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Nature Medicine Aug 2021Treatment with combined immune checkpoint blockade (CICB) targeting CTLA-4 and PD-1 is associated with clinical benefit across tumor types, but also a high rate of...
Treatment with combined immune checkpoint blockade (CICB) targeting CTLA-4 and PD-1 is associated with clinical benefit across tumor types, but also a high rate of immune-related adverse events. Insights into biomarkers and mechanisms of response and toxicity to CICB are needed. To address this, we profiled the blood, tumor and gut microbiome of 77 patients with advanced melanoma treated with CICB, with a high rate of any ≥grade 3 immune-related adverse events (49%) with parallel studies in pre-clinical models. Tumor-associated immune and genomic biomarkers of response to CICB were similar to those identified for ICB monotherapy, and toxicity from CICB was associated with a more diverse peripheral T-cell repertoire. Profiling of gut microbiota demonstrated a significantly higher abundance of Bacteroides intestinalis in patients with toxicity, with upregulation of mucosal IL-1β in patient samples of colitis and in pre-clinical models. Together, these data offer potential new therapeutic angles for targeting toxicity to CICB.
Topics: Animals; CTLA-4 Antigen; Cell Line, Tumor; Female; Gastrointestinal Microbiome; Humans; Interleukin-1beta; Melanoma; Mice; Mice, Inbred C57BL; Programmed Cell Death 1 Receptor
PubMed: 34239137
DOI: 10.1038/s41591-021-01406-6 -
Nature May 2023CrAssphage and related viruses of the order Crassvirales (hereafter referred to as crassviruses) were originally discovered by cross-assembly of metagenomic sequences....
CrAssphage and related viruses of the order Crassvirales (hereafter referred to as crassviruses) were originally discovered by cross-assembly of metagenomic sequences. They are the most abundant viruses in the human gut, are found in the majority of individual gut viromes, and account for up to 95% of the viral sequences in some individuals. Crassviruses are likely to have major roles in shaping the composition and functionality of the human microbiome, but the structures and roles of most of the virally encoded proteins are unknown, with only generic predictions resulting from bioinformatic analyses. Here we present a cryo-electron microscopy reconstruction of Bacteroides intestinalis virus ΦcrAss001, providing the structural basis for the functional assignment of most of its virion proteins. The muzzle protein forms an assembly about 1 MDa in size at the end of the tail and exhibits a previously unknown fold that we designate the 'crass fold', that is likely to serve as a gatekeeper that controls the ejection of cargos. In addition to packing the approximately 103 kb of virus DNA, the ΦcrAss001 virion has extensive storage space for virally encoded cargo proteins in the capsid and, unusually, within the tail. One of the cargo proteins is present in both the capsid and the tail, suggesting a general mechanism for protein ejection, which involves partial unfolding of proteins during their extrusion through the tail. These findings provide a structural basis for understanding the mechanisms of assembly and infection of these highly abundant crassviruses.
Topics: Humans; Capsid; Cryoelectron Microscopy; DNA Viruses; Virion; Virus Assembly; Intestines; Viral Proteins; Protein Unfolding; Protein Folding
PubMed: 37138077
DOI: 10.1038/s41586-023-06019-2 -
Cell Reports Nov 2023Interaction between the gut microbiome and host plays a key role in human health. Here, we perform a metagenome shotgun-sequencing-based analysis of Japanese...
Interaction between the gut microbiome and host plays a key role in human health. Here, we perform a metagenome shotgun-sequencing-based analysis of Japanese participants to reveal associations between the gut microbiome, host genetics, and plasma metabolome. A genome-wide association study (GWAS) for microbial species (n = 524) identifies associations between the PDE1C gene locus and Bacteroides intestinalis and between TGIF2 and TGIF2-RAB5IF gene loci and Bacteroides acidifiaciens. In a microbial gene ortholog GWAS, agaE and agaS, which are related to the metabolism of carbohydrates forming the blood group A antigen, are associated with blood group A in a manner depending on the secretor status determined by the East Asian-specific FUT2 variant. A microbiome-metabolome association analysis (n = 261) identifies associations between bile acids and microbial features such as bile acid metabolism gene orthologs including bai and 7β-hydroxysteroid dehydrogenase. Our publicly available data will be a useful resource for understanding gut microbiome-host interactions in an underrepresented population.
