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Pediatric Research Apr 2024We have identified a decreased abundance of microbial species known to have a potential anti-inflammatory, protective effect in subjects that developed Celiac Disease...
BACKGROUND AND AIMS
We have identified a decreased abundance of microbial species known to have a potential anti-inflammatory, protective effect in subjects that developed Celiac Disease (CeD) compared to those who did not. We aim to confirm the potential protective role of one of these species, namely Bacteroides vulgatus, and to mechanistically establish the effect of bacterial bioproducts on gluten-dependent changes on human gut epithelial functions.
METHODS
We identified, isolated, cultivated, and sequenced a unique novel strain (20220303-A2) of B. vulgatus found only in control subjects. Using a human gut organoid system developed from pre-celiac patients, we monitored epithelial phenotype and innate immune cytokines at baseline, after exposure to gliadin, or gliadin plus B. vulgatus cell free supernatant (CFS).
RESULTS
Following gliadin exposure, we observed increases in epithelial cell death, epithelial monolayer permeability, and secretion of pro-inflammatory cytokines. These effects were mitigated upon exposure to B. vulgatus 20220303-A2 CFS, which had matched phenotype gene product mutations. These protective effects were mediated by epigenetic reprogramming of the organoids treated with B. vulgatus CFS.
CONCLUSIONS
We identified a unique strain of B. vulgatus that may exert a beneficial role by protecting CeD epithelium against a gluten-induced break of epithelial tolerance through miRNA reprogramming.
IMPACT
Gut dysbiosis precedes the onset of celiac disease in genetically at-risk infants. This dysbiosis is characterized by the loss of protective bacterial strains in those children who will go on to develop celiac disease. The paper reports the mechanism by which one of these protective strains, B. vulgatus, ameliorates the gluten-induced break of gut epithelial homeostasis by epigenetically re-programming the target intestinal epithelium involving pathways controlling permeability, immune response, and cell turnover.
PubMed: 38177249
DOI: 10.1038/s41390-023-02960-0 -
Gastroenterology Jan 2024The 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... (Review)
Review
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.
Topics: Humans; Inflammatory Bowel Diseases; Colitis, Ulcerative; Crohn Disease; Intestines; Feces
PubMed: 37734419
DOI: 10.1053/j.gastro.2023.09.019 -
ACS Central Science Sep 2020The gut microbiota guide the development of the host immune system by setting a systemic threshold for immune activation. Lipopolysaccharides (LPSs) from gut bacteria...
The gut microbiota guide the development of the host immune system by setting a systemic threshold for immune activation. Lipopolysaccharides (LPSs) from gut bacteria are able to trigger systemic and local proinflammatory and immunomodulatory responses, and this capability strongly relies on their fine structures. Up to now, only a few LPS structures from gut commensals have been elucidated; therefore, the molecular motifs that may be important for LPS-mammalian cell interactions at the gut level are still obscure. Here, we report on the full structure of the LPS isolated from one of the prominent species of the genus , . The LPS turned out to consist of a particular chemical structure based on hypoacylated and -phosphorylated lipid A and with a galactofuranose-containing core oligosaccharide and an O-antigen built up of mannose and rhamnose. The evaluation of the immunological properties of this LPS on human models revealed a very interesting capability to produce anti-inflammatory cytokines and to induce a synergistic action of MD-2/TLR4- and TLR2-mediated signaling pathways.
PubMed: 32999936
DOI: 10.1021/acscentsci.0c00791 -
Journal of Immunology Research 2021Although the strain-dependent effects of on alleviating intestinal inflammatory diseases have been demonstrated, the literature has rarely focused on the underlying...
Although the strain-dependent effects of on alleviating intestinal inflammatory diseases have been demonstrated, the literature has rarely focused on the underlying causes of this effect. In this study, we selected four strains (FTJS5K1, FTJS7K1, FSDTA11B14, and FSDLZ51K1) with different genomic characteristics and evaluated their protective roles against dextran sulfate sodium- (DSS-) induced colitis. Compared to the other three tested strains, 7K1 more strongly ameliorated the DSS-induced weight loss, shortening of the colon length, increased disease activity index scores, colonic tissue injury, and immunomodulatory disorder. In contrast, 51K1 significantly worsened the DSS-induced alterations in the tumor necrosis factor-alpha (TNF-) concentration and colonic histopathology. A comparative genomic analysis of 7K1 and 51K1 showed that the beneficial effects of 7K1 may be associated with some of its specific genes involved in the production of short-chain fatty acids or capsular polysaccharides and enhancement of its survivability in the gut. In conclusion, these findings indicate that the supplementation of 7K1 is a potentially efficacious intervention for alleviating colitis and provides scientific support for the screening of probiotics with anticolitis effect.
Topics: Animals; Bacteroides; Colitis; Colon; Dextran Sulfate; Disease Models, Animal; Fatty Acids; Humans; Inflammatory Bowel Diseases; Male; Mice; Mice, Inbred C57BL; Polysaccharides; Species Specificity; Tumor Necrosis Factor-alpha
PubMed: 34195297
DOI: 10.1155/2021/9117805 -
Microbiome Aug 2022Crohn's disease (CD), an inflammatory bowel disease (IBD) subtype, results from pathologic interactions between host cells and its resident gut microbes. CD manifests in...
