG-1-like receptors (RLRs), on epithelial and immune cells, producing cytokines, hormones and others molecular signals, which will act as neurotransmitters within the CNS [7]. On the other hand, since the gut is heavily innervated, some studies have found that the involvement of the vagus nerve is involved in the bi-directional communication of microbiota-gut-brain axis[8,9], while others studies have showed vagus-independent effects[10,11].

Either way, a supplementing nutrition therapy with specific probiotic commensals and prebiotic can alter the excitability of enteric nervous system (ENS) sensory neurons[12-14].

Prebiotics induced growth of probiotic members within Bifidobacterium and Lactobacillus genera, showing multiple beneficial effects on host immunity and physiology[15]. Moreover, strong effects of Bifidobacterium and Lactobacillus spp on the  spp in brain-gut axis have been reported [16].

The aim of this review is to summarize current knowledge on the influence of the establishment of the gut microbiota in critical neurodevelopmental windows, and discuss recent findings of the interactions between the gut microbiota and the host’s brain-gut axis communications. In addition, the latest advances in the effects of the administration of probiotics and prebiotics to influence in specific neurological disorders are shown. Finally, recommendations for future research on this topic are also discussed.

Establishment of intestinal microbiota during early neurodevelopmental windows

The composition of the gut microbiota during critical periods of CNS development is affected by a complex process of maturation and development throughout lifespan, establishing a beneficial cohabitation with the host[17]. Until recently, the idea that foetuses are sterile in uterus and that microbial colonization of the newborn starts during and after birth has been widely accepted[18].  However, recent studies suggest a great importance in mother-to-child transfer of commensal bacteria in the uterus for the immune system development of the baby later in life[19,20].

Althought, the origin of the bacteria colonising the placenta is unknown, two different modes of maternal-infant transmission have been proposed[21]:

a) horizontally transmitted symbionts are taken up from the environment a new by each host generation for infants born by caesarean section

b) vertically transmitted symbionts are most often transferred through the female germ line for vaginally delivered infants.

It is currently unclear if it is the actual birth mode or the medical indication for this intervention that most influences brain development and behaviour[22], but it has been seen that infants delivered by caesarean are more likely to suffer several diseases like asthma, obesity or allergies in adulthood[23]. On the other hand, a study carry out by Jasarevic et al. using a mouse model of early prenatal stress, found that changes in the vaginal microbiome are associated with effects on the offspring gut microbiota, showing how maternal stress altered proteins related to vaginal immunity and abundance of Lactobacillus and caused changes in offspring metabolic profiles involved in energy balance and disruptions of amino acid profiles in the developing brain[24]. Further, several studies have analyzed meconium of newborn babies and have shown, using different methods, the presence of bacterial populations including Enterococcus, Lactococcus, Escherichia, Leuconostoc and Streptococcus genus[25]. These studies provide more evidence that the intrauterine environment is not sterile.

Another relevant and strong environmental force that influences the infant gut microbial development as well as neurodevelopment is the type of feeding. Long-term breastfeeding, particularly full breastfeeding, is one of the most studied factors influencing neurodevelopment in recent years, with several studies reporting beneficial effects on child neuropsychological development [26]. On the other hand, it has been demonstrated that breastfeeding has an important role in the establishment of the infants’ gut microbiota, since it contains bioactive molecules that are increasingly recognized as drivers of microbiota development and overall gut health [27]. Human milk is the optimal feeding source since it provides all the nutrition factors that the infant needs for a healthy development. Of the various components in human milk, oligosaccharides constitute a significant fraction, being the third most abundant molecular species in terms of concentration after lactose and lipids. Up to 200 different structures have been defined for human milk oligosaccharides (HMOs) [24]. HMOs can act as prebiotics, stimulating the growth of specific bacterial groups such as Staphylococci [28] and Bifidobacteria [29].  Regarding commensals’ origin, bacterial from mother’s skin are transferred to the baby during breast-feeding, but there is also other hypothesis wherein bacteria from the maternal gut may reach the mammary glands via maternal dendritic cells and macrophages [30]. The presence of Bifidobacteria in breast milk is important for the colonization of the infant gut. It is well established that a gut microbiota dominated by Bifidobacteria typifies that of the healthy breast-fed infant [31]. Specifically, species such as B. Infantis has demonstrated to dominate infants’ gut microbiota and benefit the host by accelerating maturation of the immune response, limiting excessive inflammation, improving intestinal permeability, and increasing acetate production [32]. In mice, it has also demonstrated to produce antidepressant-like effects and normalize peripheral pro-inflammatory cytokine and tryptophan concentrations, both of which have been implicated in depression [33-35].