Topics: Humans; Gastrointestinal Microbiome; Genome-Wide Association Study; East Asian People; Metabolome; Blood Group Antigens; Repressor Proteins; Homeodomain Proteins
PubMed: 37935197
DOI: 10.1016/j.celrep.2023.113324 -
Nature Microbiology Apr 2022Processed foods often include food additives such as xanthan gum, a complex polysaccharide with unique rheological properties, that has established widespread use as a...
Processed foods often include food additives such as xanthan gum, a complex polysaccharide with unique rheological properties, that has established widespread use as a stabilizer and thickening agent. Xanthan gum's chemical structure is distinct from those of host and dietary polysaccharides that are more commonly expected to transit the gastrointestinal tract, and little is known about its direct interaction with the gut microbiota, which plays a central role in digestion of other dietary fibre polysaccharides. Here we show that the ability to digest xanthan gum is common in human gut microbiomes from industrialized countries and appears contingent on a single uncultured bacterium in the family Ruminococcaceae. Our data reveal that this primary degrader cleaves the xanthan gum backbone before processing the released oligosaccharides using additional enzymes. Some individuals harbour Bacteroides intestinalis that is incapable of consuming polymeric xanthan gum but grows on oligosaccharide products generated by the Ruminococcaceae. Feeding xanthan gum to germfree mice colonized with a human microbiota containing the uncultured Ruminococcaceae supports the idea that the additive xanthan gum can drive expansion of the primary degrader Ruminococcaceae, along with exogenously introduced B. intestinalis. Our work demonstrates the existence of a potential xanthan gum food chain involving at least two members of different phyla of gut bacteria and provides an initial framework for understanding how widespread consumption of a recently introduced food additive influences human microbiomes.
Topics: Animals; Dietary Fiber; Food Additives; Gastrointestinal Microbiome; Humans; Mice; Polysaccharides, Bacterial
PubMed: 35365790
DOI: 10.1038/s41564-022-01093-0 -
Scientific Reports Jan 2021CrAssphages are a diverse group of related phages detected in human feces where they are the most prevalent and abundant prokaryotic virus. CrAssphages' cellular host...
CrAssphages are a diverse group of related phages detected in human feces where they are the most prevalent and abundant prokaryotic virus. CrAssphages' cellular host has been identified as the anaerobic Bacteroides intestinalis. CrAssphage has also been reported in non-human primates and environmental samples and has been proposed as a marker of human fecal contamination. Here we describe crAssphage DNA in a feline fecal sample. 95% of the ~ 100 Kb genome could be assembled and classified in genus 1 of the recently proposed Alphacrassvirinae subfamily. The cat origin of the fecal sample was confirmed by partial mitochondrial DNA sequencing. High levels of Bacteroides intestinalis DNA could also be detected in this cat's feces. Fecal samples longitudinally collected over a 4-week period showed the continuous shedding of crAssphage DNA. We therefore report the first genome sequence-confirmed detection of crAssphage in fecal samples of a non-primate mammal.
Topics: Animals; Bacteriophages; Bacteroides; Cats; Environmental Monitoring; Feces; Humans; Phylogeny; Sequence Analysis, DNA; Sewage; Water Pollution
PubMed: 33436756
DOI: 10.1038/s41598-020-80076-9 -
Nature Communications Jan 2021Some Bacteroidetes and other human colonic bacteria can degrade arabinoxylans, common polysaccharides found in dietary fiber. Previous work has identified gene clusters...
Some Bacteroidetes and other human colonic bacteria can degrade arabinoxylans, common polysaccharides found in dietary fiber. Previous work has identified gene clusters (polysaccharide-utilization loci, PULs) for degradation of simple arabinoxylans. However, the degradation of complex arabinoxylans (containing side chains such as ferulic acid, a phenolic compound) is poorly understood. Here, we identify a PUL that encodes multiple esterases for degradation of complex arabinoxylans in Bacteroides species. The PUL is specifically upregulated in the presence of complex arabinoxylans. We characterize some of the esterases biochemically and structurally, and show that they release ferulic acid from complex arabinoxylans. Growth of four different colonic Bacteroidetes members, including Bacteroides intestinalis, on complex arabinoxylans results in accumulation of ferulic acid, a compound known to have antioxidative and immunomodulatory properties.
