Explore the vast range of titles available.

The characterization of baseline microbial and functional diversity in the human microbiome has enabled studies of microbiome-related disease, diversity, biogeography, and molecular function. The National Institutes of Health Human Microbiome Project has provided one of the broadest such characterizations so far. Here we introduce a second wave of data from the study, comprising 1,631 new metagenomes (2,355 total) targeting diverse body sites with multiple time points in 265 individuals. We applied updated profiling and assembly methods to provide new characterizations of microbiome personalization. Strain identification revealed subspecies clades specific to body sites; it also quantified species with phylogenetic diversity under-represented in isolate genomes. Body-wide functional profiling classified pathways into universal, human-enriched, and body site-enriched subsets. Finally, temporal analysis decomposed microbial variation into rapidly variable, moderately variable, and stable subsets. This study furthers our knowledge of baseline human microbial diversity and enables an understanding of personalized microbiome function and dynamics. Updates from the Human Microbiome Project analyse the largest known body-wide metagenomic profile of human microbiome personalization. Delving deeper into the human microbiome The National Institutes of Health Human Microbiome Project, published in 2012, provided a broad overview of the baseline microbiome in healthy individuals using samples from 18 different body sites. In this second installment, the authors expand this dataset with new whole-metagenome sequences and additional time points to assess the diversity and spatiotemporal distributions of the microbiota at six of these body sites. Using a combination of strain profiling, species-level metagenomic functional profiling and longitudinal analyses, this study delivers deeper insights into human microbial communities and provides an important resource for understanding what constitutes a 'healthy' microbiota.

Key Points Animals are closely associated with a vast and diverse microbiota, most members of which reside in the gastrointestinal tract. Two gradients of microbial distribution exist in the gastrointestinal tract: the proximal–distal axis and the tissue–lumen axis. Several parameters, including diet, lifestyle, antibiotics and other drugs, hygiene, and the genetics and immune status of the host, shape the microbiota composition, with various consequences for host physiology. The gut microbiota is required for the development and maturation of the intestinal epithelium and immune system of the host. This microbiota affects properties of the mucus layer, promotes the development of lymphoid structures, modulates activation and differentiation of several lymphocyte populations and balances the production of immunoglobulin A and antimicrobial peptides. The gut microbiota facilitates host metabolism and adiposity by expanding nutrient sources, producing essential vitamins and carrying out xenobiotic metabolism, but also affects a wide range of other host physiological aspects, including organ morphogenesis, intestinal vascularization, tissue homeostasis, carcinogenesis, bone mass and behaviour. There is increasing evidence for a tight cross-species homeostatic interaction between the host and its microbiota, and research in this field has been facilitated by recent progress in the description and isolation of gut microbiota members, as well as in gnotobiology and host genetics. Elucidation of the molecular targets and causative connections in these host–microbiota interactions promises to reveal new possibilities to treat chronic inflammatory diseases and maintain human health. The gut microbiota, traditionally studied in the context of disease, has emerged as a key regulator during normal homeostasis. Here, Sommer and Bäckhed discuss how the gut microbiota promotes the development and homeostasis of the immune system and orchestrates several aspects of human physiology, including tissue morphogenesis, metabolism and even behaviour. Establishing and maintaining beneficial interactions between the host and its associated microbiota are key requirements for host health. Although the gut microbiota has previously been studied in the context of inflammatory diseases, it has recently become clear that this microbial community has a beneficial role during normal homeostasis, modulating the host's immune system as well as influencing host development and physiology, including organ development and morphogenesis, and host metabolism. The underlying molecular mechanisms of host–microorganism interactions remain largely unknown, but recent studies have begun to identify the key signalling pathways of the cross-species homeostatic regulation between the gut microbiota and its host.

The link between the microbes in the human gut and the development of obesity, cardiovascular disease and metabolic syndromes, such as type 2 diabetes, is becoming clearer. However, because of the complexity of the microbial community, the functional connections are less well understood. Studies in both mice and humans are helping to show what effect the gut microbiota has on host metabolism by improving energy yield from food and modulating dietary or the host-derived compounds that alter host metabolic pathways. Through increased knowledge of the mechanisms involved in the interactions between the microbiota and its host, we will be in a better position to develop treatments for metabolic disease.

