Metaproteomics reveals associations between microbiome and intestinal extracellular vesicle proteins in pediatric inflammatory bowel disease.
Zhang Xu,Deeke Shelley A,Ning Zhibin,Starr Amanda E,Butcher James,Li Jennifer,Mayne Janice,Cheng Kai,Liao Bo,Li Leyuan,Singleton Ruth,Mack David,Stintzi Alain,Figeys Daniel
Nature communications
Alterations in gut microbiota have been implicated in the pathogenesis of inflammatory bowel disease (IBD), however factors that mediate the host-microbiota interactions remain largely unknown. Here we collected mucosal-luminal interface samples from a pediatric IBD inception cohort and characterized both the human and microbiota proteins using metaproteomics. We show that microbial proteins related to oxidative stress responses are upregulated in IBD cases compared to controls. In particular, we demonstrate that the expression of human proteins related to oxidative antimicrobial activities is increased in IBD cases and correlates with the alteration of microbial functions. Additionally, we reveal that many of these human proteins are present and show altered abundance in isolated free extracellular vesicles (EVs). Therefore, our study suggests that the alteration of intestinal EV proteomes is associated with the aberrant host-microbiota interactions in IBD.
10.1038/s41467-018-05357-4
Fecal Microbiota in Pediatric Inflammatory Bowel Disease and Its Relation to Inflammation.
Kolho Kaija-Leena,Korpela Katri,Jaakkola Tytti,Pichai Madharasi V A,Zoetendal Erwin G,Salonen Anne,de Vos Willem M
The American journal of gastroenterology
OBJECTIVES:Inflammatory bowel disease (IBD) is considered to result from interplay between host and intestinal microbiota. While IBD in adults has shown to be associated with marked changes in the intestinal microbiota, there are only a few studies in children, and particularly studies focusing on therapeutic responses are lacking. Hence, this prospective study addressed the intestinal microbiota in pediatric IBD especially related to the level of inflammation. METHODS:In total, 68 pediatric patients with IBD and 26 controls provided stool and blood samples in a tertiary care hospital and 32 received anti-tumor necrosis factor-α (anti-TNF-α). Blood inflammatory markers and fecal calprotectin levels were determined. The intestinal microbiota was characterized by phylogenetic microarray and qPCR analysis. RESULTS:The microbiota varied along a gradient of increasing intestinal inflammation (indicated by calprotectin levels), which was associated with reduced microbial richness, abundance of butyrate producers, and relative abundance of Gram-positive bacteria (especially Clostridium clusters IV and XIVa). A significant association between microbiota composition and inflammation was indicated by a set of bacterial groups predicting the calprotectin levels (area under curve (AUC) of 0.85). During the induction of anti-TNF-α, the microbial diversity and similarity to the microbiota of controls increased in the responder group by week 6, but not in the non-responders (P<0.01; response related to calprotectin levels). The abundance of six groups of bacteria including those related to Eubacterium rectale and Bifidobacterium spp. predicted the response to anti-TNF-α medication. CONCLUSIONS:Intestinal microbiota represents a potential biomarker for correlating the level of inflammation and therapeutic responses to be further validated.
10.1038/ajg.2015.149
Reduced mucosal antimicrobial activity in Crohn's disease of the colon.
Nuding Sabine,Fellermann Klaus,Wehkamp Jan,Stange Eduard F
Gut
OBJECTIVES:In order to maintain the mucosal barrier against luminal microorganisms the intestinal epithelial cells synthesise various broad-spectrum antimicrobial peptides including defensins and cathelicidins. Recent studies indicate that both may be deficient in Crohn's disease. To elucidate the possible functional consequences of this deficiency antimicrobial activity in colonic mucosa from patients with inflammatory bowel disease and healthy controls was investigated. METHODS:A flow cytometric assay was established to quantitate bacterial killing and test the antibacterial activity of cationic peptide extracts from colonic biopsies taken from patients with active or inactive ileocolonic or colonic Crohn's disease (n = 22), ulcerative colitis (n = 29) and controls (n = 13) against clinical isolates of Bacteroides vulgatus and Enterococcus faecalis or the reference strains Escherichia coli American Type Culture Collection (ATCC) 25922 and Staphylococcus aureus ATCC 25923. RESULTS:Compared with controls and ulcerative colitis there was a reduced antimicrobial effect in Crohn's disease extracts that was most evident against B. vulgatus. The antimicrobial effect against E. coli and E. faecalis was significantly lower in Crohn's disease compared with ulcerative colitis. Activity against S. aureus disclosed a similar pattern, but was less pronounced. The differences were independent of the inflammation status or concurrent steroid treatment. Bacteria incubated with biopsy extracts from ulcerative colitis patients frequently showed a characteristic change in cell size and granularity, compatible with more extensive membrane disintegration, compared with bacteria incubated with extracts from controls or Crohn's disease. CONCLUSION:Crohn's disease of the colon is characterized by a diminished functional antimicrobial activity that is consistent with the reported low antibacterial peptide expression.
