Dataset Information

Relationships between gastrointestinal microbiota and blood group antigens.

ABSTRACT: FUT2 is a gene for a fucosyltransferase that encodes expression of ABO blood group antigens found on gastrointestinal mucosa and secretions. We hypothesized that the fecal microbiomes of healthy subjects, with blood group antigens A, B, and O, have differing compositions. We analyzed 33 fecal and blood specimens from healthy subjects for FUT2 genotype, and the fecal microbiome was determined by 454 pyrosequencing. Our data show that being a blood group secretor is associated with less diversity at higher orders of taxonomy; and the presence of blood group A antigens in the secretor subjects are associated with an expansion families of bacteria within the gut. Furthermore, our study confirms the previous findings that secretors and nonsecretors have differing bacterial taxa. This extends the previous findings by demonstrating that the impact of being a nonsecretor is higher than that of individual blood group antigens. Additionally, we demonstrate that both secretor status and blood group antigen expression especially affect the Lachnospiraceae family of bacteria within the gut microbiome, with lower abundances noted in nonsecretors and higher abundances in secretors of various blood groups. We further note specific differences in blood group A-secretors demonstrating that the genus Blautia is lower in the group A-secretors compared with the non-A-secretors and that this reduction is accompanied by higher abundances of members of the Rikenellaceae, Peptostreptococcaceae, Clostridiales, and Turicibacter This study offers a first insight into the relationship between the fecal microbiome and blood group antigens in secretors.

SUBMITTER: Gampa A

PROVIDER: S-EPMC5625272 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Relationships between gastrointestinal microbiota and blood group antigens.

Gampa Anuhya A Engen Phillip A PA Shobar Rima R Mutlu Ece A EA

Physiological genomics 20170714 9

FUT2 is a gene for a fucosyltransferase that encodes expression of ABO blood group antigens found on gastrointestinal mucosa and secretions. We hypothesized that the fecal microbiomes of healthy subjects, with blood group antigens A, B, and O, have differing compositions. We analyzed 33 fecal and blood specimens from healthy subjects for FUT2 genotype, and the fecal microbiome was determined by 454 pyrosequencing. Our data show that being a blood group secretor is associated with less diversity ...[more]

PMID: 28710295

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Project description:Far from being just "bugs in our guts," the microbiota interacts with the body in previously unimagined ways. Research into the genome and the microbiome has revealed that the human body and the microbiota have a long-established but only recently recognized symbiotic relationship; homeostatic balance between them regulates body function. That balance is fragile, easily disturbed, and plays a fundamental role in human health-our very survival depends on the healthy functioning of these microorganisms. Increasing rates of cardiovascular, autoimmune, and inflammatory diseases, as well as epidemics in obesity and diabetes in recent decades are believed to be explained, in part, by unintended effects on the microbiota from vaccinations, poor diets, environmental chemicals, indiscriminate antibiotic use, and "germophobia." Discovery and exploration of the brain-gut-microbiota axis have provided new insights into functional diseases of the gut, autoimmune and stress-related disorders, and the role of probiotics in treating certain affective disorders; it may even explain some aspects of autism. Research into dietary effects on the human gut microbiota led to its classification into three proposed enterotypes, but also revealed the surprising role of blood group antigens in shaping those populations. Blood group antigens have previously been associated with disease risks; their subsequent association with the microbiota may reveal mechanisms that lead to development of nutritional interventions and improved treatment modalities. Further exploration of associations between specific enteric microbes and specific metabolites will foster new dietary interventions, treatment modalities, and genetic therapies, and inevitably, their application in personalized healthcare strategies. This article is categorized under: Laboratory Methods and Technologies > Metabolomics Translational, Genomic, and Systems Medicine > Translational Medicine Physiology > Mammalian Physiology in Health and Disease.

