Association of the ILR1 and FAS gene variants with primary nonresponse to anti-tumor necrosis factor therapy in patients with Crohn disease.

INTRODUCTION: Crohn disease (CD) is a chronic inflammatory disease characterized by an uncontrolled immune response of the intestinal mucosal cells to antigens derived from the gut lumen. Specifically, the introduction of anti-tumor necrosis factor (TNF) drugs has changed the approach to the treatment of inflammatory bowel disease, and set new therapeutic goals, such as that of controlling clinical symptoms while simultaneously achieving complete endoscopic and mucosal remission. The mechanisms of action of anti-TNF drugs-and consequently the mechanisms of resistance to anti­TNF therapy-are unknown. OBJECTIVES: Our study was an attempt to discover whether the potential mechanism of nonresponse may be conditioned by polymorphisms in the genes involved in independent inflammatory or apoptotic pathways. PATIENTS AND METHODS: The study included 196 diagnosed and clinically characterized Polish patients with CD treated with anti­TNF therapy. Variants rs7539036, rs2041747, rs5746053, rs5746054, rs1061624, rs1143634, rs7896789, and rs55790676 of the FCGR3A, IL1R, TNFRSF1B, IL1B, FAS, and ADAM17 genes were genotyped using Sanger sequencing, and analyzed in the context of response to biologic treatment. RESULTS: We observed that 33 patients (16.8%) did not respond to the therapy, which was associated with carrying the rs2041747 G allele variant of the ILR1 gene (odds ratio [OR], 3.72; P = 0.009). Moreover, the presence of the FAS rs7896789 homozygous CC genotype correlated with increased susceptibility to the lack of response to the anti­TNF therapy (OR, 15.22; P = 0.003), whereas TT was identified as a potentially protective genotype. CONCLUSIONS: In patients with CD treated with anti­TNF drugs, complex pathways with multigene conditioning participate in the mechanism underlying treatment resistance. The genes involved in apoptosis, FAS and ILR1, seem to play an essential role in the lack of response to the treatment, and would be interesting objects of further population and functional research.

Alterations in Gut Microbiota Composition in Patients with COVID-19: A Pilot Study of Whole Hypervariable 16S rRNA Gene Sequencing.

It is crucial to consider the importance of the microbiome and the gut-lung axis in the context of SARS-CoV-2 infection. This pilot study examined the fecal microbial composition of patients with COVID-19 following a 3-month recovery. Using for the first time metagenomic analysis based on all hypervariable regions (V1-V9) of the 16S rRNA gene, we have identified 561 microbial species; however, 17 were specific only for the COVID-19 group (n = 8). The patients' cohorts revealed significantly greater alpha diversity of the gut microbiota compared to healthy controls (n = 14). This finding has been demonstrated by operational taxonomic units (OTUs) richness (p < 0.001) and Chao1 index (p < 0.01). The abundance of the phylum Verrucomicrobia was 30 times higher in COVID-19 patients compared to healthy subjects. Accordingly, this disproportion was also noted at other taxonomic levels: in the class Verrucomicrobiae, the family Verrucomicrobiaceae, and the genus Akkermansia. Elevated pathobionts such as Escherichia coli, Bilophila wadsworthia, and Parabacteroides distasonis were found in COVID-19 patients. Considering the gut microbiota's ability to disturb the immune response, our findings suggest the importance of the enteric microbiota in the course of SARS-CoV-2 infection. This pilot study shows that the composition of the microbial community may not be fully restored in individuals with SARS-CoV-2 following a 3-month recovery.

Methodological Changes in the Field of Paleogenetics.

Paleogenetics has significantly changed since its inception almost forty years ago. Initially, molecular techniques available to the researchers offered minimal possibilities for ancient DNA analysis. The subsequent expansion of the scientific tool cabinet allowed for more remarkable achievements, combined has with the newfound popularity of this budding field of science. Finally, a breakthrough was made with the development of next-generation sequencing (NGS) technologies and the update of DNA isolation protocols, through which even very fragmented aDNA samples could be used to sequence whole genomes. In this paper, we review the achievements made thus far and compare the methodologies utilized in this field of science, discussing their benefits and challenges.

Cytotoxicity of Thiopurine Drugs in Patients with Inflammatory Bowel Disease.

The effectiveness of thiopurine drugs in inflammatory bowel disease (IBD) was confirmed more than a half-century ago. It was proven that these can be essential immunomodulatory medications. Since then, they have been used routinely to maintain remission of Crohn's disease (CD) and ulcerative colitis (UC). The cytotoxic properties of thiopurines and the numerous adverse effects of the treatment are controversial. However, the research subject of their pharmacology, therapy monitoring, and the search for predictive markers are still very relevant. In this article, we provide an overview of the current knowledge and findings in the field of thiopurines in IBD, focusing on the aspect of their cytotoxicity. Due to thiopurines' benefits in IBD therapy, it is expected that they will still constitute an essential part of the CD and UC treatment algorithm. More studies are still required on the modulation of the action of thiopurines in combination therapy and their interaction with the gut microbiota.