10.1136/gut.2006.118646
A gene-targeted approach to investigate the intestinal butyrate-producing bacterial community.
Microbiome
BACKGROUND:Butyrate, which is produced by the human microbiome, is essential for a well-functioning colon. Bacteria that produce butyrate are phylogenetically diverse, which hinders their accurate detection based on conventional phylogenetic markers. As a result, reliable information on this important bacterial group is often lacking in microbiome research. RESULTS:In this study we describe a gene-targeted approach for 454 pyrotag sequencing and quantitative polymerase chain reaction for the final genes in the two primary bacterial butyrate synthesis pathways, butyryl-CoA:acetate CoA-transferase (but) and butyrate kinase (buk). We monitored the establishment and early succession of butyrate-producing communities in four patients with ulcerative colitis who underwent a colectomy with ileal pouch anal anastomosis and compared it with three control samples from healthy colons. All patients established an abundant butyrate-producing community (approximately 5% to 26% of the total community) in the pouch within the 2-month study, but patterns were distinctive among individuals. Only one patient harbored a community profile similar to the healthy controls, in which there was a predominance of but genes that are similar to reference genes from Acidaminococcus sp., Eubacterium sp., Faecalibacterium prausnitzii and Roseburia sp., and an almost complete absence of buk genes. Two patients were greatly enriched in buk genes similar to those of Clostridium butyricum and C. perfringens, whereas a fourth patient displayed abundant communities containing both genes. Most butyrate producers identified in previous studies were detected and the general patterns of taxa found were supported by 16S rRNA gene pyrotag analysis, but the gene-targeted approach provided more detail about the potential butyrate-producing members of the community. CONCLUSIONS:The presented approach provides quantitative and genotypic insights into butyrate-producing communities and facilitates a more specific functional characterization of the intestinal microbiome. Furthermore, our analysis refines but and buk reference annotations found in central databases.
10.1186/2049-2618-1-8
Ruminococcus gnavus: friend or foe for human health.
FEMS microbiology reviews
Ruminococcus gnavus was first identified in 1974 as a strict anaerobe in the gut of healthy individuals, and for several decades, its study has been limited to specific enzymes or bacteriocins. With the advent of metagenomics, R. gnavus has been associated both positively and negatively with an increasing number of intestinal and extraintestinal diseases from inflammatory bowel diseases to neurological disorders. This prompted renewed interest in understanding the adaptation mechanisms of R. gnavus to the gut, and the molecular mediators affecting its association with health and disease. From ca. 250 publications citing R. gnavus since 1990, 94% were published in the last 10 years. In this review, we describe the biological characterization of R. gnavus, its occurrence in the infant and adult gut microbiota and the factors influencing its colonization of the gastrointestinal tract; we also discuss the current state of our knowledge on its role in host health and disease. We highlight gaps in knowledge and discuss the hypothesis that differential health outcomes associated with R. gnavus in the gut are strain and niche specific.
10.1093/femsre/fuad014
Identification of shared and disease-specific host gene-microbiome associations across human diseases using multi-omic integration.
