Biology subjects

Peter, I.

Publications and source records attributed to Peter, I..

10 recordsLinked to original sources

bioRxiv2025

Maternal IBD-related antibodies are associated with early life gut inflammatory status and microbiota composition: insights from cord blood

PurposeAntibodies in peripheral blood are used to aid in the diagnosis of inflammatory bowel disease (IBD), but their presence in neonatal cord blood and potential effects on early life development remain unknown. MethodsWe measured anti-CBir1, ANCA, anti-OmpC, ASCA IgA, and ASCA IgG levels in the cord blood of babies born to 78 mothers with or without IBD. Their association with fecal calprotectin (FC), and microbiota composition, characterized by 16S rRNA sequencing, was assessed throughout pregnancy and during the first 3 years of life using linear mixed-effects models. ResultsAntibodies were detected in cord blood, with significantly higher levels of anti-CBir1 and ASCA IgG in babies born to mothers with Crohns disease (p = 0.002) and higher abundance of ANCA and anti-OmpC in babies of mothers with ulcerative colitis (p = 0.002), compared to controls. ASCA IgG levels positively correlated with babies FC (p = 0.006), while babies microbiota Shannon diversity was negatively associated with ANCA, anti-OmpC, and ASCA IgA levels (p = 0.003, 0.04, and 0.008, respectively). Romboutsia spp., Citrobacter spp., Pseudomonas spp., Clostridiaceae, Clostridia, and Varibaculum spp. were positively correlated with either or both ANCA and anti-OmpC levels (all multiple testing adjusted q < 0.1). ConclusionOur findings suggest that maternal IBD-associated antibodies cross the placenta barrier and may be associated with intestinal inflammation and imbalanced microbiota colonization. Whether these serological profiles negatively influence the priming of the babys immune system or IBD risk later in life remains to be determined.

immunology↗

bioRxiv2024

Targeting Specific Kinase Substrates Rescues Increased Colitis Severity Induced by the Crohn's Disease-Linked LRRK2-N2081D Variant

LRRK2 contains a kinase domain where both the N2081D Crohns disease (CD) risk and the G2019S Parkinsons disease (PD)-pathogenic variants are located. The mechanisms by which the N2081D variant increase CD risk, and how these adjacent mutations result in distinct diseases, remain unclear. To investigate the pathophysiology of the CD-linked LRRK2 N2081D variant, we generated a knock-in (KI) mouse model and compared its effects to those of the LRRK2-G2019S mutation. We find that Lrrk2N2081D KI mice demonstrate heightened sensitivity to induced colitis, resulting in more severe inflammation and intestinal damage than Lrrk2G2019SKI and wild-type mice. Analysis of Colon tissue revealed distinct mutation-dependent LRRK2 RAB substrate phosphorylation, with significantly elevated phosphorylated RAB10 levels in Lrrk2N2081D mice. In cells, we demonstrate that the N2081D mutation activates LRRK2 through a mechanism distinct from that of LRRK2-G2019S. We further find that proinflammatory stimulation enhances LRRK2 kinase activity, leading to mutation-dependent differences in RAB phosphorylation and inflammatory responses in dendritic cells. Finally, we show that genetic knockout of Rab12, but not pharmacological LRRK2 kinase inhibition, significantly reduced colitis severity in Lrrk2N2081D mice. Our study characterizes the pathogenic mechanisms of LRRK2-linked CD, highlights important structural and functional differences between disease-associated LRRK2 variants, and suggests RAB proteins as promising therapeutic targets for modulating LRRK2 activity in CD treatment.

molecular biology↗

bioRxiv2024

Association of diet and inflammation with the vaginal microbiota of pregnant individuals with or without IBD