How much does the microbiota influence the host's phenotype? Ridaura et al. ( 1241214 ; see the Perspective by Walker and Parkhill ) obtained uncultured fecal microbiota from twin pairs discordant for body mass and transplanted them into adult germ-free mice. It was discovered that adiposity is transmissible from human to mouse and that it was associated with changes in serum levels of branched-chain amino acids. Moreover, obese-phenotype mice were invaded by members of the Bacteroidales from the lean mice, but, happily, the lean animals resisted invasion by the obese microbiota. Mice carrying gut bacteria from lean humans protect their cage mates from the effects of gut bacteria from fat humans. [Also see Perspective by Walker and Parkhill ] The role of specific gut microbes in shaping body composition remains unclear. We transplanted fecal microbiota from adult female twin pairs discordant for obesity into germ-free mice fed low-fat mouse chow, as well as diets representing different levels of saturated fat and fruit and vegetable consumption typical of the U.S. diet. Increased total body and fat mass, as well as obesity-associated metabolic phenotypes, were transmissible with uncultured fecal communities and with their corresponding fecal bacterial culture collections. Cohousing mice harboring an obese twin’s microbiota (Ob) with mice containing the lean co-twin’s microbiota (Ln) prevented the development of increased body mass and obesity-associated metabolic phenotypes in Ob cage mates. Rescue correlated with invasion of specific members of Bacteroidetes from the Ln microbiota into Ob microbiota and was diet-dependent. These findings reveal transmissible, rapid, and modifiable effects of diet-by-microbiota interactions.

At marine cold seeps, gaseous and liquid hydrocarbons migrate from deep subsurface origins to the sediment-water interface. Cold seep sediments are known to host taxonomically diverse microorganisms, but little is known about their metabolic potential and depth distribution in relation to hydrocarbon and electron acceptor availability. Here we combined geophysical, geochemical, metagenomic and metabolomic measurements to profile microbial activities at a newly discovered cold seep in the deep sea. Metagenomic profiling revealed compositional and functional differentiation between near-surface sediments and deeper subsurface layers. In both sulfate-rich and sulfate-depleted depths, various archaeal and bacterial community members are actively oxidizing thermogenic hydrocarbons anaerobically. Depth distributions of hydrocarbon-oxidizing archaea revealed that they are not necessarily associated with sulfate reduction, which is especially surprising for anaerobic ethane and butane oxidizers. Overall, these findings link subseafloor microbiomes to various biochemical mechanisms for the anaerobic degradation of deeply-sourced thermogenic hydrocarbons. Describing anaerobic short chain alkane degrading archaea at a newly discovered cold seep, the authors here suggest that these organisms play much more important roles in submarine carbon cycling globally than previously thought.

Diet-microbe interactions play an important role in modulating the early-life microbiota, with Bifidobacterium strains and species dominating the gut of breast-fed infants. Here, we sought to explore how infant diet drives distinct bifidobacterial community composition and dynamics within individual infant ecosystems. Genomic characterisation of 19 strains isolated from breast-fed infants revealed a diverse genomic architecture enriched in carbohydrate metabolism genes, which was distinct to each strain, but collectively formed a pangenome across infants. Presence of gene clusters implicated in digestion of human milk oligosaccharides (HMOs) varied between species, with growth studies indicating that within single infants there were differences in the ability to utilise 2′FL and LNnT HMOs between strains. Cross-feeding experiments were performed with HMO degraders and non-HMO users (using spent or ‘conditioned’ media and direct co-culture). Further 1 H-NMR analysis identified fucose, galactose, acetate, and N-acetylglucosamine as key by-products of HMO metabolism; as demonstrated by modest growth of non-HMO users on spend media from HMO metabolism. These experiments indicate how HMO metabolism permits the sharing of resources to maximise nutrient consumption from the diet and highlights the cooperative nature of bifidobacterial strains and their role as ‘foundation’ species in the infant ecosystem. The intra- and inter-infant bifidobacterial community behaviour may contribute to the diversity and dominance of Bifidobacterium in early life and suggests avenues for future development of new diet and microbiota-based therapies to promote infant health.

The large numbers of microorganisms that inhabit mammalian body surfaces have a highly coevolved relationship with the immune system. Although many of these microbes carry out functions that are critical for host physiology, they nevertheless pose the threat of breach with ensuing pathologies. The mammalian immune system plays an essential role in maintaining homeostasis with resident microbial communities, thus ensuring that the mutualistic nature of the host-microbial relationship is maintained. At the same time, resident bacteria profoundly shape mammalian immunity. Here, we review advances in our understanding of the interactions between resident microbes and the immune system and the implications of these findings for human health.