Comparisons between breast-fed and formula-fed infants show that breast-fed infants tend to contain a more uniform population of gut microbes dominated by Bifidobacteria and Lactobacillus [36], whereas formula-fed infants exhibit higher proportions of Bacteroides, Clostridium, Streptococcus, Enterobacteria, and Veillonella spp. [37]. Further studies are needed in order to clarify whether those differences in bacterial acquisition during early life lead to neurodevelopment differences in infants.

It is generally accepted that energy intakes of the breast-fed infants are lower than those of the formula-fed infants after the first few months of life due to differences in the macronutrient composition of human milk and formula, combined with quite heterogeneous levels of milk intake [38]. Previous studies have analyzed the effect of milk fat globule membrane (MFGM) supplementation in formula-fed infants showing an increase in cognitive scores, similar to those of breastfed infants, compared to control formula[39,40]. On the other hand, it has been seen that plasma amino acid levels, in particular the plasma tryptophan are higher in the breast-fed than in the formula-fed infants, which is involved in maintenance of sleep[41]. Although infant milk formulations have evolved greatly during the last years, it is necessary to continue studying the composition and the positive effects of breast milk versus formula to improve the outcomes in formula fed infants.

The transition from the exclusively milk feeding period to solid food diet is a turning point very important in the maturation of the gut microbiota. The first 3 years of life seem to be critical for the assembly of the gut commensals ecosystem. From birth, there is a rapid rate of colonization and expansion of gut bacteria that shift from a gut dominated by Proteobacteria to an adult-like one dominated by Firmicutes and Bacteroidetes, that achieves compositional diversity and stability by the third year of life[42]. This process coincides in time with the intense synaptogenesis that occurs in the brain during early life[42-44] and pruning in the cerebral cortex, including prefrontal areas that take place across the period of childhood and adolescence, finishing the neurodevelopmental process at early adolescence [39]. So, perturbations of gut microbiota development by environmental factors may also influence brain development.

For all the above, it should be noted that postnatal neurodevelopment and gut microbiota evolution co-occur, suggesting the intriguing possibility of a bi-directional loop between brain and commensal bacteria on each other’s maturation [45].

Gut Microbiota−Brain Axis

It is well know that the brain and the gut reciprocally affect each other by constant communication. The components of the brain–gut–microbiota axis includes the CNS, the endocrine-immune system, the hypothalamus–pituitary– adrenal (HPA) axis, the autonomic nervous system, the enteric nervous system, and the intestinal microbiota[46]. This bi-directional communication enables signalling from the brain to influence the motor, sensory, and secretory modalities of the GI tract, and conversely, signalling from the gut to affect brain function, most notably the hypothalamus and amygdala that have many functions devoted to stress[47-49].

In spite of the reciprocal impact of the gastrointestinal tract on brain function has been recognized since the middle of the nineteenth century[50], traditionally microorganisms have not been considered of particular importance to the development and function of the CNS or in brain diseases. The discovery of the gut microbiome has added a new component to the complex bi-directional signalling between mind, brain, gut, and its microbiome, suggesting a profound role of an intact gut microbiota in shaping brain neurochemistry and emotional behaviour[51].