Background and aimsVaginal dysbiosis has been associated with adverse pregnancy outcomes. Here, we characterized the vaginal microbiota of pregnant individuals with inflammatory bowel disease (IBD) and investigated whether gut or vaginal inflammation and diet influence the vaginal microbiota diversity of these individuals. Study DesignWe recruited 48 individuals in their third trimester of pregnancy (IBD=23 and HC=18). We characterized the vaginal microbiota by 16S rRNA sequencing and the gut microbiota by shotgun sequencing. We measured fecal calprotectin in stool and pro-inflammatory cytokines in vaginal fluids. We determine dietary quality using validated 24-hour dietary recalls. ResultsPregnant individuals with IBD exhibit higher levels of fecal calprotectin and increased expression of Th17 pro-inflammatory cytokines (i.e., IL-6, IL-8, IL-17) in the vaginal mucosa compared to healthy pregnant individuals. High fecal calprotectin correlated with high vaginal microbiota diversity. Also, IL-4 (reduced in IBD) was associated with vaginal microbial composition. Regardless of IBD status, pregnant individuals with healthier diets and particularly optimal servings of vegetables and sugars exhibited a vaginal microbiota dominated by Lactobacillus crispatus, a species associated with a lower risk of preterm birth and bacterial vaginosis. ConclusionBesides gut inflammation, pregnant individuals with IBD also exhibit a Th17 immune tone in the vaginal mucosa. The vaginal microbiota diversity or composition, particularly high in the beneficial L. crispatus, is positively associated with healthier diets, regardless of IBD status. Why was the study conducted?An altered vaginal microbiota has been implicated in preterm birth. There is no research on the vaginal microbiome and the factors that influence it in pregnant individuals with Inflammatory Bowel Disease (IBD) at a higher risk of preterm delivery. Key findingsPregnant individuals with IBD exhibit a comparable vaginal microbiome to healthy pregnant individuals. However, pregnant individuals with IBD present a vaginal immune profile characterized by increased levels of Th17 pro-inflammatory cytokines. High dietary quality, and optimal consumption of vegetables and added sugars were associated with vaginal dominance by the beneficial L. crispatus. What does this add to what is known?Our results indicate that the vaginal immune environment and not the microbiome might explain poor pregnancy outcomes for individuals with IBD. Moreover, our study supports the importance of diet to favor L. crispatus, a bacterium associated with a lower risk of preterm birth.

microbiology↗

bioRxiv2022

Genome-wide data from medieval German Jews show that the Ashkenazi founder event pre-dated the 14th century

We report genome-wide data for 33 Ashkenazi Jews (AJ), dated to the 14th century, following a salvage excavation at the medieval Jewish cemetery of Erfurt, Germany. The Erfurt individuals are genetically similar to modern AJ and have substantial Southern European ancestry, but they show more variability in Eastern European-related ancestry than modern AJ. A third of the Erfurt individuals carried the same nearly-AJ-specific mitochondrial haplogroup and eight carried pathogenic variants known to affect AJ today. These observations, together with high levels of runs of homozygosity, suggest that the Erfurt community had already experienced the major reduction in size that affected modern AJ. However, the Erfurt bottleneck was more severe, implying substructure in medieval AJ. Together, our results suggest that the AJ founder event and the acquisition of the main sources of ancestry pre-dated the 14th century and highlight late medieval genetic heterogeneity no longer present in modern AJ.

genetics↗

bioRxiv2019

17q21.31 sub-haplotypes underlying H1-associated risk for Parkinson's disease and progressive supranuclear palsy converge on altered glial regulation

Parkinsons disease (PD) is genetically associated with the H1 haplotype of the MAPT 17q.21.31 locus, although the causal gene and variants underlying this association have not been identified. To better understand the genetic contribution of this region to PD, we fine-mapped the 17q21.31 locus in order to identify novel mechanisms conferring risk for the disease. We identified three novel H1 sub-haplotype blocks across the 17q21.31 locus associated with PD risk. Protective sub-haplotypes were associated with increased LRRC37A/2 copy number and expression in human brain tissue. We found that LRRC37A/2 is a membrane-associated protein that plays a role in cellular migration, chemotaxis and astroglial inflammation. In human substantia nigra, LRRC37A/2 was primarily expressed in astrocytes, interacted directly with soluble -synuclein, and co-localized with Lewy bodies in PD brain tissue. These data indicate that a novel candidate gene, LRRC37A/2, contributes to the association between the 17q21.31 locus and PD via its interaction with -synuclein and its effects on astrocytic function and inflammatory response. These data are the first to associate the genetic association at the 17q21.31 locus with PD pathology, and highlight the importance of variation at the 17q21.31 locus in the regulation of multiple genes other than MAPT and KANSL1, as well as its relevance to non-neuronal cell types.

