Microbiota and lifestyle interactions through the lifespan

Trends in Food Science & Technology 57 (2016) 265e272

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Microbiota and lifestyle interactions through the lifespan Simone Rampelli a, *, Marco Candela a, Silvia Turroni a, Elena Biagi a, Maren Pflueger b, Maike Wolters b, Wolfgang Ahrens b, c, Patrizia Brigidi a a

Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy Department of Epidemiological Methods and Etiological Research, Leibniz Institute for Prevention Research and Epidemiology e BIPS, Bremen, Germany c Institute of Statistics, Faculty of Mathematics and Computer Science, University Bremen, Bremen, Germany b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 18 June 2015 Received in revised form 2 March 2016 Accepted 11 March 2016 Available online 15 March 2016

Background: The human intestinal microbiota is an adaptive entity, being capable of adjusting its phylogenetic and functional profile in response to changes in diet, lifestyle and environment. Providing the host with functions important to regulate energetic homeostasis and immunological function, the gut microbiota is strategic to keep metabolic and immunological homeostasis during the entire lifespan. Scope and approach: In the present work we review studies exploring human gut microbiota variations at different age, describing the trajectory of ecosystem changes during the course of our life, from infancy to the old age. Gut microbiota variation mirroring subsistence strategy is also explored, with a particular focus on how the gut microbiota changes in response to modifications in the diet. Finally, we illustrate how an abnormal dietary intake could force microbiota to an obese-associated configuration, which concurs in compromising the host metabolic homeostasis. Key findings and conclusions: Our work allows appreciating the importance of the physiological flexibility conferred by the microbiota for modulating our metabolic and immunological phenotype along the course of our life. Further, the key role of the gut microbiota in providing an extra means of adaptive potential during our evolutionary history is highlighted, suggesting the importance of the intestinal microbiota-host interplay for the maintenance of human health and homeostasis in changing environments. On the other hand, different lifestyle and dietary factors, such as sanitization and antibiotic usage or high-fat diet, can force maladaptive changes in the microbiota configuration which could have negative effects on human health. Thus, it is important to modulate diet and lifestyle habits to keep a mutualistic gut microbiota layout along the course of our life. © 2016 Elsevier Ltd. All rights reserved.

Keywords: Microbiota Microbiome Lifestyle Obesity

1. The human intestinal microbiota The human gut harbors a complex and dynamic ecosystem of microbes e the gut microbiota e that live in close and intimate relationship with the host, and have a large impact on several aspects of our physiology. This abundant microbial community includes members of all three domains of life: Bacteria, which predominate, Eukarya and Archaea, up to1014 microbial cells (Oxley et al., 2010; Scanlan & Marchesi, 2008 and Turnbaugh et al., 2007). The gut microbiota is composed of relatively few bacterial phyla, with Firmicutes and Bacteroidetes accounting for >90% of the resident microorganisms (Eckburg et al., 2005), but it is notable for its species and strain level diversity, with thousands of species

* Corresponding author. E-mail address: [email protected] (S. Rampelli). http://dx.doi.org/10.1016/j.tifs.2016.03.003 0924-2244/© 2016 Elsevier Ltd. All rights reserved.

detected in the gut of the human population and approximately 160 prevalent species per individual (Qin et al., 2010) This peculiar structure at lower phylogenetic levels varies dramatically from one individual to the next, with only a small phylogenetic overlap between people (Qin et al., 2010, Tap et al., 2009), and can change quickly over time in a single individual under environmental and endogenous pressures (Candela, Biagi, Maccaferri, Turroni, & Brigidi, 2012 and Faith et al., 2013). Encoding 10 million non-redundant microbial genes e 400-fold more than the human gene complement e the gut microbiota is widely recognized as an integral and active organ of the human body, which provides functions indispensable to our life (Qin et al., 2010). Intestinal microbes produce indeed essential vitamins, and have the potential to metabolize a wide range of dietary substrates in a complex and intense microbiota-host transgenomic metabolism, deeply influencing our energy and metabolic homeostasis

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(Nicholson et al., 2012 and Rakoff-Nahoum, Coyne, & Comstock, 2014). In particular, the extraordinary diversity and abundance of carbohydrate-active enzymes represented in the gut microbiota complement the poor human glycobiome repertoire (El Kaoutari, Armougom, Gordon, Raoult, & Henrissat, 2013), allowing the extraction of energy from otherwise indigestible polysaccharides, breaking down dietary fiber into adsorbable short-chain fatty acids (SCFA) (Flint, Duncan, Scott, & Louis, 2015). These major products of carbohydrate fermentation, acetate, propionate and butyrate, have a critical role in shaping the host nutritional status, controlling energy production, storage, and appetite (Kimura et al., 2013; Samuel et al., 2008; and De Vadder et al., 2014). SCFA are also crucial in keeping immune homeostasis, acting both locally in the gut and remotely at other organs, thus supporting the strategic role of microbiota in promoting and maintaining a balanced immune response in the course of human life, from infancy to adulthood ~ ez, 2013 and Smith (Arpaia et al., 2013; Kamada, Seo, Chen, & Nún et al., 2013a,b). According to an increasingly large body of evidence, although almost all limited to mice, the microbes in our intestines may also have a major impact on our state of mind, through a bidirectional gut brain axis, governing anxiety and mood disorders (Schmidt, 2015). 2. Impact of lifestyle on the assembly of gut microbiota during infancy The relationship between microbes and human host in the intestine starts at birth. At birth, human beings are sterile and, since their first day of life, they are readily colonized by a pool of microorganisms coming from the mother (vaginal microbiota and fecal microbiota), from mother milk microbiota and from the surrounding environment. During the first months of life the infant gut microbial ecosystem is in continuous variations in terms of composition, and in breast-fed infants is largely dominated by Bifidobacterium showing Enterobacteriaceae as second dominant group. Thus, since our birth, a huge quantity of different microorganisms interact with the intestinal epithelial cells and the gut associated lymphoid tissue (GALT), generating a dense network of intercommunications, which probably constitutes the prerequisite for the development of the immune and metabolic homeostasis later in life (Koenig et al., 2011; Mueller, Bakacs, Combellick, Grigoryan, & Dominguez-Bello, 2015 and Palmer, Bik, DiGiulio, Relman, & Brown, 2007). The diversity and variation of the hostebacteria interactions along our infancy, and, most important, the establishment of a mutualistic developmental gut microbiota trajectory in early life, have been hypothesized as a key factor for the healthy development in childhood (Bisgaard et al., 2011; Cox et al., 2014). Several studies suggest that a shrinkage of the gut microbiota-host interactions at infancy by lifestyle practices (caesarean section, antibiotic use, formula feeding of infants) could compromise the mutualistic process of gut microbiota assembly, increasing the risk of allergic and metabolic diseases later in life (Conradi et al., 2013; Cox et al., 2014; Marra et al., 2009; Fung, Garrett, Shahane, & Kwan, 2012; Risness et al., 2011 and Tenconi et al., 2007). This concept was pioneered by the hygiene hypothesis (Strachan, 1989), which has connected for the first time a reduced microbial contact at early age, as a result of increase of hygiene practices in the Western world, to the growing epidemic of atopic eczema, allergic rhinoconjunctivitis and asthma among Western people (Blaser & Falkow, 2009; Noverr & Huffnagle, 2005 and Rautava, Luoto, Salminen, & Isolauri, 2012). The evidence in favor of the hygiene hypothesis has paved the way to comparative studies between Western and non-Western infants, to identify the effect of different subsistence strategies and hygienic practices on the process of gut microbiota assembly. In

