Enrichment of intestinal Lactobacillus by enhanced secretory IgA coating alters glucose homeostasis in P2rx7 −/− mice

The secretory immunoglobulin A (SIgA) in mammalian gut protects the organism from infections and contributes to host physiology by shaping microbiota composition. The mechanisms regulating the adaptive SIgA response towards gut microbes are poorly defined. Deletion of P2rx7, encoding for the ATP-gated ionotropic P2X7 receptor, leads to T follicular helper (Tfh) cells expansion in the Peyer\u2019s patches (PPs) of the small intestine, enhanced germinal centre (GC) reaction and IgA secretion; the resulting alterations of the gut microbiota in turn affects host metabolism. Here, we define gut microbiota modifications that correlate with deregulated SIgA secretion and metabolic alterations in P2rx7 12/ 12 mice. In particular, Lactobacillus shows enhanced SIgA coating in P2rx7 12/ 12 with respect to wild-type (WT) mice. The abundance of SIgA-coated lactobacilli positively correlates with Tfh cells number and body weight, suggesting Lactobacillus-specific SIgA response conditions host metabolism. Accordingly, oral administration of intestinal Lactobacillus isolates from P2rx7 12/ 12 mice to WT animals results in altered glucose homeostasis and fat deposition. Thus, enhanced SIgA production by P2X7 insufficiency promotes Lactobacillus colonization that interferes with systemic metabolic homeostasis. These data indicate that P2X7 receptor-mediated regulation of commensals coating by SIgA is important in tuning the selection of bacterial taxa, which condition host metabolism

Pirfenidone in idiopathic pulmonary fibrosis: real-life experience in the referral centre of Siena

Background: Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pneumonia and has a median survival after diagnosis of 2–5 years. Pirfenidone is the first approved antifibrotic drug for the treatment of IPF. Here we report the functional progress, side effects and survival data of a population of patients with IPF, diagnosed at our centre and treated with pirfenidone. Methods: We enrolled 91 patients with IPF (71 males) treated with pirfenidone. Clinical, survival and functional details were collected retrospectively at start of therapy and after 12, 24, 36 and 48 months of treatment. Lung function tests at least 12 months before starting therapy were available for 40 patients and were entered in the database, as well as side effects. Results: During the observation period (922 ± 529 days), 27 patients died, 5 patients underwent lung transplant and 10 patients interrupted therapy due to adverse events or IPF progression. The median survival was 1606 days. There was a significant reduction in disease progression rate, as measured by trend of forced vital capacity, after 1 year of therapy with respect to before treatment (p = 0.0085). Forced vital capacity reduction rate was progressively higher in the subsequent years of treatment. Treatment-related side effects were reported in 25 patients and were predominantly mild. Overall, four patients discontinued therapy due to severe photosensitivity. Conclusions: Our findings confirm the efficacy of pirfenidone in reducing functional progression of IPF and its excellent safety profile in a real-life setting. This study, designed on a long-term follow up, contributes to the growing evidence on safety, tolerability and efficacy of pirfenidone in IPF. The reviews of this paper are available via the supplemental material section

T follicular helper cells promote a beneficial gut ecosystem for host metabolic homeostasis by sensing microbiota-derived extracellular ATP

The ATP-gated ionotropic P2X7 receptor regulates T follicular helper (Tfh) cell abundance in the Peyer’s patches (PPs) of the small intestine; deletion of P2rx7, encoding for P2X7, in Tfh cells results in enhanced IgA secretion and binding to commensal bacteria. Here, we show that Tfh cell activity is important for generating a diverse bacterial community in the gut and that sensing of microbiota-derived extracellular ATP via P2X7 promotes the generation of a proficient gut ecosystem for metabolic homeostasis. The results of this study indicate that Tfh cells play a role in host-microbiota mutualism beyond protecting the intestinal mucosa by induction of affinity-matured IgA and suggest that extracellular ATP constitutes an inter-kingdom signaling molecule important for selecting a beneficial microbial community for the host via P2X7-mediated regulation of B cell help

P–575 Patients with recurrent implantation failures (RIF): chromosome abnormalities in the resulting embryos

Abstract Study question Do RIF patients have the preimplantation genetic testing for aneuploidy (PGT-A) overcome their infertility condition? Summary answer PGT-A positively impact on implantation rate in RIF patients What is known already The most common definition of RIF is failure to achieve a pregnancy after three consecutive transfers of good quality embryos. This term possibly represents a heterogeneous category of infertile couples as the causes of repeated failures can be diverse. Especially intriguing is the case of patients with an age lower than 39 years for which the oocyte quality is expected not to be compromised by the well known age effect on female fertility. The chromosome analysis of the resulting embryos has been proposed as a valid method to improve implantation in the great majority of RIF patients Study design, size, duration This retrospective study included 49 patients with at least three previous consecutive implantation failures, which underwent PGT-A from January 2016 to April 2020. Both partners had a normal karyotype. Only patients with a female age below 39 years were included, who presented with a normal uterine cavity. Couples with a severe male factor were excluded. Single frozen blastocysts were transferred according to chromosomal results Participants/materials, setting, methods Maternal age was 35.5 ± 3.1 years. All blastocysts were vitrified after trophectoderm biopsy. Whole genome amplification and array comparative genomic hybridization were performed on biopsies. Only euploid embryos were transferred. The primary outcome was the live-birth delivery rate after the first transfer Main results and the role of chance Before starting a PGT-A cycle, these patients underwent 213 embryo transfers with 251 embryos replaced. A total of 264 blastocysts were analyzed, 140 of which were aneuploid (53%). Monosomy or trisomy was reported in 67 of the diagnosed samples (67/140, 48%) whereas the remaining 73 carried complex aneuploidies (73/140, 52%). The remaining 124 blastocysts (47%) were diagnosed as euploid. All patients performed an embryo transfer resulting in 28 clinical pregnancies (57%). There were 5 spontaneous abortions and the live-birth delivery rate per patient was 47% Limitations, reasons for caution This study suffers from the weakness related to retrospectivity. In addition, as euploid embryos are still cryopreserved, the delivery rate could change at completion of the cycles Wider implications of the findings: A RIF condition can be attributed, at least in a good proportion of cases, to the generation of high percentages of aneuploid embryos. In this case, the transfer of euploid blastocysts has high chances to classify this category of RIF patients has having an embryonic cause of infertilit. Trial registration number Not applicable </jats:sec

