Intestinal microflora is increasingly considered as a functional human organ and its structure and effects are being clarified as a result of the Human Microbiome Project [1▪▪]. This project aims to produce a reference set of microbial genome sequences and to obtain a preliminary characterization of the human microbiome, to explore the relationship between diseases and changes in the human microbiome, and to develop new technologies and tools for computational analysis. The knowledge of intestinal microbiota composition, how it interacts with the host, and how it causes or contributes to human diseases have been enhanced by culture-independent techniques that allow its phylogenetic investigation and quantification [2▪].
STRUCTURE OF INTESTINAL MICROFLORA AND ITS DETERMINANTS
The entire human population can be classified in three enterotypes on the basis of intestinal microflora. Enterotype defines the quantitatively dominating taxa. Enterotype 1 is dominated by Bacteroides, enterotype 2 by Prevotella and enterotype 3 by Ruminococcus [3▪,4▪▪], and each of the three enterotypes differently affects the host metabolic functions [4▪▪,5]. The enterotypes are associated with protein and animal fat (Bacteroides) or respectively carbohydrates (Prevotella) rich diet and may change as early as within 24 h of initiating a high-fat/low-fiber or low-fat/high-fiber diet [6▪]. However the core structure of enterotypes does not change and is a lifestyle hallmark of individuals. The relationship between diet and the intestinal microflora structure emerged from a comparative evaluation of bacteria in European children, who ate a typical western diet, high in animal protein and fat, and children in Burkina Faso, who were on high-carbohydrate/low animal protein diet . The ‘European microbiome’ was dominated by Bacteroides enterotype, whereas the ‘African microbiome’ was dominated by the Prevotella enterotype. The concept that nutrition is a determinant of microbiota composition in children was confirmed in another study [8▪].
Features of a healthy microflora are its richness and evenness. Richness describes the number of bacterial species in a specific ecosystem not taking into account their relative abundance. Evenness indicates the relative abundance of each species in a specific ecosystem. These two definitions are used to describe the microbial diversity in the gastrointestinal tract [9▪].
However, the initial colonization of the intestine is also important for future microflora and functions. At birth, the intestine is sterile, and bacterial colonization begins with amniotic membrane rupture. Bacteria from the mother's intestinal and vaginal sites, and from the outer environment, colonize the neonatal gut within a few hours from birth, and appear in feces shortly thereafter. Vaginally born infants have a greater abundance of Bacteroides and Bifidobacteria compared with infants born by cesarean section  and, interestingly, the latter are at higher risk of immunological diseases [11▪]. Other important factors that contribute to build the microbiome composition are antibiotics, hygiene status and functional nutrients. The latter are increasingly used in infancy.
The time of bacterial colonization is also important as shown in animal models [12▪]. In preterm neonates, bacterial colonization is delayed, and the number of colonizing species is limited. An increasing diversity of gut microflora was observed in the first 8 weeks of life in preterm infants, and most infants had staphylococci in their stools as the main species, whereas few infants were colonized with Bifidobacterium spp. [13▪▪]. The study also showed a positive relationship between diversity of intestinal microflora and nutrient tolerance and weight gain, supporting a functional relationship between humans and their intestinal microbes.
Nutrition plays a major role at birth and after birth. Breastmilk is important, as it not only provides a range of substrates for bacterial growth [14▪] but it is also a natural bacterial inoculum that affects neonatal colonization [15▪]. Breastfed infants had 2 times the numbers of Bifidobacteria than formula-fed infants, and in the latter, Atopobium and Bacteroides were found in significant counts. Moreover, in formula-fed infants, intestinal microbiota was less complex (or ‘diverse’) than in breastfed infants [16▪]. Breastfeeding has been associated with a number of beneficial effects in the short and long term and it is likely that microflora contributes many of these effects. The profile of intestinal bifidobacterial population in infants shows the simultaneous co-occurrence of a number of bifidobacterial species [17▪]. Later in life, weaning and the introduction of solid foods are associated with the transition toward an adult-like microbiota [18▪▪] and nutrients again play a key role in determining the final microbiota composition [6▪,7,9▪].
The adult microbiota is relatively stable [19▪▪]. The temporal stability reflects the resilience of microbiome in adults and perturbations, such as antibiotic therapies, have only transient effects on the dominant microbiota. Overall, the adult microbiome is more complex than its infant equivalent, although being stable over time and similar between individuals [20▪▪]. In contrast, infant gut microbiota possesses a relatively simple structure but is rather unstable over time. The microflora in children is intrinsically plastic, affected by few variables and less exposed to factors that may change its composition compared with adults, and this provides an ideal setting to understand the functional roles of gut microbiome.