Nature microbiology
While gut microbiome and host gene regulation independently contribute to gastrointestinal disorders, it is unclear how the two may interact to influence host pathophysiology. Here we developed a machine learning-based framework to jointly analyse paired host transcriptomic (n = 208) and gut microbiome (n = 208) profiles from colonic mucosal samples of patients with colorectal cancer, inflammatory bowel disease and irritable bowel syndrome. We identified associations between gut microbes and host genes that depict shared as well as disease-specific patterns. We found that a common set of host genes and pathways implicated in gastrointestinal inflammation, gut barrier protection and energy metabolism are associated with disease-specific gut microbes. Additionally, we also found that mucosal gut microbes that have been implicated in all three diseases, such as Streptococcus, are associated with different host pathways in each disease, suggesting that similar microbes can affect host pathophysiology in a disease-specific manner through regulation of different host genes. Our framework can be applied to other diseases for the identification of host gene-microbiome associations that may influence disease outcomes.
10.1038/s41564-022-01121-z
Carcinogenic microbiota and its role in colorectal cancer development.
Seminars in cancer biology
Colorectal cancer (CRC) is one of the most common malignancies worldwide. The main risk factors for CRC are family history of colon or rectal cancer, familial polyposis syndrome or hereditary nonpolyposis, and chronic inflammatory bowel diseases (ulcerative colitis and Crohn's disease). Recent studies show that the gastrointestinal microbiota play a significant role in colorectal carcinogenesis. In this review we present the microorganisms, whose influence on the development of CRC has been proven: Bacteroides fragilis, Clostridioides and Clostridium spp., Enterococcus faecalis, Escherichia coli, Fusobacterium nucleatum, Helicobacter pylori, Peptostreptococcus anaerobius, Streptococcus bovis group, and sulfate-reducing bacteria. Moreover, the carcinogenic mechanisms of action mediated by the above bacteria are laid out.
10.1016/j.semcancer.2022.01.004
Bacillus coagulans in Combination with Chitooligosaccharides Regulates Gut Microbiota and Ameliorates the DSS-Induced Colitis in Mice.
Microbiology spectrum
Ulcerative colitis (UC) are chronic inflammatory disorders, which may be caused by intestinal barrier dysfunction, immune system disorders and intestinal microbiota dysbiosis. Synbiotic, the combination of probiotics and prebiotics, is thought to be a pragmatic approach in mitigating inflammation in UC. Bacillus coagulans has been recognized as a potential probiotic for treating intestinal diseases because of its favorable industrial and probiotic properties, including sporulation and lactic acid production. In this study, we evaluated the treatment effects of the FCYS01 spores with or without the chitooligosaccharides (COSs) on UC generated using dextran sulfate sodium (DSS) in mice. Supplementation of spores, prebiotic COSs or the synbiotic (the spores + COSs) had a significant positive effect on DSS-induced UC. The disease activity index and histological damage score were significantly reduced after these supplementations. Compared to DSS group, these supplementations also significantly modulated the cytokines IL-4, IL-6, IL-8, IL-10, and C-reactive protein (CRP) levels and significantly maintained expressions of tight junction proteins and mucin protein and promotes recovery of the intestinal barrier. In addition, these supplementations regulate the composition of gut microbiota and improve the production of short-chain fatty acids (SCFAs), through enrichment of SCFA-producing bacteria, such as and species. In summary, the synbiotic ameliorated the overall inflammatory status of the experimental UC model and showed a better treatment effect than or COSs did alone as revealed by the markers such as, colon length, IL-4 and Occludin levels. Probiotic and prebiotic are believed to be useful in alleviating the inflammatory, thereby resolving or preventing the severity of UC. Spore-forming bacteria Bacillus coagulans show advantages of stability and probiotic effects, being suggested as the important probiotics for UC treatment. Here, we demonstrate that administration of spores, chitooligosaccharides (COSs), or the synbiotic attenuates DSS-induced colitis and significantly correlates with altered gut immune responses. The treatment effect of the synbiotic is inferred to be relied on the enrichment of probiotic bacteria, such as and species, which are reported to be crucial important for gut health. Our findings facilitate the development of therapeutic and preventive strategies for UC using spore-forming lactic acid bacteria in combination with COSs.
10.1128/spectrum.00641-22
Engineered probiotic ameliorates ulcerative colitis by restoring gut microbiota and redox homeostasis.