particular, the comprehension of the factors that drive the microbiota assembly across human populations with different subsistence strategies is mandatory to extract the impact of Westernization on such process. In this perspective, the establishment of the human microbiota needs to be conceived as a coevolution trajectory, resulting from a combination of forces that are the assortment of interactions within the bacterial community, the history of assembly (dynamics of the microbial composition) and habitat conditions (diet and interactions with the human host) (Nemergut et al., 2013). In a first milestone study, a loss of gut microbiota diversity in Italian children respect to rural Burkina Faso ones was observed (De Filippo et al., 2010). In particular, the firsts completely lacked Prevotella, Xylanibacter and Treponema genera. The higher microbial diversity of African children has been connected to their high-fiber diet since weaning and a larger exposure to environmental microbes. In another work, the microbiota of US babies has been compared to rural Malawians and Amerindians, confirming a different taxonomic structure of the microbiota among rural and urban populations during the first 3 years of life (Yatsunenko et al., 2012). Interestingly, a metagenomics analysis of the same samples has identified a significant overrepresentation of genes involved in the catabolism of breast milk polysaccharides and intestinal mucosa glycans (mannans, sialylated glycans, galactose and fucosyl saccharides) in Amerindian and Malawian babies respect of the USA ones, probably mirroring differences in the quality of breast milk between the three populations and suggesting a closer interaction between bacteria and intestinal epithelial cells in rural infants (Yatsunenko et al., 2012). These findings have opened the way to further in-depth pioneering analyses, aimed to specifically investigate the effect of the mother diet during pregnancy and breast-feeding on the infant microbiota assembly (Gueimonde et al., 2006; Lahtinen et al., 2009 and Ismail et al., 2012). Taking together, these studies demonstrate that different lifestyle strategies can affect the microbiota assembly in identifiable ways along our infancy, according to the mother and infant diet and the interactions with the bacteria from food and environment. Interestingly, independently from quality of feeding and geographical origin, a healthy developmental trajectory of the infant gut microbiota shows conserved traits, as the progression from microbes that utilize human homopolysaccharides to produce lactate, such as Bifidobacterium, during the lactation period, to microorganisms associated with a solid diet (Koenig et al., 2011). Furthermore, the diversity of the infant microbiota progressively increases in the early development, reaching a maximum between 3 and 5 years of age, depending on the subject (Kostic et al., 2015; Murgas Torrazza & Neu, 2011 and Palmer et al., 2007). Interestingly, impairments or delays in the microbiota assembly during infancy have been associated with some extreme cases of severe acute malnutrition, compromising the formation of the adult-like microbiota structure (Subramanian et al., 2014, Smith et al., 2013a,b). In a first illuminating study, severe acute malnutrition in children from Bangladeshi has been associated with significant microbiota immaturity, which could be only partially ameliorated with nutritional intervention (Subramanian et al., 2014). In particular, the microbiota of malnourished children (age: 6.5e26 months) showed high levels of bacteria belonging to Enterobacteriaceae family and Streptococcus genus, which are opportunistic pro-inflammatory bacteria, and low levels of immunemodulatory Bifidobacterium. Furthermore, their microbiota did not show the progressive increases of Faecalibacterium, Clostridium and Ruminococcus genera, concomitant bacterial groups with the weaning period in healthy children and pivotal for the development of the adult-like structure (Subramanian et al., 2014). Similarly, in another well-structured work, the effects of Kwashiorkor,

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an enigmatic form of severe acute malnutrition, on the gut microbiota developmental trajectory has been studied. The Authors highlighted the association between the diseased state and a compromised process on gut microbiota assembly, showing also the possibility of inducing a transient maturation of bacterial metabolic functions in Kwashiorkor children after the treatment with peanut-based ready-to-use therapeutic food (Smith et al., 2013a,b). An emerging topic in the field of the possible connection between the infant gut microbiota assembly and the host health is the possible role of the intestinal microbiota at the linkage between the maternal and offspring obesity. Indeed, children born from obese mothers shows an increased risk to develop obesity in adulthood with respect to children of non-obese mothers (Koupil & Toivanen, 2008; Stuebe, Forman, & Michels, 2009 and Whitaker, Wright, Pepe, Seidel, & Dietz, 1997). In particular, it has been demonstrated that microbiota of children born from obese mothers is less diverse and has higher abundance of Parabacteroides and Oscillibacter, as well as lower abundance of Blautia and Eubacterium, respect to children born from lean mothers (Galley, Bailey, Kamp Dush, Schoppe-Sullivan, & Christian, 2014). Interestingly, in a primate model study, it has been shown that the dysbiotic gut microbiota configuration observed in the offspring of mother consuming high-fat diet can be partially corrected with postweaning interventions (Ma et al., 2015). 3. Adaptive flexibility of the human gut microbiota, from daily life to the co-evolutionary perspective The adult gut microbiota retains a relevant degree of plasticity, being capable of adjusting its compositional layout in response to endogenous and exogenous variables (Candela et al., 2012). As a result of this paradigm, a remarkable research effort has been made in an attempt to estimate the normal rate of gut microbiota variation on the daily timescale. In a first milestone study exploring the long-term gut microbiota stability, where 33 subjects have been sampled 2 to 13 times for 296 weeks and 4 subjects every 16 days for up to 32 weeks, the variable gut microbiota fraction was settled at 40% of the ecosystem (Faith et al., 2013). In a recent paper, Flores et al. (2014) have demonstrated that the compositional stability of the human microbiota varies within different individuals, with individuals characterized by a much more diverse gut microbial ecosystem showing a more stable community over time. These findings suggest that the concept of “personal microbiome” should be extended beyond the compositional layout by including the individual rate of change, and that the degree of individual microbiota variation should be considered as a marker of the health status (Candela et al., 2013; Holmes, Li, Marchesi, & Nicholson, 2012 and Lozupone, Stombaugh, Gordon, Jansson, & Knight, 2012). With the specific aim to dissect the lifestyle factors modulating the gut microbiota composition on a daily timescale, David et al. (2014) linked 10,000 longitudinal measurements of health and lifestyle variables e e.g. fitness, diet, exercise, dowel movements, mood, illness e with the gut microbiota composition of 2 healthy volunteers, sampled daily over the course of 1 year. The results suggest that the human gut microbial ecosystem alternates periods of apparent stability and periods of “abrupt compositional variation”. During the first, defined by the authors as periods of “stationary dynamics”, the compositional distance between samples rapidly reaches an asymptote. Indeed, samples collected closer in time did not harbor a more similar compositional structure of the gut microbiota than those collected further apart in time. According to the authors, these periods of stationary dynamics may reflect variation in niche sizes due to daily fluctuations in diet and other host factors. Indeed, the authors conclude that dietary changes are