FUNCTIONS OF GUT MICROBIOTA
Human microbiota exerts important immune, metabolic, trophic, and protective functions that are currently interpreted with a model of symbiosis between the host and intestinal microbes. Many of the effects by intestinal microbiota are realized with mechanisms that derive from coevolution of bacteria and in the host (Table 1). The commensal microflora inhibits colonization by pathogenic bacteria through a variety of local mechanisms. It also interacts with the immune system at local and systemic level. The immune system in turn protects the host from potential pathogenicity of microbial communities that provide metabolic benefits [21▪▪]. This results in a balanced homeostasis whose histological counterpart is the ‘physiological inflammation’, defined by the presence of a rich immune cell population within the intestine. A key effect of the innate immunity is to confine bacteria into the intestine preventing them from reaching the systemic immune compartment [22▪,23▪▪]. Vaishnava et al.[24▪] demonstrated that RegIIIγ, a secreted antibacterial lectin, is a fundamental immune mechanism that promotes host–bacterial mutualism by regulating the spatial relationships between microbiota and host. Flora abundant in Bacteroides with consequent intestinal inflammation was observed in a murine model deficient in the inflammasome component NLRP6, supporting the concept of the immune-driven dysbiosis [25▪].
While the host immune system controls the development of intestinal microflora, also the opposite is true as the microbiota shapes the immune system [26▪]. Round et al.[27▪▪] suggest that the immunologic distinction between pathogens and the commensal microbiota is mediated not solely by direct host mechanisms but also through specialized molecules evolved by symbiotic bacteria that enable commensal colonization. The modulation of mucosal T cells by intestinal bacteria certainly affects systemic immunity as shown by the results obtained with different animal models of microbiota-associated autoimmune diseases [28▪]. Therefore, the intestinal microbiota plays a major role in driving the immune response and vice versa. Microflora is under immune control and this provides the basis of a finely tuned symbiotic relationship.
A similar mutually beneficial relationship exists in terms of energy and nutrition supply, between gut microbiota and the host (Table 1). Bacteria provide the host with energy from indigestible dietary substrates in the form of short-chain fatty acids, whereas the host offers a nutritionally adequate environment to its commensals. A recent clinical trial showed clear associations between gut microbes and nutrient absorption indicating a possible role of microbiota in the regulation of nutrient digestion and energy harvest [29▪▪].
Finally, a novel, fascinating function by microflora is related to neuronal development [30▪]. Microbiota is an active player in the brain gut axis and affects levels of neurotrophins in mice. This translates in behavior control, brain differentiation, and neuronal survival [31▪▪]. However, a recent study showed that the microbial colonization triggers mechanisms that affect neuronal circuits involved in motor control and anxiety behavior [32▪▪].
DYSBIOSIS IN CHILDREN'S DISEASES
In order to understand the functions and dysfunctions on intestinal microflora, an obvious approach is to investigate the composition of microflora in specific diseases. A healthy state of microbiota structure, in which microorganisms with potential health benefits predominate in number over those potentially harmful, is defined ‘normobiosis’ (or eubiosis). On the contrary, ‘dysbiosis’ is a condition in which one or more potentially harmful bacterial species are dominant . In many diseases, the diversity of microflora is reduced. However, there are also specific aberrations of microflora in selected childhood diseases. The specific microflora aberrations that have been detected in specific diseases are often defined as ‘signature’, indicating that microbial aberrations may be a hallmark of that disease (Table 2). An example is provided by celiac disease in which children show a peculiar microbial pattern with abundant Firmicutes [34▪▪]. However, microbial signatures have been detected in several chronic diseases such as inflammatory bowel diseases (IBD). Many studies showed that intestinal microbiome profoundly differs between patients with IBD and healthy individuals, and intestinal dysbiosis may contribute to the risk of IBD or its relapses. Schwiertz et al. showed that the Firmicutes phylum, and particularly the species Faecalibacterium prausnitzii, is less represented in IBD patients than in controls. This effect may not be confined to IBD, as F. prausnitzii inversely correlated with the severity of disease in acute appendicitis [36▪]. Interestingly, F. prausnitzii has an anti-inflammatory effect and its presence increases with fiber consumption in adults [37▪]. All together, these data suggest that F. prausnitzii protects against intestinal inflammation.