Cell host & microbe
Probiotics are potential treatments for ulcerative colitis (UC), but their efficacy is frequently compromised by gastrointestinal conditions that limit adhesion and activity. Here, we use machine learning and bioinformatics to confirm that patients with UC have decreased prevalence of Lactobacillus genus and increased oxidative stress, which correlate with inflammation severity. Accordingly, we developed a probiotic-based therapeutic that synergistically restores intestinal redox and microbiota homeostasis. Lactobacillus casei (Lac) were induced to form a pericellular film, providing a polysaccharide network for spatially confined crystallization of ultrasmall but highly active selenium dots (Se-Lac). Upon oral administration, the selenium dot-embedded pericellular film efficiently enhanced gastric acid resistance and intestinal mucoadhesion of Lac cells. At the lesion site, the selenium dots scavenged reactive oxygen species, while Lac modulated the gut microbiota. In multiple mouse models and non-human primates, this therapeutic effectively relieved inflammation and reduced colonic damage, thus showing promise as a UC treatment.
10.1016/j.chom.2024.07.028
in Combination with Chito-oligosaccharides Modulate Inflammation and Gut Microbiota for Inflammatory Bowel Disease Treatment.
Journal of agricultural and food chemistry
Synbiotics, the combination of probiotics and prebiotics, are thought to be a pragmatic approach for the treatment of various diseases, including inflammatory bowel disease (IBD). The synergistic therapeutic effects of probiotics and prebiotics remain underexplored. , a short-chain fatty acid (SCFA) producer, has been recognized as a promising probiotic candidate that can offer health benefits. In this study, the treatment effects of synbiotics containing and chitooligosaccharides (COSs) on IBD were evaluated. The results indicated that the synbiotic supplement effectively relieved inflammation and restored intestinal barrier function. Additionally, the synbiotic supplement could contribute to the elimination of reactive oxygen species (ROS) and improve the production of SCFAs through the SCFAs-producer of . Furthermore, such the synbiotic could also regulate the composition of gut microbiota. These findings underscore the potential of and COSs as valuable living biotherapeutics for the treatment of intestinal-related diseases.
10.1021/acs.jafc.4c03486
Gut microbes from the phylogenetically diverse genus and their various contributions to gut health.
Gut microbes
Over the last two decades our understanding of the gut microbiota and its contribution to health and disease has been transformed. Among a new 'generation' of potentially beneficial microbes to have been recognized are members of the genus , who form a part of the core human gut microbiome. The genus consists of phylogenetically, and quite frequently phenotypically, diverse species, making a taxonomically unique and challenging genus. Several members of the genus produce butyrate, which plays a critical role in energy homeostasis, colonic motility, immunomodulation and suppression of inflammation in the gut. spp. also carry out bile acid and cholesterol transformations in the gut, thereby contributing to their homeostasis. Gut dysbiosis and a consequently modified representation of spp. in the gut, have been linked with various human disease states. This review provides an overview of species from a phylogenetic perspective, describes how they alter with diet and age and summarizes its association with the human gut and various health conditions.
10.1080/19490976.2020.1802866
Influence of gastrectomy for gastric cancer treatment on faecal microbiome and metabolome profiles.
Erawijantari Pande Putu,Mizutani Sayaka,Shiroma Hirotsugu,Shiba Satoshi,Nakajima Takeshi,Sakamoto Taku,Saito Yutaka,Fukuda Shinji,Yachida Shinichi,Yamada Takuji
Gut
OBJECTIVE:Recent evidence points to the gut microbiome's involvement in postoperative outcomes, including after gastrectomy. Here, we investigated the influence of gastrectomy for gastric cancer on the gut microbiome and metabolome, and how it related to postgastrectomy conditions. DESIGN:We performed shotgun metagenomics sequencing and capillary electrophoresis time-of-flight mass spectrometry-based metabolomics analyses on faecal samples collected from participants with a history of gastrectomy for gastric cancer (n=50) and compared them with control participants (n=56). RESULTS:The gut microbiota in the gastrectomy group showed higher species diversity and richness (p<0.05), together with greater abundance of aerobes, facultative anaerobes and oral microbes. Moreover, bile acids such as genotoxic deoxycholic acid and branched-chain amino acids were differentially abundant between the two groups (linear discriminant analysis (LDA) effect size (LEfSe): p<0.05, q<0.1, LDA>2.0), as were also Kyoto Encyclopedia of Genes and Genomes modules involved in nutrient transport and organic compounds biosynthesis (LEfSe: p<0.05, q<0.1, LDA>2.0). CONCLUSION:Our results reveal alterations of gut microbiota after gastrectomy, suggesting its association with postoperative comorbidities. The multi-omic approach applied in this study could complement the follow-up of patients after gastrectomy.