Topics: Bacterial Proteins; Bacteroides; Colon; Coumaric Acids; Crystallography, X-Ray; Dietary Fiber; Enzyme Assays; Esterases; Gastrointestinal Microbiome; Humans; Intestinal Mucosa; Molecular Dynamics Simulation; Multigene Family; Substrate Specificity; Xylans
PubMed: 33469030
DOI: 10.1038/s41467-020-20737-5 -
World Journal of Gastroenterology Apr 2023Celiac disease (CeD) is a multisystem immune-mediated multifactorial condition strongly associated with the intestinal microbiota.
BACKGROUND
Celiac disease (CeD) is a multisystem immune-mediated multifactorial condition strongly associated with the intestinal microbiota.
AIM
To evaluate the predictive power of the gut microbiota in the diagnosis of CeD and to search for important taxa that may help to distinguish CeD patients from controls.
METHODS
Microbial DNA from bacteria, viruses, and fungi, was isolated from mucosal and fecal samples of 40 children with CeD and 39 controls. All samples were sequenced using the HiSeq platform, the data were analyzed, and abundance and diversities were assessed. For this analysis, the predictive power of the microbiota was evaluated by calculating the area under the curve (AUC) using data for the entire microbiome. The Kruskal-Wallis test was used to evaluate the significance of the difference between AUCs. The Boruta logarithm, a wrapper built around the random forest classification algorithm, was used to identify important bacterial biomarkers for CeD.
RESULTS
In fecal samples, AUCs for bacterial, viral, and fungal microbiota were 52%, 58%, and 67.7% respectively, suggesting weak performance in predicting CeD. However, the combination of fecal bacteria and viruses showed a higher AUC of 81.8 %, indicating stronger predictive power in the diagnosis of CeD. In mucosal samples, AUCs for bacterial, viral, and fungal microbiota were 81.2%, 58.6%, and 35%, respectively, indicating that mucosal bacteria alone had the highest predictive power. Two bacteria, and , in fecal samples and one virus, , in mucosal samples are predicted to be "important" biomarkers, differentiating celiac from nonceliac disease groups. is known to degrade complex arabinoxylans and xylan which have a protective role in the intestinal mucosa. Similarly, several species have been reported to produce peptidases that hydrolyze gluten peptides, with the potential to reduce the gluten content of food. Finally, a role for in immune-mediated disease such as CeD has been reported.
CONCLUSION
The excellent predictive power of the combination of the fecal bacterial and viral microbiota with mucosal bacteria alone indicates a potential role in the diagnosis of difficult cases of CeD. and , which were found to be deficient in CeD, have a potential protective role in the development of prophylactic modalities. Further studies on the role of the microbiota in general and in particular are needed.
Topics: Humans; Child; Celiac Disease; Gastrointestinal Microbiome; Saudi Arabia; Glutens; Biomarkers; Bacteria
PubMed: 37155522
DOI: 10.3748/wjg.v29.i13.1994 -
Microorganisms May 2021spp. of the human colonic microbiome degrade complex arabinoxylans from dietary fiber and release ferulic acid. Several studies have demonstrated the beneficial effects...
spp. of the human colonic microbiome degrade complex arabinoxylans from dietary fiber and release ferulic acid. Several studies have demonstrated the beneficial effects of ferulic acid. Here, we hypothesized that ferulic acid or the ferulic acid-rich culture supernatant of , cultured in the presence of complex arabinoxylans, enhances the immune response. Ferulic acid and the culture supernatant of bacteria cultured in the presence of insoluble arabinoxylans significantly decreased the expression of tumor necrosis factor-α and increased the expression of interleukin-10 and transforming growth factor β1 from activated dendritic cells compared to controls. The number of granulocytes in mesenteric lymph nodes, the number of spleen monocytes/granulocytes, and interleukin-2 and interleukin-12 plasma levels were significantly increased in mice treated with ferulic acid or the culture supernatant of bacteria cultured with insoluble arabinoxylans. Ferulic acid or the culture supernatant of bacteria cultured with insoluble arabinoxylans increased the expression of interleukin-12, interferon-α, and interferon-β in intestinal epithelial cell lines. This study shows that ferulic acid or the ferulic acid-rich culture supernatant of the colonic bacterium , cultured with insoluble arabinoxylans, exerts anti-inflammatory activity in dendritic cells under inflammatory conditions and enhances the Th1-type immune response under physiological conditions in mice.
