Fecal microbial community changes are associated with numerous disease states, including cardiovascular disease (CVD). However, such data are merely associative. A causal contribution for gut microbiota in CVD has been further supported by a multitude of more direct experimental evidence. Indeed, gut microbiota transplantation studies, specific gut microbiota–dependent pathways, and downstream metabolites have all been shown to influence host metabolism and CVD, sometimes through specific identified host receptors. Multiple metaorganismal pathways (involving both microbe and host) both impact CVD in animal models and show striking clinical associations in human studies. For example, trimethylamine N-oxide and, more recently, phenylacetylglutamine are gut microbiota–dependent metabolites whose blood levels are associated with incident CVD risks in large-scale clinical studies. Importantly, a causal link to CVD for these and other specific gut microbial metabolites/pathways has been shown through numerous mechanistic animal model studies. Phenylacetylglutamine, for example, was recently shown to promote adverse cardiovascular phenotypes in the host via interaction with multiple ARs (adrenergic receptors)—a class of key receptors that regulate cardiovascular homeostasis. In this review, we summarize recent advances of microbiome research in CVD and related cardiometabolic phenotypes that have helped to move the field forward from associative to causative results. We focus on microbiota and metaorganismal compounds/pathways, with specific attention paid to short-chain fatty acids, secondary bile acids, trimethylamine N-oxide, and phenylacetylglutamine. We also discuss novel therapeutic strategies for directly targeting the gut microbiome to improve cardiovascular outcomes.
There is evidence that certain alleles at the HLA-DQ locus are correlated with susceptibility to insulin-dependent diabetes mellitus (IDDM) and in particular that DQ beta-chain alleles containing aspartic acid at position 57 are protective. The availability of a large group of patients with IDDM enabled us to assess the role of HLA-DQ alleles in susceptibility to the disease in order to confirm and extend recent observations derived from studies of smaller numbers of patients. Using allele-specific oligonucleotide probes and the polymerase chain reaction, we studied 266 unrelated patients with IDDM and 203 unrelated normal subjects for eight HLA-DQ beta-chain alleles. Two major findings emerged from these studies. First, the presence of an HLA-DQw1.2 allele was protective. Only 6 of the 266 patients with IDDM (2.3 percent) were positive for HLA-DQw1.2, as compared with 74 of the 203 normal subjects (36.4 percent; P less than 0.001). Thus, persons with the HLA-DQw1.2 allele, which is one of the polymorphic forms of the beta chain of the HLA-DQ molecule, rarely had IDDM, no matter which other HLA-DQ beta-chain allele they inherited ("dominant protection"). Second, the presence of the HLA-DQw8 allele increased the risk of IDDM. The relative risk of IDDM was 5.6 in persons homozygous for HLA-DQw8, and it was similar in persons with the HLA-DQw1.1/DQw8 or HLA-DQw2/DQw8 haplotype ("dominant susceptibility"). However, the relative risk of IDDM in persons who had the HLA-DQw1.2/DQw8 haplotype was 0.37, demonstrating that the protective effect of HLA-DQw1.2 predominated over the effect of HLA-DQw8. We conclude that the presence of the HLA Class II antigen DQw1.2 is strongly protective against the development of IDDM, and that complete HLA-DQ typing is necessary for accurate assessment of susceptibility to IDDM.
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