Review nature publishing group The human gut microbiota: a dynamic interplay with the host from birth to senescence settled during childhood Lorenza Putignani1, Federica Del Chierico2, Andrea Petrucca2,3, Pamela Vernocchi2,4 and Bruno Dallapiccola5 The microbiota “organ” is the central bioreactor of the gastroin- producing immunological memory (2). Indeed, the intestinal testinal tract, populated by a total of 1014 bacteria and charac- epithelium at the interface between microbiota and lymphoid terized by a genomic content (microbiome), which represents tissue plays a crucial role in the mucosa immune response more than 100 times the human genome. The microbiota (2). The IS ability to coevolve with the microbiota during the plays an important role in child health by acting as a barrier perinatal life allows the host and the microbiota to coexist in a against pathogens and their invasion with a highly dynamic relationship of mutual benefit, which consists in dispensing, in modality, exerting metabolic multistep functions and stimu- a highly coordinated way, specific immune responses toward lating the development of the host immune system, through the biomass of foreign antigens, and in discriminating false well-­organized programming, which influences all of the alarms triggered by benign antigens (2). The failure to obtain growth and aging processes. The advent of “omics” technolo- or maintain this complex homeostasis has a negative impact gies (genomics, proteomics, metabolomics), characterized by on the intestinal and systemic health (2). Once the balance complex technological platforms and advanced analytical and fails, the “disturbance” causes the disease, triggering an abnor- computational procedures, has opened new avenues to the mal inflammatory response as it happens, for example, for the knowledge of the gut microbiota ecosystem, clarifying some inflammatory bowel diseases in newborns (2). Specific determi- aspects on the establishment of microbial communities that nants of variability between host and related environment act constitute it, their modulation and active interaction with directly on the composition and density of the gut microbiota external stimuli as well as food, within the host genetic vari- immediately after birth, resulting in the functional efficiency ability. With a huge interdisciplinary effort and an interface of the newborn intestine (3). The gastrointestinal ecosystem work between basic, translational, and clinical research, micro- constituting the microbiota can be represented as a “microbial biologists, specialists in “-omics” disciplines, and clinicians are organ” (named superorgan) (4), located in the host organism now clarifying the role of the microbiota in the programming (superorganism) and characterized by a dynamic interaction process of several gut-related diseases, from the physiological with food and host cells (Figure 1). symbiosis to the microbial dysbiosis stage, through an inte- The strong relationship between gut microbiota and metab- grated systems biology approach. olism is progressively emerging as a control key in the gut “plant” energetics, defining the role of gut microbiota metabo- ROLE AND FUNCTION OF THE HUMAN MICROBIOTA lome, inflammatory response, and genesis of metabolic altera- Symbiosis and Dysbiosis of Gut Microbiota: A Landmark to Raise tions (5). First, the causal role of gut microbiota in the control Health During Early Life Stages of energy homeostasis was indicated by comparing conven- Human gut microbiota is a complex ecosystem consisting of tional to germ-free (GF) mice fed a high-fat diet (6). While a total of 1014 bacteria. Its genome, which represents more conventional mice gain weight, the GF mice continued to be than 100 times the human genome, can be defined microbi- lean although daily increased food intake (6), suggesting an ome (1). The microbiota commensals play an important role impaired feeding efficiency. Body weight gain was greater in human health by acting as a barrier against pathogens when the GF mice were colonized with the microbiota from and their invasion with a highly dynamic modality, exert- obese rather than from a lean mouse, suggesting that a given ing metabolic functions and stimulating the development of microbiota is dependent on the host genome (7). It was then the immunitary system (IS) (2). The IS consists of innate and shown that obese patients were characterized by an excess of adaptive ISs. The innate IS is the sum of physical and chemi- Firmicutes, when compared with lean controls, and the dys- cal blocks, through reactivity of local nonspecific and specific biosis was inverted under caloric restrictions (8). Interestingly, cells recruited to the site of inflammation. The adaptive IS acts obese mice