The Human Gut Microbiome: From Association to Modulation
TL;DR: The type of studies that will be essential for translating microbiome research into targeted modulations with dedicated benefits for the human host are discussed.
About: This article is published in Cell.The article was published on 2018-03-08 and is currently open access. It has received 508 citations till now. The article focuses on the topics: Microbiome.
Citations
More filters
TL;DR: The role of gut microbial metabolites derived from carbohydrate fermentation and protein fermentation in body weight control, nonalcoholic fatty liver disease, insulin resistance and type 2 diabetes mellitus is explored and the mechanisms involved are discussed.
Abstract: Evidence is accumulating that the gut microbiome is involved in the aetiology of obesity and obesity-related complications such as nonalcoholic fatty liver disease (NAFLD), insulin resistance and type 2 diabetes mellitus (T2DM). The gut microbiota is able to ferment indigestible carbohydrates (for example, dietary fibre), thereby yielding important metabolites such as short-chain fatty acids and succinate. Numerous animal studies and a handful of human studies suggest a beneficial role of these metabolites in the prevention and treatment of obesity and its comorbidities. Interestingly, the more distal colonic microbiota primarily ferments peptides and proteins, as availability of fermentable fibre, the major energy source for the microbiota, is limited here. This proteolytic fermentation yields mainly harmful products such as ammonia, phenols and branched-chain fatty acids, which might be detrimental for host gut and metabolic health. Therefore, a switch from proteolytic to saccharolytic fermentation could be of major interest for the prevention and/or treatment of metabolic diseases. This Review focuses on the role of products derived from microbial carbohydrate and protein fermentation in relation to obesity and obesity-associated insulin resistance, T2DM and NAFLD, and discusses the mechanisms involved.
683 citations
TL;DR: Interventions, including changes to lifestyle and medical innovations, are needed to prevent disease and increase late-life health in humans.
Abstract: Longer human lives have led to a global burden of late-life disease However, some older people experience little ill health, a trait that should be extended to the general population Interventions into lifestyle, including increased exercise and reduction in food intake and obesity, can help to maintain healthspan Altered gut microbiota, removal of senescent cells, blood factors obtained from young individuals and drugs can all improve late-life health in animals Application to humans will require better biomarkers of disease risk and responses to interventions, closer alignment of work in animals and humans, and increased use of electronic health records, biobank resources and cohort studies
630 citations
Lund University1, University of Copenhagen2, Molecular Medicine Partnership Unit3, ETH Zurich4, Fudan University5, German Cancer Research Center6, University of Trento7, University of São Paulo8, European Institute of Oncology9, Tokyo Institute of Technology10, Japan Society for the Promotion of Science11, University of Tokyo12, Osaka University13, National Presto Industries14, City University of New York15, National Institutes of Health16, Huntsman Cancer Institute17, University of Southern Denmark18
TL;DR: A meta-analysis of eight geographically and technically diverse fecal shotgun metagenomic studies of colorectal cancer identified a core set of 29 species significantly enriched in CRC metagenomes, establishing globally generalizable, predictive taxonomic and functional microbiome CRC signatures as a basis for future diagnostics.
Abstract: Association studies have linked microbiome alterations with many human diseases. However, they have not always reported consistent results, thereby necessitating cross-study comparisons. Here, a meta-analysis of eight geographically and technically diverse fecal shotgun metagenomic studies of colorectal cancer (CRC, n = 768), which was controlled for several confounders, identified a core set of 29 species significantly enriched in CRC metagenomes (false discovery rate (FDR) < 1 × 10−5). CRC signatures derived from single studies maintained their accuracy in other studies. By training on multiple studies, we improved detection accuracy and disease specificity for CRC. Functional analysis of CRC metagenomes revealed enriched protein and mucin catabolism genes and depleted carbohydrate degradation genes. Moreover, we inferred elevated production of secondary bile acids from CRC metagenomes, suggesting a metabolic link between cancer-associated gut microbes and a fat- and meat-rich diet. Through extensive validations, this meta-analysis firmly establishes globally generalizable, predictive taxonomic and functional microbiome CRC signatures as a basis for future diagnostics. Cross-study analysis defines fecal microbial species associated with colorectal cancer.