BACKGROUND
Crohn's disease (CD), an inflammatory bowel disease (IBD) subtype, results from pathologic interactions between host cells and its resident gut microbes. CD manifests in both isolated disease locations (ileum or colon) or a combination of locations (ileocolonic). To date, a comprehensive understanding of how isolated CD subtypes influence molecular profiles remains outstanding. To address this, we sought to define CD location signatures by leveraging a large cross-sectional feature set captured from the stool of over 200 IBD patients and healthy controls using metaproteomics, shotgun metagenomics, 16S rRNA sequencing, metabolomic profiling, and host genetics paired with clinical endoscopic assessments.
RESULTS
Neither metagenomic nor host genetics alone distinguished CD location subtypes. In contrast, ileal and colonic CD were distinguished using mass spectrometry-based methods (metabolomics or metaproteomics) or a combined multi-omic feature set. This multi-omic feature set revealed colonic CD was strongly associated with neutrophil-related proteins. Additionally, colonic CD displayed a disease-severity-related association with Bacteroides vulgatus. Colonic CD and ulcerative colitis profiles harbored strikingly similar feature enrichments compared to ileal CD, including neutrophil-related protein enrichments. Compared to colonic CD, ileal CD profiles displayed increased primary and secondary bile acid levels and concomitant shifts in taxa with noted sensitivities such as Faecalibacterium prausnitzii or affinities for bile acid-rich environments, including Gammaproteobacteria and Blautia sp. Having shown robust molecular and microbial distinctions tied to CD locations, we leveraged these profiles to generate location-specific disease severity biomarkers that surpass the performance of Calprotectin.
CONCLUSIONS
When compared using multi-omics features, colonic- and ileal-isolated CD subtypes display striking differences that suggest separate location-specific pathologies. Colonic CD's strong similarity to ulcerative colitis, including neutrophil and Bacteroides vulgatus involvement, is also evidence of a shared pathology for colonic-isolated IBD subtypes, while ileal CD maintains a unique, bile acid-driven profile. More broadly, this study demonstrates the power of multi-omics approaches for IBD biomarker discovery and elucidating the underlying biology. Video Abstract.
Topics: Bile Acids and Salts; Crohn Disease; Cross-Sectional Studies; Feces; Humans; Metagenomics; RNA, Ribosomal, 16S
PubMed: 35999575
DOI: 10.1186/s40168-022-01331-x -
International Journal of Molecular... Feb 2021Human oral and gut microbiomes are crucial for maintenance of homeostasis in the human body. , the key etiologic agent of chronic periodontitis, can cause dysbiosis in...
Human oral and gut microbiomes are crucial for maintenance of homeostasis in the human body. , the key etiologic agent of chronic periodontitis, can cause dysbiosis in the mouth and gut, which results in local and systemic infectious inflammatory diseases. Our previous work resulted in extensive biochemical and functional characterization of one of the major heme acquisition systems (Hmu), with the leading role played by the HmuY hemophore-like protein. We continued our studies on the homologous heme acquisition protein (Bvu) expressed by the dominant species of the gut microbiome. Results from spectrophotometric experiments showed that Bvu binds heme preferentially under reducing conditions using Met145 and Met172 as heme iron-coordinating ligands. Bvu captures heme bound to human serum albumin and only under reducing conditions. Importantly, HmuY is able to sequester heme complexed to Bvu. This is the first study demonstrating that expresses a heme-binding hemophore-like protein, thus increasing the number of members of a novel HmuY-like family. Data gained in this study confirm the importance of HmuY in the context of survival in regard to its ability to cause dysbiosis also in the gut microbiome.
Topics: Bacterial Proteins; Bacteroides; Heme; Humans; Porphyromonas gingivalis; Protein Binding
PubMed: 33668119
DOI: 10.3390/ijms22052237 -
IScience Nov 2021The gut microbiome has emerged as a key regulator of obesity; however, its role in brown adipose tissue (BAT) metabolism and association with obesity remain to be...
The gut microbiome has emerged as a key regulator of obesity; however, its role in brown adipose tissue (BAT) metabolism and association with obesity remain to be elucidated. We found that the levels of circulating branched-chain amino acids (BCAA) and their cognate α-ketoacids (BCKA) were significantly correlated with the body weight in humans and mice and that BCAA catabolic defects in BAT were associated with obesity in diet-induced obesity (DIO) mice. Pharmacological systemic enhancement of BCAA catabolic activity reduced plasma BCAA and BCKA levels and protected against obesity; these effects were reduced in BATectomized mice. DIO mice gavaged with and exhibited improved BAT BCAA catabolism and attenuated body weight gain, which were not observed in BATectomized DIO mice. Our data have highlighted a possible link between the gut microbiota and BAT BCAA catabolism and suggest that probiotics could be used for treating obesity.