Pleuroparenchymal fibroelastosis (PPFE) associated with giant cell arteritis: A coincidence or a novel phenotype?

Pleuroparenchymal fibroelastosis (PPFE) is a rare interstitial lung disease characterized by the fibrotic thickening of subpleural and parenchymal areas of the upper lobes. It may be both idiopathic or secondary to infections, interstitial lung diseases and/or drug exposure. Often PPFE patients report recurrent lower respiratory tract infections, suggesting that repeated inflammatory alterations induced by pulmonary infections may contribute to the development/progression of PPFE. Here, we report for the first time the case of a patient affected by Giant cell Arteritis with histologically proven PPFE. The lung involvement in GCA is rare and interstitial lung diseases are usually reported as an uncommon clinical manifestation of GCA. Our patient is probably the first case presenting PPFE associated with GCA and we wonder if this is a real associative disease or a coincidence perhaps, secondary to drug effects

O-074 Whole genome amplification (WGA) of blastocoelic fluid (BF) as an additional criterion for the selection of the most viable embryo

Abstract Study question Is the presence or absence of DNA in the blastocoelic fluid detected by whole genomic amplification (WGA) a valid method to prioritize embryos for transfer? Summary answer Blastocysts with DNA in the BF have lower ongoing pregnancy rates compared with blastocysts without DNA, both in PGT-A and in conventional IVF cycles What is known already The detection of DNA in BFs from expanded blastocysts has been reported in different studies. After amplification, this DNA can be analyzed to provide information on the blastocyst chromosome condition, but the degree to which it is representative of the corresponding embryo ploidy is still controversial. The reason of this divergence could reside in several factors, including the different status of the studied embryos. A recent study comparing euploid and aneuploid blastocysts reported a significantly higher incidence of failed BF-DNA amplification in euploid blastocysts compared with aneuploid blastocysts suggesting an effect of the embryo ploidy condition on BF content Study design, size, duration This prospective study included 142 cycles with PGT-A (Group-1; 24-chromosome analysis was performed on trophectoderm (TE) biopsies) and 121 conventional IVF consecutive cycles (Group-2) treated in the last three years. In both groups, the BF was collected from expanded blastocysts before vitrification, and submitted to WGA. Single blastocyst transfers were performed by selecting blastocysts based on BF-WGA results giving priority to those with failed amplification. In Group-1, only TE-euploid blastocysts were transferred Participants/materials, setting, methods Patients in Group-1 had a maternal age higher than in Group-2 (36.8±3 vs 34.1±3.5 years). The same protocol of vitrification was used for all patients, and only expanded blastocysts of high grade were included in the study. Amplification after WGA was evaluated by loading an aliquot of the amplified product onto a 1.5% agarose gel. An ongoing pregnancy was defined as a pregnancy regularly ongoing beyond the 16th week of gestation Main results and the role of chance In Group-1, a total of 622 blastocysts underwent trophectoderm (TE) biopsy and 261 were euploid. The BF was retrieved from 237 euploid blastocysts and submitted to WGA. Amplification failure resulted in 98 BFs, whereas 139 BF gave a positive amplification. In all, 57 clinical pregnancies resulted, 53 of which were regularly ongoing. 61 transfers were performed with euploid blastocysts with failed BF-WGA, and 81 with positive BF-WGA. When looking at the transfer outcome, the ongoing pregnancy rate was significantly higher for euploid blastocysts with failed BF-WGA (31/61, 50.8%) when compared to those with positive BF-WGA results (22/81, 27.2%, p&amp;lt;0.01). In Group-2, there were 62 clinical pregnancies, 52 of which were ongoing. In relation to the BF-WGA results, the ongoing pregnancy rate showed the same trend of Group-1, and was 20% (52/121) for blastocysts with failed BF-WGA and 59.1% (42/71, p&amp;lt;0.001) for blastocysts with positive BF-WGA Limitations, reasons for caution This is a prospective cohort study. The results should be confirmed by a prospectively randomized study Wider implications of the findings The presence of DNA in the BF could be indicative of an abnormal embryos that is trying to reach a viable condition. Therefore, failure to detect DNA after BF amplification could represent an additional criterion to select viable embryos for transfer both in PGT-A and in conventional IVF cycles Trial registration number Not applicable </jats:sec