In a prospective nationwide cohort study investigating the link between antibiotics and IBD in children, the relative risk of IBD was increased for antibiotic users compared with nonusers [38▪▪]. The association was stronger if only Crohn's disease was considered and for antibiotics given during the early life. In a study in adolescents with IBD, a layered distribution of selected microbiota components was described with a decrease in Bifidobacteria, an increase in Streptococci in Crohn's disease and in Lactobacilli in ulcerative colitis. An increase in mucin degradation by bacteria was also described in ulcerative colitis patients [39▪]. This data support the role of microbiome perturbations in IBD.
Irritable bowel syndrome (IBS), a symptom-based diagnosis defined by Rome III criteria, is associated with dysbiosis and the manipulation of intestinal microbial communities (i.e., probiotics) may effectively alleviate fastidious symptoms. Interestingly, a close relationship between a specific bacterial profile with the severity of symptoms was recently shown in pediatric IBS [40▪▪].
Necrotizing enterocolitis (NEC) is a severe and potentially fatal disease that affects preterm neonates. A decrease in microbiota diversity was observed for all preterm infants, and NEC children showed a further reduction in diversity, with a predominance of Gammaproteobacteria and a reduction of other bacterial species . However, others found an opposite pattern, and in a prospective study, bacterial diversity expressed as band richness was higher in NEC than in controls [42▪▪]. In a different study, microbiota diversity did not differ between infants with NEC and controls in the period before the disease diagnosis, but the authors found that there is a more heterogeneous microbial structure in infants developing NEC [43▪▪]. This observation supports the concept about the identification of a pattern of microbiota at high risk of NEC.
Atopy is also a condition in which microflora has been implicated. Previous studies, summarized in a recent review, showed that atopic infants have lower counts of Lactobacilli, Bifidobacteria, and Bacteroides species, and an increase in Clostridium difficile colonization, compared with nonatopic infants [44▪]. Furthermore, prospective studies on microbiota in early life showed that atopy was associated with a reduced ratio of Bifidobacteria to Clostridia and with the presence of C. difficile[45▪]. Two recent works showed that reduced microbiome diversity in early life increases the risk of atopic diseases [46▪], thereby suggesting a link between early microbial colonization and subsequent atopy.
Microflora structure in obesity is a major focus of research, and there is increasing evidence that microflora composition influences the host energy balance and that western diet profoundly changes microbiota in humans [7,47▪]. A high-carbohydrate diet affects the composition of intestinal microflora, which may play an important role in controlling energy metabolism and favor a state of low inflammation [48▪]. Microbial composition differs between obese and lean patients, and this may be related to the extraction and use of energy from food in the intestinal lumen. Changes in gut microbiome are reflected by an abnormal ratio between Firmicutes and Bacteroidetes [49▪]. Interestingly, breastmilk differs from mothers with normal or increased BMI [50▪], and this may be linked with a different microbial imprinting that may become evident in children up to 10 years of age [51▪].
MICROFLORA AS A TARGET FOR THERAPY
The data summarized above indicate that microflora plays a role in triggering – or contributing to – a number of diseases. This raises the hypothesis that modifications of microflora through antibiotics or – conversely – with probiotics or also with functional nutrients (i.e., prebiotics) may have therapeutic effects. Rifaximin was successful in reducing symptoms in a population of adults with IBS without constipation [52▪▪]. Consistent evidence of probiotic efficacy was obtained in children with IBS characterized by abdominal pain [53▪] and constipation . Interestingly, the administration of Lactobacillus casei subsp. Rhamnosus to children at risk of atopy induced a global shift in gut microbial community composition. This resulted in modifications of the relative abundance of a large number of taxa previously associated with either an increased or decreased risk for the development of allergy and atopy [55▪▪]. Overall, the results that are being obtained with probiotics in IBS and other diseases further support the concept that microflora play a role in selected diseases, probably with an age-related pattern [56▪].
However, probiotics should not be regarded as a therapy to be considered in adjunct to the traditional treatment or to be used in minor disorders. They may play an important role in very severe diseases. A general dysbiosis was detected in children with cystic fibrosis (CF) compared with their siblings [57▪]. This may explain the beneficial effects observed on intestinal inflammation and also on respiratory function in children with CF receiving probiotics . More recently, Scanlan et al.[59▪▪] showed a reduced richness, evenness and diversity of gut microbiota in CF children in a very small sample-size study. Therefore, dysbiosis may play a major role in CF and the modulation of gut microflora with probiotics may have a positive effect on intestinal and nonintestinal inflammation.