PubMed: 34805797
DOI: 10.1016/j.isci.2021.103342 -
Genome Biology and Evolution Apr 2016Like many other Bacteroides species, Bacteroides vulgatus strain mpk, a mouse fecal isolate which was shown to promote intestinal homeostasis, utilizes a variety of...
Like many other Bacteroides species, Bacteroides vulgatus strain mpk, a mouse fecal isolate which was shown to promote intestinal homeostasis, utilizes a variety of mobile elements for genome evolution. Based on sequences collected by Pacific Biosciences SMRT sequencing technology, we discuss the challenges of assembling and studying a bacterial genome of high plasticity. Additionally, we conducted comparative genomics comparing this commensal strain with the B. vulgatus type strain ATCC 8482 as well as multiple other Bacteroides and Parabacteroides strains to reveal the most important differences and identify the unique features of B. vulgatus mpk. The genome of B. vulgatus mpk harbors a large and diverse set of mobile element proteins compared with other sequenced Bacteroides strains. We found evidence of a number of different horizontal gene transfer events and a genome landscape that has been extensively altered by different mobilization events. A CRISPR/Cas system could be identified that provides a possible mechanism for preventing the integration of invading external DNA. We propose that the high genome plasticity and the introduced genome instabilities of B. vulgatus mpk arising from the various mobilization events might play an important role not only in its adaptation to the challenging intestinal environment in general, but also in its ability to interact with the gut microbiota.
Topics: Animals; Bacteroides; Base Sequence; CRISPR-Cas Systems; DNA, Bacterial; Evolution, Molecular; Gene Transfer, Horizontal; Genome, Bacterial; Intestines; Mice; Phylogeny
PubMed: 27071651
DOI: 10.1093/gbe/evw070 -
Gut Microbes 2023Accumulating evidence suggests that the bile acid regulates type 2 diabetes mellitus (T2DM) through gut microbiota-host interactions. However, the mechanisms underlying...
Accumulating evidence suggests that the bile acid regulates type 2 diabetes mellitus (T2DM) through gut microbiota-host interactions. However, the mechanisms underlying such interactions have been unclear. Here, we found that glycoursodeoxycholic acid (GUDCA) positively regulates gut microbiota by altering bile acid metabolism. GUDCA in mice resulted in higher taurolithocholic acid (TLCA) level and abundance. Together, these changes resulted in the activation of the adipose G-protein-coupled bile acid receptor, GPBAR1 (TGR5) and upregulated expression of uncoupling protein UCP-1, resulting in elevation of white adipose tissue thermogenesis. The anti-T2DM effects of GUDCA are linked with the regulation of the bile acid and gut microbiota composition. This study suggests that altering bile acid metabolism, modifying the gut microbiota may be of value for the treatment of T2DM.
Topics: Mice; Animals; Bile Acids and Salts; Gastrointestinal Microbiome; Diabetes Mellitus, Type 2; Receptors, G-Protein-Coupled; Glycolipids
PubMed: 36967529
DOI: 10.1080/19490976.2023.2192155 -
Nature Communications Oct 2021Understanding the functional potential of the gut microbiome is of primary importance for the design of innovative strategies for allergy treatment and prevention. Here... (Clinical Trial)
Clinical Trial
Understanding the functional potential of the gut microbiome is of primary importance for the design of innovative strategies for allergy treatment and prevention. Here we report the gut microbiome features of 90 children affected by food (FA) or respiratory (RA) allergies and 30 age-matched, healthy controls (CT). We identify specific microbial signatures in the gut microbiome of allergic children, such as higher abundance of Ruminococcus gnavus and Faecalibacterium prausnitzii, and a depletion of Bifidobacterium longum, Bacteroides dorei, B. vulgatus and fiber-degrading taxa. The metagenome of allergic children shows a pro-inflammatory potential, with an enrichment of genes involved in the production of bacterial lipo-polysaccharides and urease. We demonstrate that specific gut microbiome signatures at baseline can be predictable of immune tolerance acquisition. Finally, a strain-level selection occurring in the gut microbiome of allergic subjects is identified. R. gnavus strains enriched in FA and RA showed lower ability to degrade fiber, and genes involved in the production of a pro-inflammatory polysaccharide. We demonstrate that a gut microbiome dysbiosis occurs in allergic children, with R. gnavus emerging as a main player in pediatric allergy. These findings may open new strategies in the development of innovative preventive and therapeutic approaches. Trial: NCT04750980.
Topics: Allergens; Animals; Bacteroides; Bifidobacterium longum; Case-Control Studies; Child; Child, Preschool; Clostridiales; Dander; Eggs; Faecalibacterium prausnitzii; Female; Food Hypersensitivity; Gastrointestinal Microbiome; Humans; Immune Tolerance; Lipopolysaccharides; Male; Milk; Nuts; Pollen; Prunus persica; Pyroglyphidae; Respiratory Hypersensitivity; Urease
PubMed: 34645820
DOI: 10.1038/s41467-021-26266-z