Biology subjects

ALTINDIS, E.

Publications and source records attributed to ALTINDIS, E..

5 recordsLinked to original sources

bioRxiv2025

Evolution of Insulin, Insulin-like Growth Factor, and Their Cognate Receptors in Vertebrates, Invertebrates, and Viruses

The insulin and insulin-like growth factor (IGF) system regulates essential biological functions such as growth, metabolism, and development. While its physiological roles are well characterized, the evolutionary origins and molecular diversification of its ligands and receptors remain incompletely defined. Here, we present the most comprehensive phylogenetic and sequence conservation analysis of this system to date, using over 1,000 sequences from vertebrates, invertebrates, and viruses. Our analyses reveal that insulin, IGF-1, and IGF-2 form distinct monophyletic clades that diverged after the emergence of vertebrates, with IGF-1 being the most conserved ligand. We show that IGF1R-binding residues, especially in the A- and B- domains of IGF-1, are highly conserved across vertebrates, while insulins Site 2 residues, which overlap with its dimerization and hexamerization surface, are more variable--correlating with the loss of hexamer formation in hystricomorphs, reptiles, and jawless fish. Unexpectedly, we identify a 12-amino acid insert in the insulin receptor (IR) of turtles and tortoises, previously thought to be unique to mammalian IR-B isoform, suggesting an earlier evolutionary origin of isoform diversity. We also show that marsupials and monotremes retain ancestral receptor domain features shared with reptiles and birds, and that avian insulins, particularly A-chain residues, are unusually conserved. Viral insulin/IGF-like peptides (VILPs) fall into two distinct clades that resemble either IGFs or insulin. Together, these findings illuminate the evolutionary architecture of the insulin/IGF system, highlight unexpected lineage-specific adaptations, and provide a framework for understanding hormone-receptor function across biology and therapeutic design.

evolutionary biology↗

bioRxiv2024

The Impact of Parabacteroides distasonis Colonization on Hosts' Microbiome, Metabolome, Immune Responses, and Diabetes Onset

Type 1 Diabetes (T1D) is a chronic disease caused by autoimmune destruction of insulin-producing pancreatic {beta}-cells. The insulin B-chain 9-23 (insB:9-23) peptide is established as a critical epitope in triggering T1D. In our previous study, we showed that Parabacteroides distasonis, a human gut commensal, contains an insB:9-23 mimic in its hprt protein (residues, 4-18). This mimic (hprt4-18) activates insB:9-23 specific T-cells, and colonization of P. distasonis in female NOD mice enhanced diabetes onset. Additionally, the presence of hprt:4-18 sequence in the gut microbiome is associated with seropositivity in infants. However, the impact of the colonization on the gut microbiome and intestinal immune cell compositions, gut permeability, cytokine, and serum metabolome profiles were unknown. Here, we addressed this gap using specific pathogen-free (SPF) and germ-free (GF) NOD mouse models. P. distasonis colonization had a minimal impact on gut microbiome composition and merely altered 28 ASVs upon colonization. In intraepithelial lymphocytes (IELs) of P. distasonis colonized SPF NOD mice, we observed a 1.72-fold reduction in T-helper cells and a 2.3-fold reduction in T-effector cells, along with a 1.85-fold reduction in B-cell populations. Further, P. distasonis did not alter serum metabolome and cytokine levels except for a decrease in IL-15. We observed no difference in the gene expression related to gut permeability. Similar to SPF mice, P. distasonis colonization in GF NOD mice induced severe insulitis without affecting gut permeability. On the other hand, P. distasonis lysate could induce insB:9-23 specific T cells. Altogether, these findings demonstrate that P. distasonis does not stimulate a nonspecific inflammatory immune response in the intestines, nor does it cause significant alterations in the gut microbiome, gut permeability, serum metabolome, or cytokine response. However, it does induce insulitis in GF NOD mice and activates insB:9-23 specific T-cells. These findings support our original hypothesis that P. distasonis colonization stimulates a specific immune response and enhances T1D onset in NOD mice via molecular mimicry.

immunology↗

bioRxiv2024

Children Who Develop Celiac Disease Exhibit Distinct Metabolic Pathways Among Their Gut Microbiota Years Before Diagnosis

Celiac disease (CD) is an autoimmune condition caused by a loss of tolerance to gluten in genetically predisposed individuals. While 30-40% of people possess the predisposing alleles, only 1-2% of the population is diagnosed with CD. This indicates environmental factors play a role in the pathogenesis of the disease, however the trigger of gluten tolerance loss is unknown. The gut microbiome composition of CD patients differs in comparison to their healthy counterparts; however, a causal link has not been established. In this study, we examined the alterations in the composition of the gut microbiota in a retrospective, longitudinal cohort of 10 children at age 1, matched for sex, human leukocyte antigen (HLA) genotype and breastfeeding duration. All samples were obtained from the pediatric donors prior to diagnosis (CD progressors). We used Ig-A sequencing combined with 16S sequencing for samples obtained at age 1. We also identified the functional metabolic pathways enriched in CD progressors compared to the healthy controls at ages 1, 2.5 (n=15-16) and 5 (n=9-13) using data from a similar study that we previously completed. Our findings demonstrate that CD progressors have ASV-level alterations in their gut microbiome as early as the first year of life, including the increased presence of some taxa that have been previously been reported to be enriched in CD. Using PICRUSt analysis, we also showed that inflammatory- and pathogenicity-related functions are enriched in CD progressors gut microbiome years before diagnosis. These pathways include glycine, serine and threonine metabolism, N-glycan biosynthesis and fatty acid biosynthesis and beta-lactam resistance, which are potentially contributing to chronic inflammation in CD. Overall, our results indicate distinct metabolic pathways enriched in the gut microbiome of CD progressors years before diagnosis. Understanding these pathways could advance our understanding of CD pathogenesis and its link to the gut microbiome.