615 citations
University of Trento1, University of São Paulo2, European Institute of Oncology3, University of Turin4, Japan Society for the Promotion of Science5, Tokyo Institute of Technology6, University of Tokyo7, Osaka University8, National Presto Industries9, German Cancer Research Center10, Huntsman Cancer Institute11, University of Southern Denmark12, University of Copenhagen13, Virginia Bioinformatics Institute14, City University of New York15
TL;DR: The combined analysis of heterogeneous CRC cohorts identified reproducible microbiome biomarkers and accurate disease-predictive models that can form the basis for clinical prognostic tests and hypothesis-driven mechanistic studies.
Abstract: Several studies have investigated links between the gut microbiome and colorectal cancer (CRC), but questions remain about the replicability of biomarkers across cohorts and populations. We performed a meta-analysis of five publicly available datasets and two new cohorts and validated the findings on two additional cohorts, considering in total 969 fecal metagenomes. Unlike microbiome shifts associated with gastrointestinal syndromes, the gut microbiome in CRC showed reproducibly higher richness than controls (P < 0.01), partially due to expansions of species typically derived from the oral cavity. Meta-analysis of the microbiome functional potential identified gluconeogenesis and the putrefaction and fermentation pathways as being associated with CRC, whereas the stachyose and starch degradation pathways were associated with controls. Predictive microbiome signatures for CRC trained on multiple datasets showed consistently high accuracy in datasets not considered for model training and independent validation cohorts (average area under the curve, 0.84). Pooled analysis of raw metagenomes showed that the choline trimethylamine-lyase gene was overabundant in CRC (P = 0.001), identifying a relationship between microbiome choline metabolism and CRC. The combined analysis of heterogeneous CRC cohorts thus identified reproducible microbiome biomarkers and accurate disease-predictive models that can form the basis for clinical prognostic tests and hypothesis-driven mechanistic studies. Multicohort analysis identifies microbial signatures of colorectal cancer in fecal microbiomes.
478 citations
TL;DR: Overall, further research on long-term diets that include health and microbiome measures is required before clinical recommendations can be made for dietary modulation of the gut microbiota for health.
Abstract: The human gut is inhabited by trillions of microorganisms composing a dynamic ecosystem implicated in health and disease. The composition of the gut microbiota is unique to each individual and tends to remain relatively stable throughout life, yet daily transient fluctuations are observed. Diet is a key modifiable factor influencing the composition of the gut microbiota, indicating the potential for therapeutic dietary strategies to manipulate microbial diversity, composition, and stability. While diet can induce a shift in the gut microbiota, these changes appear to be temporary. Whether prolonged dietary changes can induce permanent alterations in the gut microbiota is unknown, mainly due to a lack of long-term human dietary interventions, or long-term follow-ups of short-term dietary interventions. It is possible that habitual diets have a greater influence on the gut microbiota than acute dietary strategies. This review presents the current knowledge around the response of the gut microbiota to short-term and long-term dietary interventions and identifies major factors that contribute to microbiota response to diet. Overall, further research on long-term diets that include health and microbiome measures is required before clinical recommendations can be made for dietary modulation of the gut microbiota for health.
358 citations
Cites background from "The Human Gut Microbiome: From Asso..."
...Inter-individual differences in enterotype composition are increasingly thought to explain the variation in response to a dietary intervention or perturbation [86]....
[...]
...It is these core gut microbial groups that are thought to be resilient to perturbations and which have been associated with a number of microbiome-disease associations along with differential metabolic responses to medication [86]....
[...]
References
More filters
TL;DR: The Illumina-based metagenomic sequencing, assembly and characterization of 3.3 million non-redundant microbial genes, derived from 576.7 gigabases of sequence, from faecal samples of 124 European individuals are described, indicating that the entire cohort harbours between 1,000 and 1,150 prevalent bacterial species and each individual at least 160 such species.