Finally, a very delicate field is the use of probiotics in NEC. Administration of probiotics to preterm infants resulted in the reduction of the incidence of NEC and – even more interestingly – of mortality for all causes in preterm infants [60▪]. The beneficial effects were confirmed in an updated meta-analysis . Such a dramatic outcome and the strength of supporting data, led to the indication to routine administration of probiotics to preterm infants with the aim of preventing the severe complications associated with this condition [62▪]. However, meta-analysis and recommendations are not widely shared. There are probiotic products on the market that cannot be recommended because they have not been studied sufficiently and may be harmful. Because NEC also appears to be a highly heterogeneous and etiologically multifactorial disease, targeting the neonates at highest risk with the lowest potential for harm, rather than routinely prophylaxing all infants appears prudent. Therefore, further data are expected prior to obtaining a conclusive indication in this delicate area [63▪,64▪].
Intestinal microflora is considered a fully functional human organ and its structure is the result of early life events such as feeding, illnesses, antibiotic therapies, and environmental exposure. A healthy microbiota, or eubiosis, protects from diseases, whereas an abnormal microflora structure, or dysbiosis, is linked with the risk of diseases.
A reduced diversity of gut microflora is a frequent hallmark of intestinal inflammation. Consistent abnormalities in the microbial structure have been detected in populations of children with specific diseases and have been defined as ‘microbiological signatures’ of those diseases. The word signature provides a double concept: the specific role of selected bacterial species in causing – or contributing to – specific diseases and the opportunity to recognize the disease (or monitoring its course) by analyzing microflora composition. However, the changes observed in microbial populations raise the option of targeting microflora for therapy. This is being done with increasing success in selected diseases using various strategies, including administration of probiotics.
Conflicts of interest
The authors declare that there are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 94–95).
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Using pathogen-free and germ-free mice, the authors demonstrated that the intestinal microbiota influences brain chemistry and behavior independently of the autonomic nervous system, gastrointestinal-specific neurotransmitters, or inflammation.
32▪▪. Heijtz RD, Wang S, Anuar F, et al. Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci USA 2011; 108:3047–3052.
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34▪▪. Sellitto M, Bai G, Serena G, et al. Proof of concept of microbiome-metabolome analysis and delayed gluten exposure on celiac disease autoimmunity in genetically at-risk infants. PloS One 2012; 7:e33387.
Dysbiosis in celiac disease was well described in this study highlighting the differences between the developing microbiota of infants with genetic predisposition for celiac disease and the microbiota from infants with a nonselected genetic background, with an overall lack of bacteria of the phylum Bacteriodetes along with a high abundance of Firmicutes and microbiota that do not resemble that of adults even at 2 years of age.
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In this study, the presence of Fusobacteria in mucosal lesions of suppurative appendicitis positively correlated with the severity of the appendicitis, whereas the main fecal microbiota represented by Bacteroides, Eubacterium rectale, F. prausnitzii groups and Akkermansia muciniphila were inversely related to the severity of the disease.
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38▪▪. Hviid A, Svanström H, Frisch M. Antibiotic use and inflammatory bowel diseases in childhood. Gut 2011; 60:49–54.
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This study examined the horizontal structure of the fecal microbiota in the colon in adolescents with Crohn disease or ulcerative colitis.
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Using 16S metagenomics by PhyloChip DNA hybridization and deep 454 pyrosequencing, a specific microbiome signature was identified in children with IBS. These findings indicate the important association between gastrointestinal microbes and IBS in children and the specificity of this association is reflected by the word ‘signature’ in the title.
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This is a very large study that analyzes the fecal flora of premature neonates during the first month of life. By culturing the bacteria in fecal samples, premature neonates who develop NEC are colonized predominately by G+ bacteria, in contrast to control neonates, who were colonized by a significant diversity of microflora.
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Recent advances in understanding the role of gut microbiota and allergy, asthma, and obesity are reviewed.
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The authors found an association between low intestinal microbial diversity during the first month of life and subsequent atopic eczema.
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The present article reports differences in adiponectin concentrations in the maternal colostrum and in fecal bifidobacterial counts at age 3 months between children of normal weight and children overweight at age 10 years, both pointing to the importance of the first few months of life as a window of opportunity to influence subsequent weight development.