Most of the data demonstrating the role of the microbiota within the gut-brain axis have been acquired from germ-free animal, probiotics, antibiotics, and infection studies. In humans, evidence of microbiota-gut-brain axis interactions comes from the association of dysbiosis with central nervous disorders (i.e. autism, anxiety-depressive behaviours) and functional gastrointestinal disorders. Probably, a better understanding of alterations like irritable bowel, might provide new targeted therapies[52]. For example, it has been seen that mice fed with prebiotics, diminished stressor-induced anxiety-like behaviour[53]. The potential therapeutic benefit of the gut microbiota was also demonstrated on a mouse model of autism spectrum disorder (ASD) [54] and a mouse model of Parkinson’s disease [55].

In spite of several studies have shown that changes in gut microbiota could affect the brain’s physiological, behavioural, and cognitive functions, the exact mechanism of gut microbiota-brain axis has not yet been fully understood and clarified [56]. Although many of the effects of the gut microbiota or potential probiotics on brain function are dependent on vagal activation[57], there are vagus independent mechanisms that play a important role in microbiota-brain interactions, as vagotomy fails to influence certain aspects of communication[58].

Gut microbiota has also demonstrated to play an important role in regulating blood-brain barrier (BBB) integrity. The BBB is an active interface between the circulation and the central nervous system (CNS) with a dual function: the barrier function restricts the transport from the blood to the brain of potentially toxic or harmful substances; the carrier function is responsible for the transport of nutrients to the brain and removal of metabolites [59]. In this sense, Braniste et al. (2014)[60] showed that exposure of germ-free adult mice to a pathogen-free gut microbiota normalized BBB permeability and up-regulated the expression of tight junction proteins. These results demonstrated a key role for the gut microbiome in regulating BBB permeability and suggest that maternal gut microbiome has strong influences on the offspring’s BBB integrity and propagated throughout life. All together with results discussed above about the placental microbiota composition, these findings open an intringuing research question about the mechanism of action by which mother’s gut bacteria may contribute to regulate BBB integrity and ultimately, brain function development.

Figure 1. The gut microbiota–brain axis. The central part of the figure shows the bidirectional influence between brain and gut microbiota. The left side of this figure shows modes of communication in the bidirectional crosstalk between gut microbiota and brain and the possible influences of prebiotics and probiotics on human diseases. The right side of the figure shows consequences of the gut dysbiosis/homeostasis. Intestinal dysbiosis can adversely influence gut physiology leading to inappropriate brain–gut axis signalling and associated consequences for CNS functions and disease states. Abbreviations: Non-Alcoholic Fatty Liver Disease (NAFLD), Inflammatory Bowel Disease (IBD), Attention deficit hyperactivity disorder (ADHD), Autism spectrum disorder (ASD).

Microbiota and probiotic agents have direct effects on the immune system, which is a further route of communication between gut microbes and the brain (Figure 1). The signalling molecules of the immune system, cytokines and chemokines, can access the brain from the periphery via the vagus nerve or directly via the circumventricular organs [61]. It has been seen that the effect of rifaximin, a non-systemic, broad-spectrum antibiotic, is associated with increased abundance of Lactobacillus in the ileum. When rifaximin is administrated in rats, previously stressed using chronic water avoidance or repeat restraint stressors, increases the expression of the tight junction protein occludin and decreases the expression of pro-inflammatory interleukin 17, interleukin 6, and tumor necrosis factor α mRNA in the distal ileum, which alleviate visceral hyperalgesia [62].

Tryptophan (Trp) is an α-amino acid precursor of the neurotransmitter serotonin and the hormone melatonin [63]. L-tryptophan’s metabolite, L-Kynurenine, and its further breakdown products carry out diverse biological functions, including dilating blood vessels during inflammation and regulating the immune response[64]. In addition, there is evidence that suggests that a probiotic bacterium, Bifidobacterium infantis, affects tryptophan metabolism increasing concentrations of kynurenine in plasma[34]. On the other hand, it has been seen that a depletion of the 5-hydroxytrypamine (5-HT, or serotonin) precursor-Tryptophan is associated with elevation of Indoleamine-pyrrole 2,3-dioxygenase (IDO), an immunomodulatory enzyme, during immune activation and transiently during primary gut colonization [65-67]. Besides, it has been discovered that different gut microbial species affects host physiology, producing diverses neuromolecules involved in mood regulation such as Lactobacillus and Bifidobacterium spp. that generate gamma-aminobutyric acid (GABA), Candida, Streptococcus, Escherichia and Enterococcus spp. synthesise 5-HT, and Bacillus spp. that produces dopamine[68].