10.1136/gutjnl-2019-319188
Gut Microbiome Composition Is Associated With Future Onset of Crohn's Disease in Healthy First-Degree Relatives.
Gastroenterology
BACKGROUND & AIMS:The cause of Crohn's disease (CD) is unknown, but the current hypothesis is that microbial or environmental factors induce gut inflammation in genetically susceptible individuals, leading to chronic intestinal inflammation. Case-control studies of patients with CD have cataloged alterations in the gut microbiome composition; however, these studies fail to distinguish whether the altered gut microbiome composition is associated with initiation of CD or is the result of inflammation or drug treatment. METHODS:In this prospective cohort study, 3483 healthy first-degree relatives (FDRs) of patients with CD were recruited to identify the gut microbiome composition that precedes the onset of CD and to what extent this composition predicts the risk of developing CD. We applied a machine learning approach to the analysis of the gut microbiome composition (based on 16S ribosomal RNA sequencing) to define a microbial signature that associates with future development of CD. The performance of the model was assessed in an independent validation cohort. RESULTS:In the validation cohort, the microbiome risk score (MRS) model yielded a hazard ratio of 2.24 (95% confidence interval, 1.03-4.84; P = .04), using the median of the MRS from the discovery cohort as the threshold. The MRS demonstrated a temporal validity by capturing individuals that developed CD up to 5 years before disease onset (area under the curve > 0.65). The 5 most important taxa contributing to the MRS included Ruminococcus torques, Blautia, Colidextribacter, an uncultured genus-level group from Oscillospiraceae, and Roseburia. CONCLUSION:This study is the first to demonstrate that gut microbiome composition is associated with future onset of CD and suggests that gut microbiome is a contributor in the pathogenesis of CD.
10.1053/j.gastro.2023.05.032
Pathobionts in Inflammatory Bowel Disease: Origins, Underlying Mechanisms, and Implications for Clinical Care.
Gastroenterology
The gut microbiota plays a significant role in the pathogenesis of both forms of inflammatory bowel disease (IBD), namely, Crohn's disease (CD) and ulcerative colitis (UC). Although evidence suggests dysbiosis and loss of beneficial microbial species can exacerbate IBD, many new studies have identified microbes with pathogenic qualities, termed "pathobionts," within the intestines of patients with IBD. The concept of pathobionts initiating or driving the chronicity of IBD has largely focused on the putative aggravating role that adherent invasive Escherichia coli may play in CD. However, recent studies have identified additional bacterial and fungal pathobionts in patients with CD and UC. This review will highlight the characteristics of these pathobionts and their implications for IBD treatment. Beyond exploring the origins of pathobionts, we discuss those associated with specific clinical features and the potential mechanisms involved, such as creeping fat (Clostridium innocuum) and impaired wound healing (Debaryomyces hansenii) in patients with CD as well as the increased fecal proteolytic activity (Bacteroides vulgatus) seen as a biomarker for UC severity. Finally, we examine the potential impact of pathobionts on current IBD therapies, and several new approaches to target pathobionts currently in the early stages of development. Despite recognizing that pathobionts likely contribute to the pathogenesis of IBD, more work is needed to define their modes of action. Determining whether causal relationships exist between pathobionts and specific disease characteristics could pave the way for improved care for patients, particularly for those not responding to current IBD therapies.
10.1053/j.gastro.2023.09.019
Gut microbiota-derived metabolites as key actors in inflammatory bowel disease.