showed similar intestinal dysbiosis, suggesting a as a specific second line, responding to antigen variability and common mice/humans mechanism (9). Burcelin et al. (10) 1Unit of Parasitology, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy; 2Unit of Metagenomics, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy; 3Department of ­Diagnostic Science, Sant’Andrea Hospital, Rome, Italy; 4Interdipartimental Centre for Industrial Research-CIRI-AGRIFOOD, Alma Mater Studiorum, University of Bologna, ­Bologna, Italy; 5Scientific Directorate, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy. Correspondence: Lorenza Putignani ([email protected]) Received 19 July 2013; accepted 14 January 2014; advance online publication 21 May 2014. doi:10.1038/pr.2014.49 2 Pediatric RESEArCH Volume 76 | Number 1 | July 2014 Copyright © 2014 International Pediatric Research Foundation, Inc. Human gut microbiota programming Review Superorganism resistance. The TLR-2 deficient mice became resistant to insu- Gut Symbiosis lin and therefore obese, suggesting a correlation with the microbiota in the gut increased fat storage or with the augmented levels of gastroin- testinal lipopolysaccharide (LPS) permeability and absorption. Recent data have started to characterize the human dysbiosis also during liver disease (17), showing a statistically signifi- Bacteria Host cant increase of Proteobacteria in pediatric obesity, compared Metagenome with nonalcoholic steatohepatitis (18). Metabolic diseases are linked with disruption of both innate and adaptive ISs (19). It is now widely accepted that overproduction of some cytokines Microbiome (e.g., tumor necrosis factor-α and interleukin-1) contributes to insulin resistance thereby promoting diabetes (20), through infiltration into adipose tissue, leading to a tissue metabolic Diet inflammation (21), as well as Gram (−) LPS components (22), Environment which then circulate in the blood through LPS-binding pro- teins and lipoproteins accumulated during the feeding period (23). In the proximal gut segments, even under homeostasis, Inflammation Xeno-metabolome where the microbiota is rare, some commensal bacteria can be Individual phenotype in close contact with the epithelial cells. The IS scavenges these bacteria and generates primary T-cell responses, either immu- nogenic or tolerogenic (24). However, this concept, validated Intestinal in healthy subjects and in patients with inflammatory bowel Symbiosis diseases in the gut disease, has to be reconsidered in metabolic diseases, because gut dysbiosis can be induced within a few days or weeks by Dysbiosis in the gut a diet change (25), allowing pathogens to penetrate the body without being destroyed by the innate and specific adaptive ISs, through a nucleotide-binding oligomerization domain 1- Figure 1. Graphical representation of the superorganism, its interactions and LPS-cluster of differentiation 14–dependent translocation with the various variability determinants, and related individual pheno- types. The largest microbiome is located in our gastrointestinal tract, and it mechanism, which, when hampered, improves insulin sensi- is influenced by several external factors, such as diet, inflammation stage, tivity (26). Thereby, the blood might not be a direct route for environment, and xeno-metabolome. Each microbiome constitutes an bacterial translocation, suggesting the possibility of a tissue individual phenotype, able to describe symbiosis-, dysbiosis-, and disease- microbiota, also mediating allergy response (27). To identify related gut conditions. million of bacterial genes involved in the control of metabolism is a demanding task. This deserves sophisticated computational showed that C57BL6 mice, fed a high-fat diet, had metabolic pathways that may drive in the assignment of diversified bacte- phenotypes highly heterogeneous, with different levels of dia- rial roles: (i) resilient bacteria (acting in “early” inflammation), betes and obesity, suggesting a metabolic “epigenetic” adapta- (ii) responsive bacteria (players in “late” inflammation), and tion unrelated to diet or genotype. Additionally, also antibiotic (iii) (e.g., infections, inflammatory bowel diseases status) hence treatment of obese mice was described as an important dysbi- translating “roles” into the framework of “real case sample otic effect affecting Firmicutes/Bacteroidetes vs. Proteobacteria diversity” (28). However, to date, case–control studies include ratio (11). Besides hyperglycemia (12), insulin resistance was only limited numbers of individuals/patients, while genome- associated with gut microbiota changes, even in patients with wide and metabolic-wide studies should be necessary to pro- similar body weight, strongly correlating with obesity and type