Moreover, gut microbiota can recognise and synthesise metabolites like bile acids, vitamins, choline and short chain fatty acids (SCFAs) that are essential for host health, some of them playing an important role in brain development such as SCFAs. Butyrate, acetate and propionate (SCFAs) are the end products of anaerobic fermentation of dietary fibre and starch in the large intestine and evidences indicate their influence in the microbiota-gut-brain axis, entering in the circulation via portal vein [69]. It has been demonstrated that butyrate can cross the BBB since oral butyrate induces a dose-dependent increase in neuronal and glial nuclear histone H3 acetylation in mice, due to its potential to inhibit histone deacetylation[70]. Propionate and others SCFAs have been ascribed as ligands to G-protein coupled receptors (GPRs) 41 and 43, which may also be involved in the regulation of adipogenesis and adipokine release mediated via GPRs[71].

In conclusion, although in recent years there has been a progress in the critical role of microbial cues that affect brain development and especially impacts those neuronal circuitries that underlie social behaviour in mammals; more research in the field is needed in order to unravel the functioning of the intricate microbiota-gut-brain axis network.

Probiotics

The Food and Agriculture Organization of the United Nations and the World Health Organization (FAO/WHO) proposed in 2001 the definition of probiotics like “live micro-organisms which, when administered in adequate amounts, confer a health benefit on the host”[72], reaffirmed in 2014[73]. However, few standard safety guidelines currently exist about their oral administration, highlighting that recently a Clinical Guide to Probiotic Products has been published in Canada and the USA which lists only products tested in humans[74]. Therefore, the application of some probiotics (Lactobacillus, Bifidobacterium) and prebiotics (inulin, oligofructose) do not require approval from the Food and Drug Administration (FDA) and are present in our daily dietary intake[75]. New advances has been reported about new possible probiotics, such as Faecalibacterium prausnitzii, Eubacterium rectale or Roseburia spp., which produce butyrate, considered beneficial to health [76], but further studies should be carried out to use them in humans.

Probiotics have been suggested to play a role in a variety of human disease, such as improvement in non-alcoholic fatty liver disease (NAFLD), prevention of allergic diseases and asthma or protection against atopic disease in the infant during pregnancy and breast-feeding[77-79]. In addition, probiotics also reduce the duration of antibiotic therapy and improve the immune-related disease, such as inflammatory bowel diseases (IBDs), celiac disease, metabolic syndrome, and diabetes [80,81].

In recent years, the search for probiotics that can affect cognitive functions has therefore increased (Table 1). Such probiotics are called psychobiotics and defined as live organisms that when ingested in adequate amounts produce beneficial health effects to patients suffering from psychiatric illness [82]. To study the ability of probiotics in preventing depression in humans, Messaoudi et al [83,84], administered a multispecies probiotic containing Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 (PF) for 30 days decreasing the global scores of hospital anxiety and depression scale (HADs), and the global severity index of the Hopkins symptoms checklist (HSCL-90), due to the decrease of the sub-scores of somatization, depression and anger- hostility spheres. Conversely, a recent study carried out by Romijn et al [85], administered a multispecies probiotic containing Lactobacillus helveticus and Bifidobacterium longum, in 79 participants that were not taking psychotropic medications at that moment and with at least moderate scores on self-report mood measures. They found no evidence that the probiotic formulation was effective in treating low mood, or in moderating the levels of inflammatory and other biomarkers. The lack of observed effect on mood symptoms may be due to the severity, chronicity or treatment resistance of the individuals participating in the interventional study.

Other probiotics are known to modulate the production of serotonin in the brain. Low serotonin levels have been linked with depression. Bifidobacterium infantis has been suggested like potential antidepressant probiotics, because its oral ingestion increased levels of the serotonin precursor, tryptophan, in the plasma of rats [34].