Abstract: To understand the impact of gut microbes on human health and well-being it is crucial to assess their genetic potential. Here we describe the Illumina-based metagenomic sequencing, assembly and characterization of 3.3 million non-redundant microbial genes, derived from 576.7 gigabases of sequence, from faecal samples of 124 European individuals. The gene set, ~150 times larger than the human gene complement, contains an overwhelming majority of the prevalent (more frequent) microbial genes of the cohort and probably includes a large proportion of the prevalent human intestinal microbial genes. The genes are largely shared among individuals of the cohort. Over 99% of the genes are bacterial, indicating that the entire cohort harbours between 1,000 and 1,150 prevalent bacterial species and each individual at least 160 such species, which are also largely shared. We define and describe the minimal gut metagenome and the minimal gut bacterial genome in terms of functions present in all individuals and most bacteria, respectively
9,268 citations
TL;DR: The Human Microbiome Project Consortium reported the first results of their analysis of microbial communities from distinct, clinically relevant body habitats in a human cohort; the insights into the microbial communities of a healthy population lay foundations for future exploration of the epidemiology, ecology and translational applications of the human microbiome as discussed by the authors.
Abstract: The Human Microbiome Project Consortium reports the first results of their analysis of microbial communities from distinct, clinically relevant body habitats in a human cohort; the insights into the microbial communities of a healthy population lay foundations for future exploration of the epidemiology, ecology and translational applications of the human microbiome.
8,410 citations
TL;DR: A majority of the bacterial sequences corresponded to uncultivated species and novel microorganisms, and significant intersubject variability and differences between stool and mucosa community composition were discovered.
Abstract: The human endogenous intestinal microflora is an essential “organ” in providing nourishment, regulating epithelial development, and instructing innate immunity; yet, surprisingly, basic features remain poorly described. We examined 13,355 prokaryotic ribosomal RNA gene sequences from multiple colonic mucosal sites and feces of healthy subjects to improve our understanding of gut microbial diversity. A majority of the bacterial sequences corresponded to uncultivated species and novel microorganisms. We discovered significant intersubject variability and differences between stool and mucosa community composition. Characterization of this immensely diverse ecosystem is the first step in elucidating its role in health and disease.
7,049 citations
"The Human Gut Microbiome: From Asso..." refers background in this paper
...This illustrates the dynamics of the field: just over a decade ago, early human fecal metagenomes contained mostly unclassifiable reads (Eckburg et al., 2005), and even in 2013, only around half the reads in a gut metagenome mapped to reference genomes (Sunagawa et al....
[...]
...This illustrates the dynamics of the field: just over a decade ago, early human fecal metagenomes contained mostly unclassifiable reads (Eckburg et al., 2005), and even in 2013, only around half the reads in a gut metagenome mapped to reference genomes (Sunagawa et al., 2013)....
[...]
TL;DR: Increases in the abundance and activity of Bilophila wadsworthia on the animal-based diet support a link between dietary fat, bile acids and the outgrowth of microorganisms capable of triggering inflammatory bowel disease.
Abstract: Long-term dietary intake influences the structure and activity of the trillions of microorganisms residing in the human gut, but it remains unclear how rapidly and reproducibly the human gut microbiome responds to short-term macronutrient change. Here we show that the short-term consumption of diets composed entirely of animal or plant products alters microbial community structure and overwhelms inter-individual differences in microbial gene expression. The animal-based diet increased the abundance of bile-tolerant microorganisms (Alistipes, Bilophila and Bacteroides) and decreased the levels of Firmicutes that metabolize dietary plant polysaccharides (Roseburia, Eubacterium rectale and Ruminococcus bromii). Microbial activity mirrored differences between herbivorous and carnivorous mammals, reflecting trade-offs between carbohydrate and protein fermentation. Foodborne microbes from both diets transiently colonized the gut, including bacteria, fungi and even viruses. Finally, increases in the abundance and activity of Bilophila wadsworthia on the animal-based diet support a link between dietary fat, bile acids and the outgrowth of microorganisms capable of triggering inflammatory bowel disease. In concert, these results demonstrate that the gut microbiome can rapidly respond to altered diet, potentially facilitating the diversity of human dietary lifestyles.