Antibiotic treatment disturbs the commensal microbiota and is often followed by infection with enteric pathogens such as Salmonella typhimurium and Clostridium difficile; pathogen expansion is fuelled by antibiotic-driven accumulation of commensal-liberated host mucosal carbohydrates. Gut microbes support pathogen proliferation Intestinal microbiota can provide protection against invading pathogens through competition for resources and production of specific antimicrobial products. But disruption of the microbiota with antibiotics can contribute to the emergence of several enteric pathogens. Justin Sonnenburg and colleagues show here that two antibiotic-associated pathogens, Salmonella enterica serovar Typhimurium and Clostridium difficile , catabolize microbiota-liberated host sugars to fuel their growth in the mouse gut. In particular, the ability to use sialic acid cleaved from host polysaccharides by Bacteroides thetaiotaomicron is important for pathogen expansion. These findings identify a role for the gut microbiota in facilitating enteric pathogen infection and provide new options for developing therapeutics. The human intestine, colonized by a dense community of resident microbes, is a frequent target of bacterial pathogens. Undisturbed, this intestinal microbiota provides protection from bacterial infections. Conversely, disruption of the microbiota with oral antibiotics often precedes the emergence of several enteric pathogens 1 , 2 , 3 , 4 . How pathogens capitalize upon the failure of microbiota-afforded protection is largely unknown. Here we show that two antibiotic-associated pathogens, Salmonella enterica serovar Typhimurium ( S. typhimurium ) and Clostridium difficile , use a common strategy of catabolizing microbiota-liberated mucosal carbohydrates during their expansion within the gut. S. typhimurium accesses fucose and sialic acid within the lumen of the gut in a microbiota-dependent manner, and genetic ablation of the respective catabolic pathways reduces its competitiveness in vivo . Similarly, C. difficile expansion is aided by microbiota-induced elevation of sialic acid levels in vivo . Colonization of gnotobiotic mice with a sialidase-deficient mutant of Bacteroides thetaiotaomicron , a model gut symbiont, reduces free sialic acid levels resulting in C. difficile downregulating its sialic acid catabolic pathway and exhibiting impaired expansion. These effects are reversed by exogenous dietary administration of free sialic acid. Furthermore, antibiotic treatment of conventional mice induces a spike in free sialic acid and mutants of both Salmonella and C. difficile that are unable to catabolize sialic acid exhibit impaired expansion. These data show that antibiotic-induced disruption of the resident microbiota and subsequent alteration in mucosal carbohydrate availability are exploited by these two distantly related enteric pathogens in a similar manner. This insight suggests new therapeutic approaches for preventing diseases caused by antibiotic-associated pathogens.

The clinical and economic burden of Clostridium difficile infection (CDI) is significant. Recurrent CDI management has emerged as a major challenge with suboptimal response to standard therapy. Fecal microbiota transplantation (FMT) has been used as a treatment to reconstitute the normal microbial homeostasis and break the cycle of antibiotic agents that may further disrupt the microbiome. Given the lack of randomized-controlled trials (RCTs) and limitations in previous systematic reviews, we aimed to conduct a systematic review with robust methods to determine the efficacy and safety profile of FMT in CDI. An electronic search was conducted using MEDLINE (1946-March 2012), EMBASE (1974-March 2012) and Cochrane Central Register of Controlled Trials (2012). The search strategy was not limited by language. Abstract data were excluded and only completed studies that underwent the full, rigorous peer-review process were included. Studies that used FMT via any delivery modality for laboratory or endoscopically proven CDI with clinical resolution as primary outcome were included. A sample size of 10 or more patients was a further criterion. Elements of the Centre for Reviews and Dissemination checklist and the National Institute of Clinical Excellence quality assessment for case series checklist were employed to determine study quality. Eligibility assessment and data extraction were performed by two independent researchers. Both unweighted pooled resolution rates (UPR) and weighted pooled resolution rates (WPR) were calculated with corresponding 95% confidence intervals (CI) for overall studies, as well as predefined subgroups. Eleven studies with a total of 273 CDI patients treated with FMT were identified; no RCTs were found as none have been published. Two-hundred and forty-five out of 273 patients experienced clinical resolution (UPR 89.7%; WPR 89.1% (95% CI 84 to 93%)). There was no statistically significant heterogeneity between studies (Cochran Q test P=0.13, I(2)=33.7%). A priori subgroup analysis suggested that lower gastrointestinal FMT delivery (UPR 91.4%; WPR 91.2% (95% CI 86 to 95%)) led to a trend towards higher clinical resolution rates than the upper gastrointestinal route (UPR 82.3%; WPR 80.6% (95% CI 69-90%)) (proportion difference of WPR was 10.6% (95% CI -0.6 to 22%)). No difference in clinical outcomes was detected between anonymous vs. patient selected donors. There were no reported adverse events associated with FMT and follow-up was variable from weeks to years. FMT holds considerable promise as a therapy for recurrent CDI but well-designed, RCTs and long-term follow-up registries are still required. These are needed to identify the right patient, efficacy and safety profile of FMT before this approach can be widely advocated.