Another pathway by which probiotics affect mood is their ability to modulate pain in the gut. A recent study reported that the effect of Lactobacillus reuteri DSM 17938 in the treatment of children with functional abdominal pain (FAP) and irritable bowel syndrome (IBS), is associated with a possible reduction of the intensity of pain[86]. In this sense, other study also reported that a probiotic mixture of Bifidobacterium infantis M-63, breve M-16V, and longum BB536 was associated to improvement in children with inflammatory bowel disease (IBS) but not in children with functional dyspepsia (FD)[87].

A disturbance in the gut microbiota, which is usually induced by a bacterial infection or chronic antibiotic exposure, has been described as a potential contributor to ASD[88]. Only few studies have been carried out to find the influence of probiotics in subjects with ASD. One study reported that the administration of Lactobacillus acidophilus in 22 ASD subjects decreased D-arabinitol concentration and ratio of D-arabinitol to L-arabinitol in urine, which is a metabolite of most pathogenic Candida species and its extraction in urine is elevated in autistic patients [89]. Another study reported that a combination of L. acidophilus, L.casei., L.delbrueckii, Bifidobacterium longum and B.bifidum, formulated with imunomodulator Del-Immune V ( Lactobacillus rhamnosus V lysate) decreased severity of ASD symptoms and improved GI symptoms in 33 children [90]. Moreover, a recent study with “Children Dophilus” (a combination of 3 species of Lactobacillus, 2 species of Bifidobacterium and 1 strain of Streptococcus) in 10 ASD children, showed GI dysfunction was higher in ASD children and siblings compared with controls at baseline and a very strong association of the amount of Desulfovibrio spp. with the severity of autism. After the intervention the Bacteroidetes/Firmicutes ratio, Desulfovibrio spp. and the amount of Bifidobacterium spp. were normalized in faeces of autistic children[91]. However, the effects of treatments with probiotics on children with ASD need to be evaluated through rigorous controlled trial. Before long a study will be carried out by Santochi et al. This study will administer in a group of 100 preschoolers with ASD, a multispecies probiotic (one strain of Streptococcus thermophilus DSM 24731, three strains of Bifidobacterium (B.breve DSM 24732, B. longum DSM 24736, B. infantis DSM 24737), and four strains of Lactobacillus (L. acidophilus DSM 24735, L. plantarum DSM 24730, L. paracasei DSM 24733, L. delbrueckii subsp. bulgaricus DSM 24734), which will try to provide new insights clinical and neurophysiological patterns in response to probiotic mixture in ASD patients[92].

Another pathologies where probiotics are being tested are schizophrenia and bipolar disorder. One of the first trials of probiotic compounds in schizophrenia used a combined probiotic of Lactobacillus rhammosus strain GG and Bifidobacterium animals subsp. Lactis strain Bb12, whose results showed no significant difference in psychiatric symptom severity between probiotic and placebo supplementation[93]. However, other studies have found that the probiotic supplementation significantly alter the levels of several serum proteins including von Willebrand factor, brain derived neurotrophic factor and lowered the level of antibodies to the fungus Candida albicans [94,95].

Despite these few evidences supporting the use of probiotics in human with certain neurological disorders, future studies on this topic are needed to define probiotics risk in the therapeutic interventions, as well as to find potential probiotics for effective modulation of these disorders. Finally, note that probiotic health effects are usually strain specific so it is important to characterize probiotics to the strain level and with current nomenclature and subsequently deposit them in an international culture collection[96]. Therefore, the effects of one probiotic strain should not be generalized to others without confirmation in separate studies.

Prebiotics

Although, in 1921, Rettger & Cheplin[97] initiated research about how the consumption of carbohydrates stimulated the enrichment with Lactobacilli, the prebiotic concept was first defined in 1995 as a “non-digestible food ingredient that beneficially affects the host by selectively stimulating the growth and/or activity of one or a limited number of bacteria already resident in the colon”[98]. However, numerous definitions have been made since then[99-101] and the current International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus panel proposes the definition of prebiotic like: a substrate that is selectively utilized by host microorganisms conferring a health benefit[102]. Thus, antibiotics, minerals, vitamins and bacteriophages are not considered prebiotics because affect composition of the microbiota through mechanisms not involving selective utilization by host microorganisms.