7,032 citations
"The Human Gut Microbiome: From Asso..." refers background in this paper
...For example, radical switches to all-plant- or animal-based diets on the microbiome have a differential impact, and specific groups of taxa respond similarly across individuals (David et al., 2014)....
[...]
...These include microbiome signatures of broad nutritional categories, such as plant- and animal-based diets (David et al., 2014; Muegge et al., 2011), and longer-term dietary patterns (Smits et al., 2017; Wu et al., 2011)....
[...]
...These include microbiome signatures of broad nutritional categories, such as plant- and animal-based diets (David et al., 2014; Muegge et al., 2011), and longer-term dietary patterns (Smits et al....
[...]
TL;DR: The faecal microbial communities of adult female monozygotic and dizygotic twin pairs concordant for leanness or obesity, and their mothers are characterized to address how host genotype, environmental exposure and host adiposity influence the gut microbiome.
Abstract: The human distal gut harbours a vast ensemble of microbes (the microbiota) that provide important metabolic capabilities, including the ability to extract energy from otherwise indigestible dietary polysaccharides. Studies of a few unrelated, healthy adults have revealed substantial diversity in their gut communities, as measured by sequencing 16S rRNA genes, yet how this diversity relates to function and to the rest of the genes in the collective genomes of the microbiota (the gut microbiome) remains obscure. Studies of lean and obese mice suggest that the gut microbiota affects energy balance by influencing the efficiency of calorie harvest from the diet, and how this harvested energy is used and stored. Here we characterize the faecal microbial communities of adult female monozygotic and dizygotic twin pairs concordant for leanness or obesity, and their mothers, to address how host genotype, environmental exposure and host adiposity influence the gut microbiome. Analysis of 154 individuals yielded 9,920 near full-length and 1,937,461 partial bacterial 16S rRNA sequences, plus 2.14 gigabases from their microbiomes. The results reveal that the human gut microbiome is shared among family members, but that each person's gut microbial community varies in the specific bacterial lineages present, with a comparable degree of co-variation between adult monozygotic and dizygotic twin pairs. However, there was a wide array of shared microbial genes among sampled individuals, comprising an extensive, identifiable 'core microbiome' at the gene, rather than at the organismal lineage, level. Obesity is associated with phylum-level changes in the microbiota, reduced bacterial diversity and altered representation of bacterial genes and metabolic pathways. These results demonstrate that a diversity of organismal assemblages can nonetheless yield a core microbiome at a functional level, and that deviations from this core are associated with different physiological states (obese compared with lean).
6,970 citations
"The Human Gut Microbiome: From Asso..." refers background in this paper
...Microbiome associations to body mass index (BMI) and obesity have received considerable attention, with links reported to decreased taxonomic (Turnbaugh et al., 2009) and functional (Le Chatelier et al....
[...]
...Other disease states, in contrast, are associated with marked shifts in overall compositional features, such as reduced diversity or richness, as is, for example, the case for obesity (Le Chatelier et al., 2013; Turnbaugh et al., 2009) or inflammatory bowel disease (IBD) (Manichanh et al....
[...]
...Microbiome associations to body mass index (BMI) and obesity have received considerable attention, with links reported to decreased taxonomic (Turnbaugh et al., 2009) and functional (Le Chatelier et al., 2013) diversity....
[...]
...…in contrast, are associated with marked shifts in overall compositional features, such as reduced diversity or richness, as is, for example, the case for obesity (Le Chatelier et al., 2013; Turnbaugh et al., 2009) or inflammatory bowel disease (IBD) (Manichanh et al., 2006; Ott et al., 2004)....
[...]