neuroscience↗

bioRxiv2018

Association between chronic hepatitis C virus infection and myocardial infarction in people living with HIV in the United States

Hepatitis C virus (HCV) is common among people living with HIV (PLWH). The potential for extrahepatic manifestations of HCV, including myocardial infarction (MI), is a topic of active research. MI is classified into types, predominantly atheroembolic Type 1 MI (T1MI) and supply-demand mismatch Type 2 MI (T2MI). We examined the association between HCV and MI in the CFAR Network of Integrated Clinical Systems (CNICS), a multi-center clinical cohort of PLWH. MIs were centrally adjudicated and categorized by type using the Universal MI definition. We estimated the association between chronic HCV (RNA+) and time to MI adjusting for demographic characteristics, cardiovascular risk factors, clinical characteristics and substance use. Among 24,755 PLWH aged [≥]18, there were 336 T1MI and 330 T2MI during a median of 4.2 years of follow-up. HCV was associated with a 68% greater risk of T2MI (adjusted hazard ratio (aHR) 1.68, 95% CI: 1.22, 2.30) but not T1MI (aHR 0.96, 95% CI: 0.63, 1.45). In a cause-specific analysis of T2MI, HCV was associated with a 2-fold greater risk of T2MI attributed to sepsis (aHR 2.26, 95% CI: 1.34, 3.81). Extrahepatic manifestations of HCV in this high-risk population are an important area for continued research.

epidemiology↗

bioRxiv2018

Gut microbiota density influences host physiology and is shaped by host and microbial factors

To identify factors that regulate gut microbiota density and the impact of varied microbiota density on health, we assayed this fundamental ecosystem property in fecal samples across mammals, human disease, and therapeutic interventions. Physiologic features of the host (carrying capacity) and the fitness of the gut microbiota shape microbiota density. Therapeutic manipulation of microbiota density in mice altered host metabolic and immune homeostasis. In humans, gut microbiota density was reduced in Crohns disease, ulcerative colitis, and ileal pouch-anal anastomosis. The gut microbiota in recurrent Clostridium difficile infection had lower density and reduced fitness that were restored by fecal microbiota transplantation. Understanding the interplay between microbiota and disease in terms of microbiota density, host carrying capacity, and microbiota fitness provide new insights into microbiome structure and microbiome targeted therapeutics.

microbiology↗

bioRxiv2018

Microbial Engraftment and Efficacy of Fecal Microbiota Transplant for Clostridium difficile Patients With and Without IBD

Background & AimsRecurrent and refractory Clostridium difficile infections (CDI) are effectively treated with fecal microbiota transplant (FMT). Uncertainty exists regarding the effectiveness of FMT for CDI with underlying inflammatory bowel disease (IBD), its effects on disease activity and its effectiveness transferring the donor microbiome to patients with and without IBD. This study aims to determine FMTs effectiveness in subjects with and without IBD, its impact on IBD activity, the level of microbiome engraftment, and predictors of CDI recurrence.\n\nMethodsSubjects with and without IBD who underwent FMT for recurrent or refractory CDI between 2013 and 2016 at The Mount Sinai Hospital were followed for up to 6 months. The primary outcome was CDI recurrence 6 months after FMT. Secondary outcomes were (1) CDI recurrence 2 months after FMT; (2) Frequency of IBD flare after FMT; (3) Microbiome engraftment after FMT; (4) Predictors of CDI recurrence.\n\nResultsOverall, 134 patients, 46 with IBD, were treated with FMT. There was no difference in recurrence in patients with and without IBD at 2 months (22.5% vs 17.9%; p=0.63) and 6 months (38.7% vs 36.5%; p>0.99). Proton pump inhibitor use, severe CDI, and comorbid conditions were predictors of recurrence. The pre-FMT microbiome was not predictive of CDI recurrence. Subjects with active disease requiring medication escalation had reduced engraftment. There was no difference in engraftment based on IBD endoscopic severity at FMT.\n\nConclusionsIBD did not affect CDI recurrence rates 6 months after FMT. Pre-FMT microbiome was not predictive of recurrence, and microbial engraftment was dependent on IBD treatment escalation but not on underlying disease severity.

