Showing papers by "Rustam Aminov published in 2008"

Predominant role of host genetics in controlling the composition of gut microbiota

Abstract: Background The human gastrointestinal tract is inhabited by a very diverse symbiotic microbiota, the composition of which depends on host genetics and the environment. Several studies suggested that the host genetics may influence the composition of gut microbiota but no genes involved in host control were proposed. We investigated the effects of the wild type and mutated alleles of the gene, which encodes the protein called pyrin, one of the regulators of innate immunity, on the composition of gut commensal bacteria. Mutations in MEFV lead to the autoinflammatory disorder, familial Mediterranean fever (FMF, MIM249100), which is characterized by recurrent self-resolving attacks of fever and polyserositis, with no clinical signs of disease in remission. Methodology/Principal Findings A total of 19 FMF patients and eight healthy individuals were genotyped for mutations in the MEFV gene and gut bacterial diversity was assessed by sequencing 16S rRNA gene libraries and FISH analysis. These analyses demonstrated significant changes in bacterial community structure in FMF characterized by depletion of total numbers of bacteria, loss of diversity, and major shifts in bacterial populations within the Bacteroidetes, Firmicutes and Proteobacteria phyla in attack. In remission with no clinical signs of disease, bacterial diversity values were comparable with control but still, the bacterial composition was substantially deviant from the norm. Discriminant function analyses of gut bacterial diversity revealed highly specific, well-separated and distinct grouping, which depended on the allele carrier status of the host. Conclusions/Significance This is the first report that clearly establishes the link between the host genotype and the corresponding shifts in the gut microbiota (the latter confirmed by two independent techniques). It suggests that the host genetics is a key factor in host-microbe interaction determining a specific profile of commensal microbiota in the human gut.

Elevated systemic antibodies towards commensal gut microbiota in autoinflammatory condition.

Abstract: Background Familial Mediterranean fever (FMF) is an autoinflammatory condition, which is characterized by acute, self-limiting episodes of fever and serositis and chronic subclinical inflammation in remission. Here we investigated the consequence of this condition on the level of systemic antibodies directed towards common intestinal bacteria. Methodology/Principal Findings The level of systemic antibodies towards the antigens of Bacteroides, Parabacteroides, Escherichia, Enteroccocus and Lactobaccilus was measured by ELISA in FMF patients at various stages of the disease and in healthy controls. The difference between remission and attack was not significant. IgG antibodies against the antigens of Bacteroides, Parabacteroides, Escherichia and Enteroccocus were significantly increased in FMF compared to control while IgA levels were not significantly affected. Western blot analyses demonstrated the IgG reactivity against multiple antigens of commensal bacteria in FMF. Serological expression cloning was performed to identify these antigens. No single dominant antigen was identified; the response was generalized and directed against a variety of proteins from Bacteroides, Parabacteroides, Escherichia, and other gut commensals. Conclusions/Significance This autoinflammatory syndrome is characterized by the increased systemic reactivity against commensal gut microbiota. This is probably the consequence of hypersensitivity of the inflammasome in FMF that triggers the inflammation and contributes to the excessive translocation of bacteria and bacterial antigens through the gut barrier.

Molecular Genetics of Familial Mediterranean Fever

Abstract: Familial Mediterranean fever (FMF) is an autoinflammatory disease, which is prevalent in populations of the Mediterranean ancestry. Traditionally, FMF was considered as an autosomal recessive genetic disorder; however, several studies showed that a heterozygote state might also result in disease. Mutations responsible for the disease are located in the MEFV gene encoding a protein called pyrin/marenostrin/TRIM20. FMF is characterised by seemingly unprovoked periodic activation of innate immunity, with fever and serosal inflammation. Among more than 300 mutations in the MEFV gene, five mutations (M694V, V726A, M680I, M694I and E148Q) are the most common in classically affected populations (Armenians, Arabs, Jews and Turks). Disease severity depends on specific MEFV mutations and also on a number of other genetic or environmental modifiers. Certain evolutionary aspects of the disease were intensively investigated including the origin of major MEFV mutations, structure-and-function and evolution of pyrin and potential selective advantage of heterozygous carriage. Key Concepts Familial Mediterranean fever (FMF, MIM 249100) is an autoinflammatory genetic disease, and it is prevalent in populations of Mediterranean origin. The highest incidence of the disorder is documented in four ethnic groups Armenians, Arabs, Jews and Turks, which are considered as ‘classically affected populations’. Clinical manifestations of FMF include periodic occurrence of fever and inflammation in the peritoneum, synovium or pleura. Renal amyloidosis is the most serious complication of the disease. The disease is caused by mutations in the MEFV (MEditerraneanFeVer) gene, which is composed of 10 exons and located on chromosome 16 (16p13.3). MEFV encodes a protein named pyrin or marenostrin or TRIM20, which is a key component of innate immunity. Presently, more than 300 MEFV mutations have been identified. Five mutations (M694V, V726A, M680I and M694I in exon 10 and E148Q in exon 2) are most frequent in classically affected populations. Severity of FMF depends on specific MEFV mutations as well as on a number of other genetic and environmental modifiers. The most common MEFV mutations display a relatively ancient origin, with the subsequent penetration to other populations following migratory and interbreeding processes. The high carriage rate of MEFV mutations in classically affected populations may be explained by a potential selection for the heterozygote genotype, which may have conferred some sort of selective advantage for populations in the area but currently there is no proof for this. Keywords: Familial Mediterranean fever; MEFV; Mediterranean basin; pyrin; evolution of pyrin