Among the group of substances recognized for their ability to influence gastrointestinal health are certain soluble fermentable fibres, some non-digestible oligosaccharides and the HMOs (Table 2). It has been described how fiber influences satiety. One mechanism is by increasing chewing time of fiber-rich foods, which promotes saliva and gastric acid production and increase gastric distention, triggering afferent vagal signals of fullness contributing to this end. Another mechanism is by slowing gastric emptying and decreasing the rate of glucose absorption in the small intestine. Consequently, the insulin response may also be attenuated; this is sometimes correlated with satiation and satiety.[103]. Various hormones (i.e., ghrelin, polypeptide YY, glucagon-like peptide) have been related with satiety, which are sent  to the brain, regulating food intake and overall energy balance [104]. Recently in a randomized, double-blind, placebo-controlled trial with 42 children (ages 7–12 with overweight and obesity), Hume et al. investigated the effect of oligofructose-enriched inulin/d administration versus placebo (maltodextrin); prebiotic supplementation improved subjective appetite ratings, reducing energy intake in older but not in younger children[105].

Non-digestible oligosaccharides (NDOs) are low molecular weight carbohydrates in nature that are intermediates between simple sugars and polysaccharides. Enrichment of diet with NDOs has given the opportunity of improving the gut microecology, including bacterial populations, biochemical profiles and physiological effects, so their prebiotics uses have rapidly increased in the last few years[106]. The effects of non-digestible oligosaccharides in the treatment of neurodevelopmental disorders are unclear. Food-based therapies probably could be beneficial for children with a genetic pre-disposition to develop ASD or attention deficit hyperactivity disorder (ADHD)[107]. NDOs are suggested to selectively stimulate growth and/or activity of bifidobacteria and lactic acid bacteria in the colon, which may influence host neural development[108,109].

Human milk oligosaccharides have been recognized for their ability to influence gastrointestinal health and increase the proportion of Bifidobacteriaceae and Bacteroidaceae[110,111]. Although researchers have tried to assign a role for those prebiotics in neurodevelopment, many studies indicate that there is no influence. Van den berg et al., have found no evidences that the use of cGOS/lcFOS/pAOS in preterm infants at 24 months improves neurodevelopmental outcomes[112]. LeCouffe et al., studied the effect of enteral supplementation of a prebiotic mixture (neutral and acidic oligosaccharides) in the neonatal period, but they found that this supplementation had no effect on neurodevelopment [113]. However, they agreed that lower Bifidobacteria counts and serious neonatal infections during the neonatal period were associated with lower neurodevelopmental outcomes, indicating the relevance of microbiome and immune responses in neurodevelopmental processes.

Further studies should be carried out to determine whether prebiotics can be considered for the prevention of neurodevelopmental disorders in infants and to understand the mechanism of action by stimulating certain bacterial taxa or bacterial activities within the gut microbiota. Efficacy, safety and dosing schedules should be established for each prebiotic product in long-term follow-up studies.

Synbiotics

The term synbiotic is used when a product contains both probiotics and prebiotics[114]. This term should be reserved for products in which the prebiotic compound selectively favours the probiotic strain. However, one might argue that synergism is attained in vivo by ingestion of lactobacilli as probiotic on the one hand and promotion of indigenous bifidobacteria by a prebiotic compound on the other hand.