Lavelle Aonghus,Sokol Harry
Nature reviews. Gastroenterology & hepatology
A key role of the gut microbiota in the establishment and maintenance of health, as well as in the pathogenesis of disease, has been identified over the past two decades. One of the primary modes by which the gut microbiota interacts with the host is by means of metabolites, which are small molecules that are produced as intermediate or end products of microbial metabolism. These metabolites can derive from bacterial metabolism of dietary substrates, modification of host molecules, such as bile acids, or directly from bacteria. Signals from microbial metabolites influence immune maturation, immune homeostasis, host energy metabolism and maintenance of mucosal integrity. Alterations in the composition and function of the microbiota have been described in many studies on IBD. Alterations have also been described in the metabolite profiles of patients with IBD. Furthermore, specific classes of metabolites, notably bile acids, short-chain fatty acids and tryptophan metabolites, have been implicated in the pathogenesis of IBD. This Review aims to define the key classes of microbial-derived metabolites that are altered in IBD, describe the pathophysiological basis of these associations and identify future targets for precision therapeutic modulation.
10.1038/s41575-019-0258-z
Inflammatory Bowel Diseases (IBD) and the Microbiome-Searching the Crime Scene for Clues.
Gastroenterology
Inflammatory bowel diseases (IBD) develop via convergence of environmental, microbial, immunological, and genetic factors. Alterations in the gut microbiota have been associated with development and progression of IBD, but it is not clear which populations of microbes are involved or how they might contribute to IBD. We review the genetic and environmental factors affecting the gut microbiota, the roles of gut microbes and their bioproducts in the development and clinical course of IBD, and strategies by which microbiome-based therapies can be used to prevent, manage, and eventually cure IBD. We discuss research findings that help bridge the gap between the basic sciences and clinical application.
10.1053/j.gastro.2020.09.056
Enterococcus-derived tyramine hijacks α-adrenergic receptor in intestinal stem cells to exacerbate colitis.
Cell host & microbe
Inflammatory bowel disease (IBD) is characterized by dysbiosis of the gut microbiota and dysfunction of intestinal stem cells (ISCs). However, the direct interactions between IBD microbial factors and ISCs are undescribed. Here, we identify α-adrenergic receptor (ADRA2A) as a highly expressed GPCR in ISCs. Through PRESTO-Tango screening, we demonstrate that tyramine, primarily produced by Enterococcus via tyrosine decarboxylase (tyrDC), serves as a microbial ligand for ADRA2A. Using an engineered tyrDC-deficient Enterococcus faecalis strain and intestinal epithelial cell-specific Adra2a knockout mice, we show that Enterococcus-derived tyramine suppresses ISC proliferation, thereby impairing epithelial regeneration and exacerbating DSS-induced colitis through ADRA2A. Importantly, blocking the axis with an ADRA2A antagonist, yohimbine, disrupts tyramine-mediated suppression on ISCs and alleviates colitis. Our findings highlight a microbial ligand-GPCR pair in ISCs, revealing a causal link between microbial regulation of ISCs and colitis exacerbation and yielding a targeted therapeutic approach to restore ISC function in colitis.
10.1016/j.chom.2024.04.020
Reverse metabolomics for the discovery of chemical structures from humans.
Nature
Determining the structure and phenotypic context of molecules detected in untargeted metabolomics experiments remains challenging. Here we present reverse metabolomics as a discovery strategy, whereby tandem mass spectrometry spectra acquired from newly synthesized compounds are searched for in public metabolomics datasets to uncover phenotypic associations. To demonstrate the concept, we broadly synthesized and explored multiple classes of metabolites in humans, including N-acyl amides, fatty acid esters of hydroxy fatty acids, bile acid esters and conjugated bile acids. Using repository-scale analysis, we discovered that some conjugated bile acids are associated with inflammatory bowel disease (IBD). Validation using four distinct human IBD cohorts showed that cholic acids conjugated to Glu, Ile/Leu, Phe, Thr, Trp or Tyr are increased in Crohn's disease. Several of these compounds and related structures affected pathways associated with IBD, such as interferon-γ production in CD4 T cells and agonism of the pregnane X receptor. Culture of bacteria belonging to the Bifidobacterium, Clostridium and Enterococcus genera produced these bile amidates. Because searching repositories with tandem mass spectrometry spectra has only recently become possible, this reverse metabolomics approach can now be used as a general strategy to discover other molecules from human and animal ecosystems.
10.1038/s41586-023-06906-8