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the most relevant environmental factors influencing the compositional structure of the gut microbiota, while no link was observed between the gut microbiota structure and variables like sleep, exercise or mood. Differently, notable host actions and health changes force “abrupt compositional variations” in the gut microbiota structure (David et al., 2014). In particular, the exposure to relevant dietary and environmental changes consequently to a trip to a developing nation, or an episode of food poisoning and the following Salmonella infection, resulted in a deep perturbation of the gut microbiota structure. Interestingly, while in the first case the gut microbiota reverted to its pre-travel state in 14 days after returning to the American metropolitan area, in the second case a new and stable gut microbiota compositional equilibrium persisted after the perturbation. Interestingly, according to the Authors, the observed gut microbiota variations mainly involve changes in the relative abundance of already present bacteria, while the colonization of new species is relatively rare. These behaviors also explain the high degree of stability of the individual specificity of gut microbiota profile (Lozupone et al., 2012), which is probably the most stable feature of the gut microbiota across time. The gut microbiota variability in response to different diets relies on the different propensity of gut microorganisms to degrade dietary substrates (Fischbach & Sonnenburg, 2011), such as the type of ingested carbohydrates, protein or fat (Flint et al., 2015). Variations in the gut microbiota composition following dietary changes are visible within 24 h (Walker et al., 2011), and result in specific gut microbiota-host co-metabolic layouts, which, ultimately, mold the host health and disease (Muegge et al., 2011). For instance, the transition from a plant-based to an animal-based diet forces relevant changes in the community composition and metabolic end products 1 day after the diet modification (David et al., 2014). In particular, a polysaccharide-rich plant-based diet favors butyrate producers, such as Roseburia, Eubacterium rectale and Faecalibacterium prausnitzii. Conversely, an animal-based diet results in the increase of potentially putrefactive and bile-tolerant microbial components, such as Bilophila wadsworthia and Alistipes. Differently from short-term dietary response that results in a rapid adjustment of the relative abundance of individual gut microbiota components, long-term dietary patterns have been associated with differentiable compositional steady states of the gut microbial ecosystem (Wu et al., 2011). Different components in the diet select for specific microbiotahost co-metabolic layouts and result in the production of dietspecific metabolic outputs that mold the host physiology (Fig. 1). For instance, complex polysaccharides result in a saccharolytic metabolism in the gut and select for a highly diverse community of polysaccharide-degrading bacteria. Establishing a syntrophic metabolic network, polysaccharide degraders produce healthpromoting SCFA. Conversely, protein selects for a proteolytic metabolism in the gut, with a low diverse community of specialized proteolytic microorganisms, resulting in the production of SCFA and branched-chain fatty acids (BCFA), but also the diseaseassociated phenolic and indolic metabolites, and methylamines (Moco et al., 2014). Finally, animal fat selects for a low diverse community of bile resistant microorganisms, such as Erysipelotrichi, Enterobacteriaceae and the sulfate-reducing B. wadsworthia. This ecosystem configuration results in the production of several disease-associated metabolic compounds, such as H2S and secondary bile acids (Tilg & Moschen, 2014). Thus, it has been hypothesized that the mutualistic agreement between human beings and their intestinal microbes principally relies on a constant consumption of plant foods with only occasional consumption of animal foods (David et al., 2014), well matching the dietary habits of traditional hunter-gatherers and rural societies, subsistence strategies corresponding to the vast majority of our evolutionary

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Fig. 1. Gut microbiota-host co-metabolic layouts in response to dietary components. Graphical representation of the three main gut microbiota-host co-metabolic layouts that connect dietary components, the gut microbiota functional layout and the corresponding metabolic endpoints, and the final impact on the host physiology. The first functional layout is driven by complex polysaccharides, which results in a saccharolytic metabolism in the gut. This selects for a highly diverse community of polysaccharidedegrading microorganisms that establish a syntropic network and lead to the production of SCFA, health-promoting metabolites with a key role for our energetic and immune homeostasis. Amino acids select for a proteolytic metabolism with a low diverse microbiota community enriched in specialized proteolytic bacteria that produce a vast range of metabolic end products: SCFA and BCFA, but also the diseasepromoting phenolic and indolic metabolites and methylamines. Finally, dietary fat drives an adaptive microbiota response in the gut, selecting for a low diverse community of bile resistant microorganisms and resulting in the production of proinflammatory H2S and disease-promoting secondary bile acids.

history. Shifting the focus from the daily scale to a co-evolutionary scale, we witness what is probably the most important example of the adaptive plasticity of the human gut microbiota (Quercia et al., 2014), the variation in response to subsistence strategy. Indeed, several explorative studies have been recently carried out to document the gut microbiota configuration in human populations showing different subsistence practices (Martinez et al., 2015; Obregon-Tito et al., 2015; Rampelli et al., 2015; Schnorr et al., 2014 and Yatsunenko et al., 2012). These studies have highlighted the importance of the gut microbiota as a source of the necessary metabolic flexibility for the human adaptation to the three main subsistence strategies which characterized our recent evolutionary history: hunter-gathering, rural communities and Western urban societies (Obregon-Tito et al., 2015). Indeed, Traditional populations, including hunter-gatherers and rural communities, are characterized by a gut microbiota ecosystem with high bacterial richness and low inter-individual variation (Martinez et al., 2015; Obregon-Tito et al., 2015; Schnorr et al., 2014). Conversely, Western urban populations show lower gut microbiota diversity, but higher inter-individual variation. From the compositional point of view, the gut microbial ecosystem of traditional populations is enriched in Prevotella, Succinivibrio and Treponema, all microorganisms with an extremely low prevalence in the gut of urban populations. Differently, the urban gut microbiota shows higher abundance of Bacteroidetes and members of the Lachnospiraceae and Ruminococcaceae families, which are nevertheless well represented also in the gut microbial ecosystem from traditional populations. Even though the overall compositional differences in the microbiota structure between traditional and urban populations are robust to geographical origin (Obregon-Tito et al., 2015; Zhang et al., 2010), it is important to keep in mind that these differences involve only a minor fraction of the ecosystem, while copious abundant phylotypes are shared between rural and Western individuals (Martinez et al., 2015). Interestingly, the gut microbiota of hunter-gatherers forms a distinctive subcluster among the traditional populations (Obregon-