PubMed: 34067445
DOI: 10.3390/microorganisms9061126 -
MSystems Apr 2024The microbial utilization of dietary carbohydrates is closely linked to the pivotal role of the gut microbiome in human health. Inherent to the modulation of complex...
UNLABELLED
The microbial utilization of dietary carbohydrates is closely linked to the pivotal role of the gut microbiome in human health. Inherent to the modulation of complex microbial communities, a prebiotic implies the selective utilization of a specific substrate, relying on the metabolic capacities of targeted microbes. In this study, we investigated the metabolic capacities of 17 commensal bacteria of the human gut microbiome toward dietary carbohydrates with prebiotic potential. First, experiments allowed the classification of bacterial growth and fermentation profiles in response to various carbon sources, including agave inulin, corn fiber, polydextrose, and citrus pectin. The influence of phylogenetic affiliation appeared to statistically outweigh carbon sources in determining the degree of carbohydrate utilization. Second, we narrowed our focus on six commensal bacteria representative of the and phyla to perform an untargeted high-resolution liquid chromatography-mass spectrometry metabolomic analysis: , , , , and exhibited distinct metabolomic profiles in response to different carbon sources. The relative abundance of bacterial metabolites was significantly influenced by dietary carbohydrates, with these effects being strain-specific and/or carbohydrate-specific. Particularly, the findings indicated an elevation in short-chain fatty acids and other metabolites, including succinate, gamma-aminobutyric acid, and nicotinic acid. These metabolites were associated with putative health benefits. Finally, an RNA-Seq transcriptomic approach provided deeper insights into the underlying mechanisms of carbohydrate metabolization. Restricting our focus on four commensal bacteria, including , and , carbon sources did significantly modulate the level of bacterial genes related to the enzymatic machinery involved in the metabolization of dietary carbohydrates. This study provides a holistic view of the molecular strategies induced during the dynamic interplay between dietary carbohydrates with prebiotic potential and gut commensal bacteria.
IMPORTANCE
This study explores at a molecular level the interactions between commensal health-relevant bacteria and dietary carbohydrates holding prebiotic potential. We showed that prebiotic breakdown involves the specific activation of gene expression related to carbohydrate metabolism. We also identified metabolites produced by each bacteria that are potentially related to our digestive health. The characterization of the functional activities of health-relevant bacteria toward prebiotic substances can yield a better application of prebiotics in clinical interventions and personalized nutrition. Overall, this study highlights the importance of identifying the impact of prebiotics at a low resolution of the gut microbiota to characterize the activities of targeted bacteria that can play a crucial role in our health.
Topics: Humans; Prebiotics; Dietary Carbohydrates; Phylogeny; Bacteria; Carbon
PubMed: 38441031
DOI: 10.1128/msystems.01401-23 -
BMC Biology Aug 2021The crAss-like phages are ubiquitous and highly abundant members of the human gut virome that infect commensal bacteria of the order Bacteroidales. Although incapable of...
BACKGROUND
The crAss-like phages are ubiquitous and highly abundant members of the human gut virome that infect commensal bacteria of the order Bacteroidales. Although incapable of lysogeny, these viruses demonstrate long-term persistence in the human gut microbiome, dominating the virome in some individuals.
RESULTS
Here we show that rapid phase variation of alternate capsular polysaccharides in Bacteroides intestinalis cultures plays an important role in a dynamic equilibrium between phage sensitivity and resistance, allowing phage and bacteria to multiply in parallel. The data also suggests the role of a concomitant phage persistence mechanism associated with delayed lysis of infected cells, similar to carrier state infection. From an ecological and evolutionary standpoint, this type of phage-host interaction is consistent with the Piggyback-the-Winner model, which suggests a preference towards lysogenic or other "benign" forms of phage infection when the host is stably present at high abundance.
CONCLUSION
Long-term persistence of bacteriophage and host could result from mutually beneficial mechanisms driving bacterial strain-level diversity and phage survival in complex environments.
Topics: Bacteria; Bacteriophages; Bacteroides; Humans; Phase Variation; Phylogeny
PubMed: 34407825
DOI: 10.1186/s12915-021-01084-3