Several studies have shown the positive synergistic effects of synbiotics on obesity, diabetes, non-alcoholic fatty liver disease, necrotizing enterocolitis in very low birth weight infants, and treatment of hepatic encephalopathy[115-119]. Despite of these findings, few studies have been carried out to date in relation to the use of synbiotics in neurodevelopmental disorders (Table 2). Malaguarnera et al. found that Bifidobacterium longum plus FOS in the treatment of minimal hepatic encephalopathy (MHE) appears to improve cognitive function[120]. On the other hand, Firmansyah et al. administered milk containing synbiotics (BL999, LPR, and prebiotics) and LCPUFA to 393 healthy toddlers at 12 month-old for 12 months. However, they found that the change in cognitive and adaptive behaviour scores between 12 and 16 months was higher but not significantly different in the synbiotics group compared with the control group[121].

Future work is needed to determine how synbiotics might contribute to alleviate neurological diseases. Work in this area should also be directed to exploring new potential synbiotics and their effects during sensitive time-windows for susceptibility in infant neurodevelopmental disorders.

Future perspectives

During last years, numerous in vivo and in vitro studies have been carried out in order to know the influence of probiotics and prebiotics in host physiology. From these studies it follows that the gut microbiota can regulate inflammation, adiposity, satiety, energy expenditure and glucose metabolism[122]. Although in vivo experiments have advanced in animals, there are very few good, double-blind, placebo-controlled clinical trials for assessing the effects of probiotics and prebiotics on modulating human metabolism[123,124].

Most efforts have focused on provide insight into the mechanisms by which certain probiotics regulate the colonization and protect against pathogens through activation of the mucosal immune system and competition for limited nutrients[125,126], however, this highlights the urgent need for a deeper understanding of probiotics dynamics in the gut. Alternative approaches against lifestyle diseases such as Alzheimer’s disease, autism, attention-deficit-hyperactivity disease, among others, could be the manipulation of the gut ecosystem by recombinant probiotics expressing therapeutic biomolecules, faecal microbiota transplantation and phage therapy. Paton et al. expressed glycosyltransferase genes from Neisseria meningitidis or Campylobacter jejuni in a harmless Escherichia coli strain (CWG308), to create a recombinant probiotic for treatment and prevention of diarrheal disease caused by enterotoxigenic Escherichia coli strains[127]. The same group similarly developed a recombinant probiotic for treatment and prevention of cholera[128]. On the other hand, a recent study has shown that Microbiota Transfer Therapy (MTT) improves ASD symptoms in children, which persisted for at least 8 weeks after treatment ended[129]. Finally, for phage therapy, with the increase in antibiotic­resistant bacteria, the interest in using phage or phage­derived proteins to treat bacterial infections has intensified. The only approved phage therapy clinical trial in the human gut was carried out in 120 patients with diarrhoea caused by Escherichia coli, which were infected by a coliphage mix. The treatment failed to solve diarrhoea, although no adverse effects of phages were noted [130]. Even so, an alternative for the future could be phage cocktails customized. These phages would target directly to pre-identified bacterial pathogens, but the main inconvenient would be the high inter­individual variation of the gut microbiome and the legislative approval. Further clinical trials are needed to probe the effectiveness of this treatment.[131,132].

Several evidences have suggested the role of prebiotics as novel strategies to prevent progression of several diseases. Verma et al. found in a comparative study where they administrated prebiotics inulin or lactulose during the initiation phase of chemically induced colon carcinogenesis in rats with 1,2-dimethylhydrazine dihydrochloride (DMH), that prebiotic inulin may possess better prophylactic potential to reduced biomarkers of colon carcinogenesis in the initiation phase[133]. Future prebiotic studies should strive to confirm causality between an observed health benefit and microbiota-mediated mechanisms. To this end, well-controlled, placebo, blinded in vivo studies that exploit the newest multi-omic technologies are necessary. In the case of prebiotic for humans, a full assessment of gut microbiota using next-generation molecular procedures to exploit selective substrate use, like metabolomics applied to faeces, could identify reliable biomarkers of beneficial effects[134].

In summary, the understanding of individual probiotics and prebiotics activities is essential to evaluate specific doses and to ascertain potential adverse reactions and beneficial outcomes for humans’ physiology. Therefore, further studies are still needed to confirm and clarify the possible mechanisms involved and whether probiotics and prebiotics may constitute new therapeutic strategies to prevent human diseases.

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