Tito et al., 2015). In a recent paper, Rampelli et al. (2015) compared the gut metagenome structure between Hadza hunter-gatherers and Italian urban population. This work allowed us to highlight the functional traits of the gut metagenome of these two populations aligning with two dichotomous models of human life and subsistence (Fig. 2). Indeed, the gut metagenome of Hadza huntergatherers is enriched in functions to derive energy from the broad spectrum of plant polysaccharides included in their diet. Fascinatingly, this efficient carbohydrate processing system is matched by gut microbiota functions for carbohydrate bioconversion to aromatic amino acids, the latter particularly absent in the Hadza diet. This admirable example of adaptive functional flexibility of the gut microbiota highlights the importance of this bacterial ecosystem to support the host nutritional homeostasis in the context of the hunter-gatherer lifestyle that imply the continuous fluctuation of the available food resources. Analogously, the gut microbiota of urban populations shows traces of an adaptive response to the Western urban lifestyle. Indeed, the gut metagenome of Western people is enriched in genes involved in the degradation of simple sugars, well matching the high consumption of refined carbohydrates in their diet. Moreover, the overrepresentation of functions involved in bile transformation, lipid metabolism and galactose metabolism may reflect an adaptive gut microbiota response to the high dairy consumption in the Western diet. Notably, the gut metagenome of urban Italians is also enriched in pathways involved in the degradation of xenobiotic compounds, such as naphthalene, chloroalkane, benzoate and xylene. This could represent a functional microbiota response to the exposure of toxic compounds ubiquitous in an industrialized urban environment. 4. Does the western microbiota deviate from mutualism? All the so-called “diseases of civilization” (e.g. obesity, type 2 diabetes, asthma, allergies and inflammatory bowel disease (IBD)) have been associated with dysbiosis of the gut microbial ecosystem (Tong et al., 2013), which may involve the decrease of the bacterial diversity. The continued increase of these diseases in Western countries raises the question of whether the gut microbiota of Western people is out of ecological balance, leading to a compromised microbiota-host mutualistic relationship with feedback consequences for human health (Bleich, Cutler, Murray, & Adams, 2008; Caballero, 2007; Flegal, Carroll, Ogden, & Curtin, 2010; Warinner, Speller, Collins, & Lewis, 2015 and Swinburn et al., 2011). In this scenario, the observation of a distinctive and low diverse gut microbiota configuration in urban Western citizens suggested a possible pressure by dietary and lifestyle-associated factors characterizing the urban Western lifestyle, toward a partially compromised microbiota compositional layout. In order to explain how Western factors have progressively compromised the ecological balance of the gut microbiota in Western populations, Sonnenburg and Sonnenburg (2014) recently postulated the multiple-hit hypothesis. According to this theory, several factors that occurred along the transition from rural communities to modern urban societies may have concurred in the progressive loss of key species - known as “old friends” - from the human gut. In particular, deprivation of complex plant polysaccharides in the diet, food processing, sanitization and the massive antibiotic usage both in food production and pharm would have deprived the human host of the environmental interaction needed to acquire a diverse gut microbiota. This would have led to the progressive loss of the gut microbial ecosystem diversity in Western populations, depriving the host of the vast array of microbiota functions important to complement our physiology (Rampelli et al., 2015). According to the multiple-hit hypothesis, several Western lifestyle and dietary factors synergized to force the transition to the

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Fig. 2. Functional layout of the gut metagenome in Hadza hunter-gatherers and urban Italian citizens. A) The gut microbiota of the Hadza is characterized by functions allowing to provide the host with SCFA from the diverse dietary sources characteristic of the Hadza diet, ranging from a vast array of complex polysaccharides from plant foods, to the amino acids from baobab fruit and game meat. The Hadza gut microbiota is capable of several bioconversions, producing aromatic amino acids (which are particularly lessened in the Hadza diet) from intermediates of the carbohydrate metabolism, and producing glycogen (important to enhance carbon assimilation) from dietary amino acids, such as branchedchain amino acids from game meat and glycine, alanine, aspartate and glutamate from baobab fruit. Finally, the anabolic potential of the Hadza gut microbiota also includes the capacity to produce aromatic amino acids, providing an additional boost of amino acids lessened in the Hadza diet. B) The Italian gut microbiota is characterized by the propensity to produce SCFA from simple sugars present in pasta and confectionaries, and lactose and lipids from dairy, both key components of the Mediterranean diet. Further, the Italian gut microbiota is characterized by anabolic pathways for the production of branched-chain amino acids, which are lessened in the diet of the Italian persons.

Western-like gut microbiota configuration (Obregon-Tito et al., 2015). This raises the issue of whether, and to what degree, the subsistence-associated gut microbiota layouts are constrained, and if changes in subsistence and lifestyle are sufficient to guide the transition from one gut microbiota configuration to another. In a very recent paper involving a 2-week dietary exchange between African Americans and rural South Africans, O'Keefe et al. (2015) provided some light in this direction. During the first part of the study, the authors characterized the compositional and functional structure of the gut microbiota in African Americans and rural

Africans living in their own homes and eating their usual diet: highfat low-fiber Western-style for the first, high-fiber low-fat Africanstyle for the latter. As expected, the two groups showed remarkable differences in the gut microbiota layout. In particular, an extensive co-occurring network of fiber-degrading Firmicutes capable to establish a syntrophic metabolism leading to butyrate production characterized the rural African gut microbiota. Conversely, the African American gut microbial ecosystem showed a lower degree of bacterial metabolic interconnections and the propensity towards the production of secondary bile acids and choline. Then the study