microbiology↗

bioRxiv2020

Parabacteroides distasonis insulin B:9-23 epitope mimic stimulates insulin specific T-cells and enhances Type 1 Diabetes in NOD mice

Type 1 Diabetes (T1D) is an autoimmune disease characterized by the destruction of pancreatic {beta}-cells. One of the earliest aspects of this process is development of autoantibodies and T-cells directed at an epitope in the B-chain of insulin (insB:9-23). Analysis of microbial protein sequences with homology to insB:9-23 sequence revealed 17 peptides showing >50% identity to insB:9-23. Of these, one peptide, found in the normal human gut commensal Parabacteroides distasonis, activated both human T cell clones from T1D patients and T-cell hybridomas from non-obese diabetic (NOD) mice specific to insB:9-23. Immunization of NOD mice with P. distasonis insB:9-23 peptide mimic or insB:9-23 peptide verified immune cross-reactivity. Colonization of female NOD mice with P. distasonis accelerated the development of T1D, increasing macrophages, dendritic cells and destructive CD8+ T-cells, while decreasing FoxP3+ regulatory T-cells. Western blot analysis identified P. distasonis reacting antibodies in sera of NOD mice colonized with P. distasonis and human T1D patients. Furthermore, adoptive transfer of splenocytes from P. distasonis treated mice to NOD/SCID mice enhanced disease phenotype in the recipients. Finally, analysis of human infant gut microbiome data revealed that exposure of infants to P. distasonis may modulate disease pathogenesis. Taken together, these data demonstrate the potential role for an insB:9-23-mimimetic peptide from gut microbiota as a molecular trigger or modifier of T1D pathogenesis. SIGNIFICANCE STATEMENTIn Type 1 diabetes (T1D), immune cells destroy pancreatic {beta}-cells. The trigger of this response, however, is unknown. Some sequences (epitopes) in the insulin molecule form a major target for this autoimmune response. We have identified a sequence in a human gut bacterium that can mimetic this insulin epitope. Immune cells specific to insulin cross-react with this bacterial mimetic. Further, this bacterium can accelerate diabetes onset in a mouse model of T1D, inducing destructive and decreasing protective immune cells. We found this mimetic in the gut of children developing T1D. Furthermore, T1D patients have a stronger immune response to this bacterium compared to healthy individuals. Taken together, this bacterial mimetic in human gut has the potential to trigger/modify T1D onset.

immunology↗

bioRxiv2020

Children Developing Celiac Disease Have a Distinct and Proinflammatory Gut Microbiota in the First 5 Years of Life

Celiac disease (CD) is an autoimmune disorder triggered by gluten consumption. To identify the role of gut microbes in CD onset, we performed a longitudinal study focusing on two important phases of gut microbiota development at ages 2.5 and 5 (n=16). We obtained samples from children who developed CD during or after the study (CD progressors) and age, sex, and HLA-matched healthy controls. CD progressors had a distinct gut microbiota composition and IgA-sequencing identified unique IgA targets in the gut. Three cytokines, one chemokine, and 19 plasma metabolites were significantly altered in CD progressors at age 5. Feeding C57BL/6J mice with taurodeoxycholic acid (TDCA), a 2-fold increased microbiota-derived metabolite in CD progressors, caused villous atrophy, increased intraepithelial lymphocytes (IELs), CD4+ T-cells, Natural Killer cells, and Qa-1 expression on T-cells while decreasing T-regulatory cells in IELs. Thus, TDCA drives inflammation in the small intestines that potentially contribute to the CD onset. HighlightsO_LICD progressors have a distinct gut microbiome composition compared to healthy controls in two important phases of gut microbiota development (age 2.5 and 5 years) C_LIO_LICD progressors have more IgA-coated bacteria in their gut at age 5 compared to healthy controls. Further, IgA-sequencing identified unique bacterial targets in CD progressors. C_LIO_LIThree plasma proinflammatory cytokines and a chemokine were increased in CD progressors years before diagnosis, indicating an early inflammatory response. C_LIO_LIWe identified 19 metabolites that are significantly altered in CD progress at age 5 and microbiota-derived TDCA increased two-fold. C_LIO_LITDCA treatment in B6 mice increased CD4+ cells and NK cells while decreasing CD8+ T-regulatory (Treg) cells. It also increased Qa-1 expression on immune cells. C_LI

microbiology↗