microbiology↗

bioRxiv2017

A study of Kibbutzim in Israel reveals risk factors for cardiometabolictraits and subtle population structure

Genetic studies in isolated populations have provided increased power for identifying loci associated with complex diseases and traits. We present here the Kibbutzim Family Study (KFS), initiated for investigating environmental and genetic determinants of cardiometabolic traits in extended Israeli families living in communes characterized by long-term social stability and homogeneous environment. Extensive information on cardiometabolic traits, as well as genome-wide genetic data, was collected on 901 individuals, making this study, to the best of our knowledge, the largest of its kind in Israel. We have thoroughly characterized the KFS genetic structure, observing that most participants were of Ashkenazi Jewish (AJ) origin, and confirming a recent severe bottleneck in their recent history (point estimates: effective size {approx}450 individuals, 23 generations ago). Focusing on genetic variants enriched in KFS compared with non-Finnish Europeans, we demonstrated that AJ-specific variants are largely involved in cancer-related pathways. Using linear mixed models, we conducted an association study of these enriched variants with 16 cardiometabolic traits. We found 24 variants to be significantly associated with cardiometabolic traits. The strongest association, which we also replicated, was between a variant upstream of the MSRA gene, {approx}200-fold enriched in KFS, and weight (P=3.6{middle dot}10-8). In summary, the KFS is a valuable resource for the study of the population genetics of Israel as well as the genetics of cardiometabolic traits in a homogeneous environment.

genetics↗

bioRxiv2017

High-depth whole genome sequencing of a large population-specific reference panel: Enhancing sensitivity, accuracy, and imputation

BackgroundWhile increasingly large reference panels for genome-wide imputation have been recently made available, the degree to which imputation accuracy can be enhanced by population-specific reference panels remains an open question. In the present study, we sequenced at full-depth ([≥]30x) a moderately large (n=738) cohort of samples drawn from the Ashkenazi Jewish population across two platforms (Illumina X Ten and Complete Genomics, Inc.). We developed and refined a series of quality control steps to optimize sensitivity, specificity, and comprehensiveness of variant calls in the reference panel, and then tested the accuracy of imputation against target cohorts drawn from the same population.\n\nResultsFor samples sequenced on the Illumina X Ten platform, quality thresholds were identified that permitted highly accurate calling of single nucleotide variants across 94% of the genome. The Complete Genomics, Inc. platform was more conservative (fewer variants called) compared to the Illumina platform, but also demonstrated relatively greater numbers of false positives that needed to be filtered. Quality control procedures also permitted detection of novel genome reads that are not mapped to current reference or alternate assemblies. After stringent quality control, the population-specific reference panel produced more accurate and comprehensive imputation results relative to publicly available, large cosmopolitan reference panels. The population-specific reference panel also permitted enhanced filtering of clinically irrelevant variants from personal genomes.\n\nConclusionsOur primary results demonstrate enhanced accuracy of a population-specific imputation panel relative to cosmopolitan panels, especially in the range of infrequent (<5% non-reference allele frequency) and rare (<1% non-reference allele frequency) variants that may be most critical to further progress in mapping of complex phenotypes.

genomics↗