52▪▪. Pimentel M, Lembo A, Chey WD, et al. Rifaximin therapy for patients with irritable bowel syndrome without constipation. N Engl J Med 2011; 364:22–32.
In this double-blind, placebo-controlled trial, treatment with rifaximin in patients who had IBS without constipation provided significant relief of IBS symptoms, bloating, abdominal pain, and loose or watery stools.
53▪. Horvath A, Dziechciarz P, Szajewska H. Meta-analysis: Lactobacillus rhamnosus GG for abdominal pain-related functional gastrointestinal disorders in childhood. Aliment Pharmacol Ther 2011; 33:1302–1310.
The meta-analysis describes the use of Lactobacillus rhamnosus GG increasing treatment success in children with abdominal pain-related functional gastrointestinal disorders, particularly among children with IBS.
54. Coccorullo P, Strisciuglio C, Martinelli M, et al. Lactobacillus reuteri (DSM 17938) in infants with functional chronic constipation: a double-blind, randomized, placebo-controlled study. J Pediatr 2010; 157:598–602.
55▪▪. Cox MJ, Huang YJ, Fujimura KE, et al. Lactobacillus casei abundance is associated with profound shifts in the infant gut microbiome. PloS One 2010; 5:e8745.
Lactobacillus casei subsp. Rhamnosus underwent profound shifts in the global distribution of bacterial intestinal communities. This suggests that administration of a single species of probiotic may have a general profound effect on the global structure of microbiota.
56▪. Simrén M, Barbara G, Flint HJ, et al.
Intestinal microbiota in functional bowel disorders: a Rome foundation report. Gut 2012. [Epub ahead of print]
In this article, the authors provide a critical review of the hypotheses regarding the pathogenetic involvement of microbiota in functional gastrointestinal disorders and evaluate the results of microbiota-directed interventions.
57▪. Duytschaever G, Huys G, Bekaert M, et al. Cross-sectional and longitudinal comparisons of the predominant fecal microbiota compositions of a group of pediatric patients with cystic fibrosis and their healthy siblings. Appl Environ Microbiol 2011; 77:8015–8024.
Using conventional culturing and population fingerprinting by DGGE of 16S rRNA amplicons, this study compared the predominant fecal microbiota of 21 patients with CF and 24 healthy siblings in a cross-sectional study.
58. Bruzzese E, Raia V, Gaudiello G, et al. Intestinal inflammation is a frequent feature of cystic fibrosis and is reduced by probiotic administration. Aliment Pharmacol Ther 2004; 20:813–819.
59▪▪. Scanlan PD, Buckling A, Kong W, et al.
Gut dysbiosis in cystic fibrosis. J Cyst Fibros 2012; 11:454–455.
This pilot study showed that CF patients exhibited lower taxonomic richness, evenness and diversity than the healthy children supporting the hypothesis that a feature of CF is intestinal microbial dysbiosis.
60▪. Bonsante F, Iacobelli S, Gouyon JB. Routine probiotic use in very preterm infants: retrospective comparison of two cohorts. Am J Perinatol 2012. [Epub ahead of print]
This is a very large study that show the efficacy of probiotic supplementation in reducing mortality and morbidities in very low-birthweight infants with NEC.
61. Deshpande G, Rao S, Patole S, Bulsara M. Updated meta-analysis of probiotics for preventing necrotizing enterocolitis in preterm neonates. Pediatrics 2010; 125:921–930.
62▪. Deshpande CG, Rao SC, Keil AD, Patole SK. Evidence-based guidelines for use of probiotics in preterm neonates. BMC Med 2011; 9:92–105.
The authors developed evidence-based guidelines for probiotic supplementation in preterm neonates.
63▪. Mihatsch WA, Braegger CP, Decsi T, et al. Critical systematic review of the level of evidence for routine use of probiotics for reduction of mortality and prevention of necrotizing enterocolitis and sepsis in preterm infants. Clin Nutr 2012; 31:6–15.
The authors systematically analyze the level of evidence of published controlled randomized trials on probiotics in preterm infants concluding that there is insufficient evidence to recommend routine probiotics.
64▪. Neu J. Routine probiotics for premature infants: let's be careful!. J Pediatr 2011; 158:672–674.
The author concludes that routine use of probiotics in preterm infants should be a cautious approach that still requires many more studies to support the scientific evidence.