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involved a 2-week dietary shift between the two populations, which remained in their own homes. African Americans were fed with the African-style diet, while rural Africans were shifted to the Western-style diet. Interestingly, the dietary exchange was sufficient to “Africanize” the gut microbiota of African Americans and vice versa, demonstrating the pilotable nature of the subsistenceassociated gut microbiota layouts, and the potential of dietary changes to drive the transition of the gut microbiota layout from traditional to urban configurations. Even if there is a lack of consensus on the obese-associated gut microbiota configuration, particularly for what concerns the Bacteroidetes/Firmicutes ratio (Duncan et al., 2008), the gut microbiota changes occurring in obese people probably represent the extreme limit of microbiota deviation from mutualism in response to the Western urban lifestyle (Candela et al., 2012). Indeed, the high-fat high-sugar dietary habits of obese people select for what has been defined as obesity-associated gut microbiota, generally characterized by low biodiversity, and enriched in certain Firmicutes such as Erysipelotrichaceae, as well as the sulfate reducer B. wadsworthia and pro-inflammatory ecosystem components, such as Enterobacteriaceae (Turnbaugh et al., 2009, Ridaura et al., 2013). This dysbiotic configuration of the obese-associated gut microbiota has probably a multifactorial role in consolidating the disease (Cox & Blaser, 2013). Indeed, according to the energy harvest hypothesis, the gut microbial ecosystem of obese people shows an increased efficiency of energy extraction from dietary sugars, providing the host with an extra load of energy from the diet (Schwiertz et al., 2010, Patil et al., 2012). Furthermore, the simultaneous overabundance of sulfate-reducing bacteria and pro-inflammatory Enterobacteriaceae in the gut microbial ecosystem of obese people, provides an additional inflammatory burden in the gut (Cani et al., 2009), consolidating metabolic inflammation and insulin resistance in obesity. Since the prevalence of obesity is increasing in most part of the world, in particular in infants (Ahrens et al., 2011), and this disease clusters with cardiovascular risk factors, as hypertension, dyslipidemia and insulin resistance (Ahrens et al., 2014), future interventions should monitor not only the dietary behavior and the physical activity, but also the microbiota configuration to retrieve a complete medical case of the obese patients. 5. Microbiota and lifestyle interactions in elderly The aging process is known to affect the structure of the gut microbiota, both compositionally (Biagi et al., 2013) and functionally (Rampelli et al., 2013), with specific signatures that seem to noticeably vary depending on the country where the study is performed (Biagi, Candela, Fairweather-Tait, Franceschi, & Brigidi, 2012). Therefore, the most challenging aspect in studying the agerelated changes of the gut microbiota is to separate the effects of the aging process itself, i.e. the physiological modification of human organs and systems that occurs with increasing age, from those of changes in lifestyle that aging implies. Age-related impairments, such as tooth loss and chewing difficulties, impaired sense of taste and smell and mild physical disability lead to changes in lifestyle and diet (Inzitari et al., 2011 and Apostolopoulou et al., 2012) that, in turn, are very well known short- and long-term determinants impacting on the gut microbiota. Indeed, the high inter-individual variability observed in older people (Claesson et al., 2011) could mirror the trajectories of the microbiota under the effect of different lifestyle and diet changes along with aging. These changes are characteristic of each elderly individual and depend on the personal physiological, cognitive and socio-economic condition of the subjects. To our knowledge, very few studies have tried to compare aging people with different lifestyle, providing a glimpse of knowledge in the field. Claesson et al. (2012) showed correlation

between the intestinal microbiota of Irish elderly and living settings (community-dwellings, day-hospital, rehabilitation or long-term residential care), which are linked to peculiar dietary habits and lifestyle. Since the microbiota profile of the few younger adults included as study controls clustered together with those of freeliving elderly, it would be tempting to speculate that lifestyle and diet have a higher impact on the microbiota composition than the aging process itself. However, it was also reported that seniors residing in hospitals and nursing homes had higher age-associated co-morbidities, such as frailty and inflammation, with respect to the community-dwelling ones, highlighting again the difficulty in separating health condition and lifestyle in aging people. More recently, Park et al. (2015) compared the microbiota of people belonging to different age groups residing in urbanized towns and rural elderly people with high longevity index in South Korea. The Firmicutes to Bacteroidetes ratios and the gut microbiota profiles at high phylogenetic level of aging people (40e69 years old, but also >70 years old) in rural areas were more similar to those of urban children than to older adults living in urbanized settings who, in turn, showed higher level of fecal lipopolysaccharides. Most interestingly, urban elderly showed a completely different set of OTU belonging to the known anti-inflammatory genus Faecalibacterium, with respect to both urban children and rural elderly who instead possessed the same Faecalibacterium members. People living in rural longevity villages were reported to consume a diet with a lower ratio of animal to total food intake with respect to people in urbanized towns. This could highlight how strongly prolonged lifestyle and long-term dietary habits, i.e. those of people who live their whole life in the same rural village, can shape the microbiota composition that, in this particular case, has been shown to maintain an anti-inflammatory layout similar to that of children all through the limits of human life. 6. Conclusions Pioneer longitudinal gut microbiota studies have associated a compromised trajectory of microbiota assembly during our infancy with the onset of metabolic and immunological diseases later in life. These studies underline the importance of a mutualistic process of microbiota assembly during our infancy, which could be suggested as a possible biomarker for a correct immunological and metabolical programming of the infant. Peculiarities of the gut microbiota assembly under different lifestyle pressures have been also described. In this context, it would be very interesting to better illustrate these peculiarities at functional and molecular level, allowing us to appreciate their real importance for the infant development and physiology, both in terms of protein/enzyme expression and metabolic substrates/products. It would be particularly innovative if future studies were focused on the interactomics of the microbiota, to reveal bacterial metabolites and proteins involved in bacteriaebacteria and bacteriaeenterocytes interaction processes. In the current Western scenario, where the so-called “diseases of civilization” are currently increasing and their connection with gut microbiota dysbioses has been suggested, we need to put more attention in the preservation of our mutualistic bacterial counterpart. Several Western factors with the potential to compromise the ecological balance of our gut microbial ecosystem have been suggested. However, further research needs to be carried out to dissect the importance of the different dietary and lifestyle factors as drivers of the gut microbiota Westernization process, particularly in terms of reduction of the compositional diversity and functional plasticity of the ecosystem. This knowledge will allow us to refine dietary and cultural habits in Western societies with the specific aim to preserve the diversity of the symbiotic microbial component

