The current understanding of inflammatory bowel disease (IBD) pathogenesis implicates a complex interaction between host genetics, host immunity, microbiome, and environmental exposures. Mechanisms ...gleaned from genetics and molecular pathogenesis offer clues to the critical triggers of mucosal inflammation and guide the development of therapeutic interventions. A complex network of interactions between host genetic factors, microbes, and microbial metabolites governs intestinal homeostasis, making classification and mechanistic dissection of involved pathways challenging. In this Review, we discuss these challenges, areas of active translation, and opportunities for development of next-generation therapies.
Mechanistic and functional links between host-microbiome interplay and irritable bowel disease pathology are building, presenting exciting but challenging opportunities to manipulate the microbiome for therapeutic benefit.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Centenarians have a decreased susceptibility to ageing-associated illnesses, chronic inflammation and infectious diseases
. Here we show that centenarians have a distinct gut microbiome that is ...enriched in microorganisms that are capable of generating unique secondary bile acids, including various isoforms of lithocholic acid (LCA): iso-, 3-oxo-, allo-, 3-oxoallo- and isoallolithocholic acid. Among these bile acids, the biosynthetic pathway for isoalloLCA had not been described previously. By screening 68 bacterial isolates from the faecal microbiota of a centenarian, we identified Odoribacteraceae strains as effective producers of isoalloLCA both in vitro and in vivo. Furthermore, we found that the enzymes 5α-reductase (5AR) and 3β-hydroxysteroid dehydrogenase (3β-HSDH) were responsible for the production of isoalloLCA. IsoalloLCA exerted potent antimicrobial effects against Gram-positive (but not Gram-negative) multidrug-resistant pathogens, including Clostridioides difficile and Enterococcus faecium. These findings suggest that the metabolism of specific bile acids may be involved in reducing the risk of infection with pathobionts, thereby potentially contributing to the maintenance of intestinal homeostasis.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
The human microbiome encodes extensive metabolic capabilities, but our understanding of the mechanisms linking gut microbes to human metabolism remains limited. Here, we focus on the conversion of ...cholesterol to the poorly absorbed sterol coprostanol by the gut microbiota to develop a framework for the identification of functional enzymes and microbes. By integrating paired metagenomics and metabolomics data from existing cohorts with biochemical knowledge and experimentation, we predict and validate a group of microbial cholesterol dehydrogenases that contribute to coprostanol formation. These enzymes are encoded by ismA genes in a clade of uncultured microorganisms, which are prevalent in geographically diverse human cohorts. Individuals harboring coprostanol-forming microbes have significantly lower fecal cholesterol levels and lower serum total cholesterol with effects comparable to those attributed to variations in lipid homeostasis genes. Thus, cholesterol metabolism by these microbes may play important roles in reducing intestinal and serum cholesterol concentrations, directly impacting human health.
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•Bioinformatics enabled discovery of ismA, a microbial cholesterol dehydrogenase•Metagenomic species with ismA genes form coprostanol in microbial communities•ismA+ species are associated with decreased fecal and serum cholesterol in humans•Effect sizes of ismA+ species on serum cholesterol are on par with human genetics
The consequences of cholesterol metabolism by the gut microbiome were largely unknown. Kenny, Plichta et al. identified and characterized microbial cholesterol dehydrogenase enzymes encoded by uncultured metagenomic species of bacteria. The presence of these cholesterol-metabolizing bacteria is associated with decreased stool and serum total cholesterol in human cohorts.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Intestinal adaptive immune responses influence host health, yet only a few intestinal bacteria species that induce cognate adaptive immune responses during homeostasis have been identified. Here, we ...show that
, an intestinal bacterium associated with systemic effects on host metabolism and PD-1 checkpoint immunotherapy, induces immunoglobulin G1 (IgG1) antibodies and antigen-specific T cell responses in mice. Unlike previously characterized mucosal responses, T cell responses to
are limited to T follicular helper cells in a gnotobiotic setting, without appreciable induction of other T helper fates or migration to the lamina propria. However,
-specific responses are context dependent and adopt other fates in conventional mice. These findings suggest that, during homeostasis, contextual signals influence T cell responses to the microbiota and modulate host immune function.