Project description:Human norovirus (HuNoV) is the major agent for viral gastroenteritis, causing >700 million infections yearly. Fucose-containing carbohydrates named histo-blood group antigens (HBGAs) are known (co)receptors for HuNoV. Moreover, bacteria of the gut microbiota expressing HBGA-like structures have shown an enhancing effect on HuNoV replication in an in vitro model. Here, we studied the role of HBGAs and the host microbiota during HuNoV infection in zebrafish larvae. Using whole-mount immunohistochemistry, we visualized the fucose expression in the zebrafish gut for the HBGA Lewis X [LeX, α(1,3)-fucose] and core fucose [α(1,6)-fucose]. Costaining of HuNoV-infected larvae proved colocalization of LeX and to a lower extent core fucose with the viral capsid protein VP1, indicating the presence of fucose residues on infected cells. Upon blocking of fucose expression by a fluorinated fucose analogue, HuNoV replication was strongly reduced. Furthermore, by comparing HuNoV replication in conventional and germfree zebrafish larvae, we found that the natural zebrafish microbiome does not have an effect on HuNoV replication, contrary to earlier reports about the human gut microbiome. Interestingly, monoassociation with the HBGA-expressing Enterobacter cloacae resulted in a minor decrease in HuNoV replication, which was not triggered by a stronger innate immune response. Overall, we show here that fucose has an essential role for HuNoV infection in zebrafish larvae, as in the human host, but their natural gut microbiome does not affect viral replication. IMPORTANCE Despite causing over 700 million infections yearly, many gaps remain in the knowledge of human norovirus (HuNoV) biology due to an historical lack of efficient cultivation systems. Fucose-containing carbohydrate structures, named histo-blood group antigens, are known to be important (co)receptors for viral entry in humans, while the natural gut microbiota is suggested to enhance viral replication. This study shows a conserved mechanism of entry for HuNoV in the novel zebrafish infection model, highlighting the pivotal opportunity this model represents to study entry mechanisms and identify the cellular receptor of HuNoV. Our results shed light on the interaction of HuNoV with the zebrafish microbiota, contributing to the understanding of the interplay between gut microbiota and enteric viruses. The ease of generating germfree animals that can be colonized with human gut bacteria is an additional advantage of using zebrafish larvae in virology. This small animal model constitutes an innovative alternative to high-severity animal models.

Project description:Norovirus (NoV) is a causative agent of acute gastroenteritis. NoV binds to histo-blood group antigens (HBGAs), namely, ABH antigens and Lewis (Le) antigens, in which type 1 and type 2 carbohydrate core structures constitute antigenically distinct variants. Norwalk virus, the prototype strain of norovirus, binds to the gastroduodenal junction, and this binding is correlated with the presence of H type 1 antigen but not with that of H type 2 antigen (S. Marionneau, N. Ruvoen, B. Le Moullac-Vaidye, M. Clement, A. Cailleau-Thomas, G. Ruiz-Palacois, P. Huang, X. Jiang, and J. Le Pendu, Gastroenterology 122:1967-1977, 2002). It has been unknown whether NoV distinguishes between the type 1 and type 2 chains of A and B antigens. In this study, we synthesized A type 1, A type 2, B type 1, and B type 2 pentasaccharides in vitro and examined the function of the core structures in the binding between NoV virus-like particles (VLPs) and HBGAs. The attachment of five genogroup I (GI) VLPs from 5 genotypes and 11 GII VLPs from 8 genotypes, GI/1, GI/2, GI/3, GI/4, GI/8, GII/1, GII/3, GII/4, GII/5, GII/6, GII/7, GII/12, and GII/14, to ABH and Le HBGAs was analyzed by enzyme-linked immunosorbent assay-based binding assays and Biacore analyses. GI/1, GI/2, GI/3, GI/4, GI/8, and GII/4 VLPs were more efficiently bound to A type 2 than A type 1, and GI/8 and GII/4 VLPs were more efficiently bound to B type 2 than B type 1, indicating that NoV VLPs distinguish between type 1 and type 2 carbohydrates. The dissociation of GII/4 VLPs from B type 1 was slower than that from B type 2 in the Biacore experiments; moreover, the binding to B type 1 was stronger than that to B type 2 in the ELISA experiments. These results indicated that the type 1 carbohydrates bind more tightly to NoV VLPs than the type 2 carbohydrates. This property may afford NoV tissue specificity. GII/4 is known to be a global epidemic genotype and binds to more HBGAs than other genotypes. This characteristic may be linked with the worldwide transmission of GII/4 strains. GI/2, GI/3, GI/4, GI/8, GII/4, and GII/7 VLPs bound to Le(a) expressed by nonsecretors, suggesting that NoV can infect individuals regardless of secretor phenotype. Overall, our results indicated that HBGAs are important factors in determining tissue specificity and the risk of transmission.