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living in our gut. Finally, assuming that living environment and diet have such impact on the features of an aging microbiota, heavier than the impact of aging physiology itself, comparing the results of the studies on the gut microbiota of aging people living in different countries and with different subsistence is a challenging task, in which lifestyle and dietary differences must be taken into account as possible determinants of the depicted variability. Acknowledgments Funding for this work was provided by the MyNewGut FP7KBBE project (Grant agreement no.: 613979). References Ahrens, W., Bammann, K., Siani, A., Buchecker, K., De, H. S., Iacoviello, L., et al. (2011). The IDEFICS cohort: design, characteristics and participation in the baseline survey. International Journal of Obesity, 35, S3eS15. Ahrens, W., Moreno, L. A., Marild, S., Molnar, D., Siani, A., De Henauw, S., et al. (2014). Metabolic syndrome in young children: definitions and results of the IDEFICS study. International Journal of Obesity, 38, S4eS14. Apostolopoulou, M., Savopoulos, C., Michalakis, K., Coppack, S., Dardavessis, T., & Hatzitolios, A. (2012). Age, weight and obesity. Maturitas, 71, 115e119. Arpaia, N., Campbell, C., Fan, X., Dikiy, S., van der Veeken, J., deRoos, P., et al. (2013). Metabolites produced by commensal bacteria promote peripheral regulatory Tcell generation. Nature, 504, 451e455. Biagi, E., Candela, M., Fairweather-Tait, S., Franceschi, C., & Brigidi, P. (2012). Aging of the human metaorganism: the microbial counterpart. Age, 1, 247e267. Biagi, E., Candela, M., Turroni, S., Garagnani, P., Franceschi, C., & Brigidi, P. (2013). Ageing and gut microbes: perspectives for health maintenance and longevity. Pharmacological Research, 1, 11e20. Bisgaard, H., Li, N., Bonnelykke, K., Chawes, B. L., Skov, T., Paludan-Müller, G., et al. (2011). Reduced diversity of the intestinal microbiota during infancy is associated with increased risk of allergic disease at school age. Journal of Allergy and Clinical Immunology, 128, 646e652. Blaser, M. J., & Falkow, S. (2009). What are the consequences of the disappearing human microbiota? Nature Reviews Microbiology, 12, 887e894. Bleich, S., Cutler, D., Murray, C., & Adams, A. (2008). Why is the developed world obese? Annual Review of Public Health, 29, 273e295. Caballero, B. (2007). The global epidemic of obesity: an overview. Epidemiologic Reviews, 29, 1e5. Candela, M., Biagi, E., Maccaferri, S., Turroni, S., & Brigidi, P. (2012). Intestinal microbiota is a plastic factor responding to environmental changes. Trends in Microbiology, 20, 385e391. Candela, M., Biagi, E., Turroni, S., Maccaferri, S., Figini, P., & Brigidi, P. (2013). Dynamic efficiency of the human intestinal microbiota. Critical Reviews in Microbiology, 41, 1e7. Cani, P. D., Possemiers, S., Van de Wiele, T., Guiot, Y., Everard, A., Rottier, O., et al. (2009). Changes in gut microbiota control inflammation in obese mice through a mechanism involving GLP-2-driven improvement of gut permeability. Gut, 58, 1091e1103. Claesson, M. J., Cusack, S., O'Sullivan, O., Greene-Diniz, R., de Weerd, H., Flannery, E., et al. (2011). Composition, variability, and temporal stability of the intestinal microbiota of the elderly. Proceedings of the National Academy of Sciences, 108, 4586e4591. Claesson, M. J., Jeffery, I. B., Conde, S., Power, S. E., O'Connor, E. M., Cusack, S., et al. (2012). Gut microbiota composition correlates with diet and health in the elderly. Nature, 7410, 178e184. Conradi, S., Malzahn, U., Paul, F., Quill, S., Harms, L., Then Bergh, F., et al. (2013). Breastfeeding is associated with lower risk for multiple sclerosis. Multiple Sclerosis, 5, 553e558. Cox, L. M., & Blaser, M. J. (2013). Pathways in microbe-induced obesity. Cell Metabolism, 6, 883e894. Cox, L. M., Yamanishi, S., Sohn, J., Alekseyenko, A. V., Leung, J. M., Cho, I., et al. (2014). Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell, 158, 705e721. David, L. A., Materna, A. C., Friedman, J., Campos-Baptista, M. I., Blackburn, M. C., Perrotta, A., et al. (2014). Host lifestyle affects human microbiota on daily timescales. Genome Biology, 15, R89. De Filippo, C., Cavalieri, D., Paola, Di, Ramazzotti, M., Poullet, J. B., Massart, S., et al. (2010). Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. Proceedings of the National Academy of Sciences, 107, 14691e14696. De Vadder, F., Kovatcheva-Datchary, P., Goncalves, D., Vinera, J., Zitoun, C., Duchampt, A., et al. (2014). Microbiota-generated metabolites promote metabolic benefits via gut-brain neural circuits. Cell, 156, 84e96. Duncan, S. H., Lobley, G. E., Holtrop, G., Ince, J., Johnstone, A. M., Louis, P., et al. (2008). Human colonic microbiota associated with diet, obesity and weight loss. International Journal of Obesity, 32, 1720e1724. Eckburg, P. B., Bik, E. M., Bernstein, C. N., Purdom, E., Dethlefsen, L., Sargent, M., et al.