There is a growing appreciation for the importance of the gut microbiota as a therapeutic target in various diseases. However, there are only a handful of known commensal strains that can potentially ...be used to manipulate host physiological functions. Here we isolate a consortium of 11 bacterial strains from healthy human donor faeces that is capable of robustly inducing interferon-γ-producing CD8 T cells in the intestine. These 11 strains act together to mediate the induction without causing inflammation in a manner that is dependent on CD103
dendritic cells and major histocompatibility (MHC) class Ia molecules. Colonization of mice with the 11-strain mixture enhances both host resistance against Listeria monocytogenes infection and the therapeutic efficacy of immune checkpoint inhibitors in syngeneic tumour models. The 11 strains primarily represent rare, low-abundance components of the human microbiome, and thus have great potential as broadly effective biotherapeutics.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
Despite the accelerating number of uncultivated virus sequences discovered in metagenomics and their apparent importance for health and disease, the human gut virome and its interactions with ...bacteria in the gastrointestinal tract are not well understood. This is partly due to a paucity of whole-virome datasets and limitations in current approaches for identifying viral sequences in metagenomics data. Here, combining a deep-learning based metagenomics binning algorithm with paired metagenome and metavirome datasets, we develop Phages from Metagenomics Binning (PHAMB), an approach that allows the binning of thousands of viral genomes directly from bulk metagenomics data, while simultaneously enabling clustering of viral genomes into accurate taxonomic viral populations. When applied on the Human Microbiome Project 2 (HMP2) dataset, PHAMB recovered 6,077 high-quality genomes from 1,024 viral populations, and identified viral-microbial host interactions. PHAMB can be advantageously applied to existing and future metagenomes to illuminate viral ecological dynamics with other microbiome constituents.
Phase variation, the reversible alternation between genetic states, enables infection by pathogens and colonization by commensals. However, the diversity of phase variation remains underexplored. We ...developed the PhaseFinder algorithm to quantify DNA inversion-mediated phase variation. A systematic search of 54,875 bacterial genomes identified 4686 intergenic invertible DNA regions (invertons), revealing an enrichment in host-associated bacteria. Invertons containing promoters often regulate extracellular products, underscoring the importance of surface diversity for gut colonization. We found invertons containing promoters regulating antibiotic resistance genes that shift to the ON orientation after antibiotic treatment in human metagenomic data and in vitro, thereby mitigating the cost of antibiotic resistance. We observed that the orientations of some invertons diverge after fecal microbiota transplant, potentially as a result of individual-specific selective forces.
Abstract
Increased levels of proteases, such as trypsin, in the distal intestine have been implicated in intestinal pathological conditions
1–3
. However, the players and mechanisms that underlie ...protease regulation in the intestinal lumen have remained unclear. Here we show that
Paraprevotella
strains isolated from the faecal microbiome of healthy human donors are potent trypsin-degrading commensals. Mechanistically,
Paraprevotella
recruit trypsin to the bacterial surface through type IX secretion system-dependent polysaccharide-anchoring proteins to promote trypsin autolysis.
Paraprevotella
colonization protects IgA from trypsin degradation and enhances the effectiveness of oral vaccines against
Citrobacter rodentium
. Moreover,
Paraprevotella
colonization inhibits lethal infection with murine hepatitis virus-2, a mouse coronavirus that is dependent on trypsin and trypsin-like proteases for entry into host cells
4,5
. Consistently, carriage of putative genes involved in trypsin degradation in the gut microbiome was associated with reduced severity of diarrhoea in patients with SARS-CoV-2 infection. Thus, trypsin-degrading commensal colonization may contribute to the maintenance of intestinal homeostasis and protection from pathogen infection.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
The perinatal period represents a critical window for cognitive and immune system development, promoted by maternal and infant gut microbiomes and their metabolites. Here, we tracked the ...co-development of microbiomes and metabolomes from late pregnancy to 1 year of age using longitudinal multi-omics data from a cohort of 70 mother-infant dyads. We discovered large-scale mother-to-infant interspecies transfer of mobile genetic elements, frequently involving genes associated with diet-related adaptations. Infant gut metabolomes were less diverse than maternal but featured hundreds of unique metabolites and microbe-metabolite associations not detected in mothers. Metabolomes and serum cytokine signatures of infants who received regular—but not extensively hydrolyzed—formula were distinct from those of exclusively breastfed infants. Taken together, our integrative analysis expands the concept of vertical transmission of the gut microbiome and provides original insights into the development of maternal and infant microbiomes and metabolomes during late pregnancy and early life.
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•Mobile genetic elements from maternal bacteria shape offspring gut microbiomes•Microbiome and metabolome shifts in pregnancy may impact maternal metabolic health•The infant gut harbors unique metabolites and species-metabolite relationships•Diet modulates metabolomic profiles and immune system maturation in infants
Maternal gut bacteria that fail to engraft in infants instead influence the assembly and metabolic potential of the infant gut microbiome through horizontal gene transfer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Little is known about how colonic transit time relates to human colonic metabolism and its importance for host health, although a firm stool consistency, a proxy for a long colonic transit time, has ...recently been positively associated with gut microbial richness. Here, we show that colonic transit time in humans, assessed using radio-opaque markers, is associated with overall gut microbial composition, diversity and metabolism. We find that a long colonic transit time associates with high microbial richness and is accompanied by a shift in colonic metabolism from carbohydrate fermentation to protein catabolism as reflected by higher urinary levels of potentially deleterious protein-derived metabolites. Additionally, shorter colonic transit time correlates with metabolites possibly reflecting increased renewal of the colonic mucosa. Together, this suggests that a high gut microbial richness does not per se imply a healthy gut microbial ecosystem and points at colonic transit time as a highly important factor to consider in microbiome and metabolomics studies.