Project description:UnlabelledHuman noroviruses are the dominant cause of outbreaks of gastroenteritis around the world. Human noroviruses interact with the polymorphic human histo-blood group antigens (HBGAs), and this interaction is thought to be important for infection. Indeed, synthetic HBGAs or HBGA-expressing enteric bacteria were shown to enhance norovirus infection in B cells. A number of studies have found a possible relationship between HBGA type and norovirus susceptibility. The genogroup II, genotype 4 (GII.4) noroviruses are the dominant cluster, evolve every other year, and are thought to modify their binding interactions with different HBGA types. Here we show high-resolution X-ray crystal structures of the capsid protruding (P) domains from epidemic GII.4 variants from 2004, 2006, and 2012, cocrystallized with a panel of HBGA types (H type 2, Lewis Y, Lewis B, Lewis A, Lewis X, A type, and B type). Many of the HBGA binding interactions were found to be complex, involving capsid loop movements, alternative HBGA conformations, and HBGA rotations. We showed that a loop (residues 391 to 395) was elegantly repositioned to allow for Lewis Y binding. This loop was also slightly shifted to provide direct hydrogen- and water-mediated bonds with Lewis B. We considered that the flexible loop modulated Lewis HBGA binding. The GII.4 noroviruses have dominated outbreaks over the past decade, which may be explained by their exquisite HBGA binding mechanisms, their fondness for Lewis HBGAs, and their temporal amino acid modifications.ImportanceOur data provide a comprehensive picture of GII.4 P domain and HBGA binding interactions. The exceptionally high resolutions of our X-ray crystal structures allowed us to accurately recognize novel GII.4 P domain interactions with numerous HBGA types. We showed that the GII.4 P domain-HBGA interactions involved complex binding mechanisms that were not previously observed in norovirus structural studies. Many of the GII.4 P domain-HBGA interactions we identified were negative in earlier enzyme-linked immunosorbent assay (ELISA)-based studies. Altogether, our data show that the GII.4 norovirus P domains can accommodate numerous HBGA types.

Project description:Background and purposeWe investigated the causal relationships between the gut microbiota (GM), stroke, and potential metabolite mediators using Mendelian randomization (MR).MethodsWe leveraged the summary statistics of GM (n=18,340 in the MiBioGen consortium), blood metabolites (n=115,078 in the UK Biobank), and stroke (cases n=60,176 and controls n=1,310,725 in the Global Biobank Meta-Analysis Initiative) from the largest genome-wide association studies to date. We performed bidirectional MR analyses to explore the causal relationships between the GM and stroke, and two mediation analyses, two-step MR and multivariable MR, to discover potential mediating metabolites.ResultsTen taxa were causally associated with stroke, and stroke led to changes in 27 taxa. In the two-step MR, Bifidobacteriales order, Bifidobacteriaceae family, Desulfovibrio genus, apolipoprotein A1 (ApoA1), phospholipids in high-density lipoprotein (HDL_PL), and the ratio of apolipoprotein B to ApoA1 (ApoB/ApoA1) were causally associated with stroke (all P<0.044). The causal associations between Bifidobacteriales order, Bifidobacteriaceae family and stroke were validated using the weighted median method in an independent cohort. The three GM taxa were all positively associated with ApoA1 and HDL_PL, whereas Desulfovibrio genus was negatively associated with ApoB/ApoA1 (all P<0.010). Additionally, the causal associations between the three GM taxa and ApoA1 remained significant after correcting for the false discovery rate (all q-values <0.027). Multivariable MR showed that the associations between Bifidobacteriales order, Bifidobacteriaceae family and stroke were mediated by ApoA1 and HDL_PL, each accounting for 6.5% (P=0.028) and 4.6% (P=0.033); the association between Desulfovibrio genus and stroke was mediated by ApoA1, HDL_PL, and ApoB/ApoA1, with mediated proportions of 7.6% (P=0.019), 4.2% (P=0.035), and 9.1% (P=0.013), respectively.ConclusionThe current MR study provides evidence supporting the causal relationships between several specific GM taxa and stroke and potential mediating metabolites.

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Relationships between gastrointestinal microbiota and blood group antigens.

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Relationships between gastrointestinal microbiota and blood group antigens.

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