271

(2005). Diversity of the human intestinal microbial flora. Science, 308, 1635e1638. El Kaoutari, A., Armougom, F., Gordon, J. I., Raoult, D., & Henrissat, B. (2013). The abundance and variety of carbohydrate-active enzymes in the human gut microbiota. Nature Review Microbiology, 11, 497e504. Faith, J. J., Guruge, J. L., Charbonneau, M., Subramanian, S., Seedorf, H., Goodman, A. L., et al. (2013). The long-term stability of the human gut microbiota. Science, 341, 1237439. Fischbach, M. A., & Sonnenburg, J. L. (2011). Eating for two: how metabolism establishes interspecies interactions in the gut. Cell Host & Microbe, 10, 336e347. Flegal, K. M., Carroll, M. D., Ogden, C. L., & Curtin, L. R. (2010). Prevalence and trends in obesity among US Adults, 1999e2008. Journal of American Medical Association, 303, 235e241. Flint, H. J., Duncan, S. H., Scott, K. P., & Louis, P. (2015). Links between diet, gut microbiota composition and gut metabolism. Proceedings of the Nutrition Society, 74, 13e22. Flores, G. E., Caporaso, J. G., Henley, J. B., Rideout, J. R., Domogala, D., Chase, J., et al. (2014). Temporal variability is a personalized feature of the human microbiome. Genome Biology, 15, 531. Fung, I., Garrett, J. P., Shahane, A., & Kwan, M. (2012). Do bugs control our fate? The influence of the microbiome on autoimmunity. Current Allergy and Asthma Reports, 12, 511e519. Galley, J. D., Bailey, M., Kamp Dush, C., Schoppe-Sullivan, S., & Christian, L. M. (2014). Maternal obesity is associated with alterations in the gut microbiome in toddlers. PloS One, 9, e113026. €ki, M., Isolauri, E., Benno, Y., & Salminen, S. Gueimonde, M., Sakata, S., Kallioma (2006). Effect of maternal consumption of lactobacillus GG on transfer and establishment of fecal bifidobacterial microbiota in neonates. Journal of Pediatric Gastroenterology and Nutrition, 42, 166e170. Holmes, E., Li, J. V., Marchesi, J. R., & Nicholson, J. K. (2012). Gut microbiota composition and activity in relation to host metabolic phenotype and disease risk. Cell Metabolism, 16, 559e564. Inzitari, M., Doets, E., Bartali, B., Benetou, V., Di Bari, M., Visser, M., et al. (2011). Nutrition in the age-related disablement process. The Journal of Nutrition Health and Aging, 15, 599e604. Ismail, I. H., Oppedisano, F., Joseph, S. J., Boyle, R. J., Robins-Browne, R. M., Tang, M. L. K., et al. (2012). Prenatal administration of Lactobacillus rhamnosus has no effect on the diversity of the early infant gut microbiota. Pediatric Allergy and Immunology, 23, 255e258. ~ ez, G. (2013). Role of the gut microbiota in Kamada, N., Seo, S. U., Chen, G. Y., & Nún immunity and inflammatory disease. Nature Reviews Immunology, 13, 321e335. Kimura, I., Ozawa, K., Inoue, D., Imamura, T., Kimura, K., Maeda, T., et al. (2013). The gut microbiota suppresses insulin-mediated fat accumulation via the shortchain fatty acid receptor GPR43. Nature Communications, 4, 1829. Koenig, J. E., Spor, A., Scalfone, N., Fricker, A. D., Stombaugh, J., Knight, R., et al. (2011). Succession of microbial consortia in the developing infant gut microbiome. Proceedings of the National Academy of Sciences, 108, 4578e4585. € tyla €inen, T., H€ €inen, A. M., Kostic, A. D., Gevers, D., Siljander, H., Vatanen, T., Hyo am€ ala et al. (2015). The dynamics of the human infant gut microbiome in development and in progression toward type 1 diabetes. Cell Host & Microbe, 17, 260e273. Koupil, I., & Toivanen, P. (2008). Social and early-life determinants of overweight and obesity in 18-year-old swedish men. International Journal of Obesity, 32, 73e81. Lahtinen, S. J., Boyle, R. J., Kivivuori, S., Oppedisano, F., Smith, K. R., RobinsBrowne, R., et al. (2009). Prenatal probiotic administration can influence bifidobacterium microbiota development in infants at high risk of allergy. The Journal of Allergy and Clinical Immunology, 123, 499e501. Lozupone, C. A., Stombaugh, J. I., Gordon, J. I., Jansson, J. K., & Knight, R. (2012). Diversity, stability and resilience of the human gut microbiota. Nature, 489, 220e230. Ma, J., Prince, A. L., Bader, D., Hu, M., Ganu, R., Baquero, K., et al. (2015). High-fat maternal diet during pregnancy persistently alters the offspring microbiome in a primate model. Nature Communications, 5. Marra, F., Marra, C. A., Richardson, K., Lynd, L. D., Kozyrskyj, A., Patrick, D. M., et al. (2009). Antibiotic use in children is associated with increased risk of asthma. Pediatrics, 123, 1003e1010. mez, M. X., Murat Eren, A., Siba, P. M., Martínez, I., Stegen, J. C., Maldonado-Go Greenhill, A. R., et al. (2015). The gut microbiota of rural Papua New Guineans: composition, diversity patterns, and ecological processes. Cell Reports, 11, 527e538. Moco, S., Candela, M., Chuang, E., Draper, C., Cominetti, O., Montoliu, I., et al. (2014). Systems biology approaches for inflammatory bowel disease: emphasis on gut microbial metabolism. Inflammatory Bowel Diseases, 20, 2104e2114. Muegge, B. D., Kuczynski, J., Knights, D., Clemente, J. C., Gonzalez, A., Fontana, L., et al. (2011). Diet drives convergence in gut microbiome functions across mammalian phylogeny and within humans. Science, 332, 970e974. Mueller, N. T., Bakacs, E., Combellick, J., Grigoryan, Z., & Dominguez-Bello, M. G. (2015). The infant microbiome development: mom matters. Trends in Molecular Medicine, 21, 109e117. Murgas Torrazza, R., & Neu, J. (2011). The developing intestinal microbiome and its relationship to health and disease in the neonate. Journal of Perinatology, 31, S29eS34. Nemergut, D. R., Schmidt, S. K., Fukami, T., O'Neill, S. P., Bilinski, T. M., Stanish, L. F., et al. (2013). Patterns and processes of microbial community assembly.

272

S. Rampelli et al. / Trends in Food Science & Technology 57 (2016) 265e272

Microbiology and Molecular Biology Reviews, 77, 342e356. Nicholson, J. K., Holmes, E., Kinross, J., Burcelin, R., Gibson, G., Jia, W., et al. (2012). Host-gut microbiota metabolic interactions. Science, 336, 1262e1267. Noverr, M. C., & Huffnagle, G. B. (2005). The ‘microflora hypothesis’ of allergic diseases. Clinical and Experimental Allergy, 35, 1511e1520. Obregon-Tito, A. J., Tito, R. Y., Metcalf, J., Sankaranarayanan, K., Clemente, J. C., Ursell, L. K., et al. (2015). Subsistence strategies in traditional societies distinguish gut microbiomes. Nature Communications, 6, 6505. Oxley, A. P., Lanfranconi, M. P., Würdemann, D., Ott, S., Schreiber, S., McGenity, T. J., et al. (2010). Halophilic archaea in the human intestinal mucosa. Environmental Microbiology, 12, 2398e2410. O'Keefe, S. J. D., Li, J. V., Lahti, L., Ou, J., Carbonero, F., Mohammed, K., et al. (2015). Fat, fibre and cancer risk in African Americans and rural Africans. Nature Communications, 6, 6342. Palmer, C., Bik, E. M., DiGiulio, D. B., Relman, D. A., & Brown, P. O. (2007). Development of the human infant intestinal microbiota. PLoS Biology, 5, e177. Park, S. H., Kim, K. A., Ahn, Y. T., Jeong, J. J., Huh, C. S., & Kim, D. H. (2015). Comparative analysis of gut microbiota in elderly people of urbanized towns and longevity villages. BMC Microbiology, 15, 49. Patil, D. P., Dhotre, D. P., Chavan, S. G., Sultan, A., Jain, D. S., Lanjekar, V. B., et al. (2012). Molecular analysis of gut microbiota in obesity among Indian individuals. Journal of Biosciences, 27, 647e657. Qin, J., Li, R., Raes, J., Arumugam, M., Burgdorf, K. S., Manichanh, C., et al. (2010). A human gut microbial gene catalogue established by metagenomic sequencing. Nature, 464, 59e65. Quercia, S., Candela, M., Giuliani, C., Turroni, S., Luiselli, D., Rampelli, S., et al. (2014). From lifetime to evolution: timescales of human gut microbiota adaptation. Frontiers in Microbiology, 5, 587. Rakoff-Nahoum, S., Coyne, M. J., & Comstock, L. E. (2014). An ecological network of polysaccharide utilization among human intestinal symbionts. Current Biology, 24, 40e49. Rampelli, S., Candela, M., Turroni, S., Biagi, E., Collino, S., Franceschi, C., et al. (2013). Functional metagenomic profiling of intestinal microbiome in extreme ageing. Aging (Albany NY), 5, 902e912. Rampelli, S., Schnorr, S. L., Consolandi, C., Turroni, S., Severgnini, M., Peano, C., et al. (2015). Metagenome sequencing of the Hadza hunter-gatherer gut microbiota. Current Biology, 25, 1e12. Rautava, S., Luoto, R., Salminen, S., & Isolauri, E. (2012). Microbial contact during pregnancy, intestinal colonization and human disease. Nature Reviews Gastroenterology & Hepatology, 9, 565e576. Ridaura, V. K., Faith, J. J., Rey, F. E., Cheng, J., Duncan, A. E., Kau, A. L., et al. (2013). Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science, 341, 1241214. Risnes, K. R., Belanger, K., Murk, W., & Bracken, M. B. (2011). Antibiotic exposure by 6 months and asthma and allergy at 6 years: Findings in a cohort of 1,401 US children. American Journal of Epidemiology, 173, 310e318. Samuel, B. S., Shaito, A., Motoike, T., Rey, F. E., Backhed, F., Manchester, J. K., et al. (2008). Effects of the gut microbiota on host adiposity are modulated by the short-chain fatty-acid binding G protein-coupled receptor, Gpr41. Proceedings of the National Academy of Sciences of the United States of America, 105, 16767e16772. Scanlan, P. D., & Marchesi, J. R. (2008). Micro-eukaryotic diversity of the human distal gut microbiota: qualitative assessment using culture-dependent and -independent analysis of faeces. The ISME Journal, 2, 1183e1193. Schmidt, C. (2015). Mental health: thinking from the gut. Nature, 518, S12eS15. Schnorr, S. L., Candela, M., Rampelli, S., Centanni, M., Consolandi, C., Basaglia, G., et al. (2014). Gut microbiome of the Hadza hunter-gatherers. Nature

Communications, 5, 3654. Schwiertz, A., Taras, D., Sch€ afer, K., Beijer, S., Bos, N. A., Donus, C., et al. (2010). Microbiota and SCFA in lean and overweight healthy subjects. Obesity, 18, 190e195. Smith, P. M., Howitt, M. R., Panikov, N., Michaud, M., Gallini, C. A., Bohlooly, Y. M., et al. (2013a). The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science, 341, 569e573. Smith, M. I., Yatsunenko, T., Manary, M. J., Trehan, I., Mkakosya, R., Cheng, J., et al. (2013b). Gut microbiomes of Malawian twin pairs discordant for kwashiorkor. Science, 339, 548e554. Sonnenburg, E. D., & Sonnenburg, J. L. (2014). Starving our microbial self: the deleterious consequences of a diet deficient in microbiota-accessible carbohydrates. Cell Metabolism, 20, 779e786. Strachan, D. P. (1989). Hay fever, hygiene, and household size. British Medical Journal, 299, 1259e1260. Stuebe, A. M., Forman, M. R., & Michels, K. B. (2009). Maternal-recalled gestational weight gain, pre-pregnancy body mass index, and obesity in the daughter. International Journal of Obesity (London), 33, 743e752. Subramanian, S., Huq, S., Yatsunenko, T., Haque, R., Mahfuz, M., Alam, M. A., et al. (2014). Persistent gut microbiota immaturity in malnourished Bangladeshi children. Nature, 510, 417e421. Swinburn, B. A., Sacks, G., Hall, K. D., McPherson, K., Finegood, D. T., Moodie, M. L., et al. (2011). The global obesity pandemic: shaped by global drivers and local environments. Lancet, 378, 804e814. Tap, J., Mondot, S., Levenez, F., Pelletier, E., Caron, C., Furet, J. P., et al. (2009). Towards the human intestinal microbiota phylogenetic core. Environmental Microbiology, 11, 2574e2584. Tenconi, M. T., Devoti, G., Comelli, M., Pinon, M., Capocchiano, A., Calcaterra, V., et al. (2007). Major childhood infectious diseases and other determinants associated with type 1 diabetes: a case-control study. Acta Diabetologica, 44, 14e19. Tilg, H., & Moschen, A. R. (2014). Microbiota and diabetes: an evolving relationship. Gut, 63, 1513e1521. Tong, M., Li, X., Wegener Parfrey, L., Roth, B., Ippoliti, A., Wei, B., et al. (2013). A modular organization of the human intestinal mucosal microbiota and its association with inflammatory bowel disease. PLoS One, 8, e80702. Turnbaugh, P. J., Hamady, M., Yatsunenko, T., Cantarel, B. L., Duncan, A., Ley, R. E., et al. (2009). A core gut microbiome in obese and lean twins. Nature, 457, 480e484. Turnbaugh, P. J., Ley, R. E., Hamady, M., Fraser-Liggett, C. M., Knight, R., & Gordon, J. I. (2007). The human microbiome project. Nature, 449, 804e810. Walker, A. W., Ince, J., Duncan, S. H., Webster, L. M., Holtrop, G., Ze, X., et al. (2011). Dominant and diet-responsive groups of bacteria within the human colonic microbiota. The ISME Journal, 5, 220e230. Warinner, C., Speller, C., Collins, M. J., & Lewis, C. M., Jr. (2015). Ancient human microbiomes. Journal of Human Evolution, 79, 125e136. Whitaker, R. C., Wright, J. A., Pepe, M. S., Seidel, K. D., & Dietz, W. H. (1997). Predicting obesity in young adulthood from childhood and parental obesity. The New England Journal of Medicine, 337, 869e873. Wu, G. D., Chen, J., Hoffmann, C., Bittinger, K., Chen, Y. Y., Keilbaugh, S. A., et al. (2011). Linking long-term dietary patterns with gut microbial enterotypes. Science, 334, 105e108. Yatsunenko, T., Rey, F. E., Manary, M. J., Trehan, I., Dominguez-Bello, M. G., Contreras, M., et al. (2012). Human gut microbiome viewed across age and geography. Nature, 486, 222e227. Zhang, C., Zhang, M., Wang, S., Han, R., Cao, Y., Hua, W., et al. (2010). Interactions between gut microbiota, host genetics and diet relevant to development of metabolic syndromes in mice. The ISME Journal, 4, 232e241.