Treatment of Type 1 Diabetes by Microbiome Maintenance

See “Intestinal Cathelicidin Antimicrobial Peptide Shapes a Protective Neonatal Gut Microbiota against Pancreatic Autoimmunity,” by Liang W, Enée E, Andre-Vallee C, et al, on page XXX. See “Intestinal Cathelicidin Antimicrobial Peptide Shapes a Protective Neonatal Gut Microbiota against Pancreatic Autoimmunity,” by Liang W, Enée E, Andre-Vallee C, et al, on page XXX. Gastroenterologists are well-acquainted with the gut microbiome; they interact with it on a daily basis. Now comes a report from an investigative team led by Liang et al1Liang W, Enée E, Andre-Vallee C, et al. Intestinal cathelicidin antimicrobial peptide shapes a protective neonatal gut microbiota against pancreatic autoimmunity. Gastroenterology Dec 21 [Epub ahead of print].Google Scholar (and published in this issue of Gastroenterology) in which a microbiome abnormality is held to be at the root of type I diabetes (T1D) and a key to its possible prevention.2Liang W. Enee E. Andre-Vallee C. et al.Intestinal cathelicidin anti-microbial peptide shapes a protective neonatal gut microbiota against pancreatic autoimmunity.Gastroenterology. 2021 Dec 29; (S0016-5085(21)04168-8. doi: 10.1053/j.gastro.2021.12.272. Online ahead of print)Abstract Full Text Full Text PDF Google Scholar This group presents evidence that newborn female NOD mice (mice genetically predisposed to autoimmune diabetes) have intestinal epithelial cells that lack the ability to produce cathelicidin-related antimicrobial peptide (CRAMP), an AMP that configures the microbiome of the colon during the preweaning period. This deficiency results in a dysbiosis, which is an abnormality of the microbiome, that, in turn, leads to the appearance of bacteria that cause epithelial cells to produce type I interferon (interferon-I). The interferon-I then “imprints” the mucosal dendritic cell population so that the latter becomes an effector cell population with a permanent capacity to produce proinflammatory cytokines or induce cytolytic T cells and a decreased capacity to induce regulatory T cells (Tregs). These effector dendritic cells, upon migration to the pancreas, can induce pancreatic islet cell reactive cytolytic T cells that cause islet beta-cell destruction and diabetes. That this is in fact the case is supported by the finding that diabetes in NOD mice can be ameliorated by local CRAMP administration or with a CRAMP-producing probiotic organism. Thus, the suggestion by the authors that the development of T1D in human at-risk children may also be prevented with early administration of a probiotic expressing a CRAMP-like antimicrobial organism. In that this work was conducted exclusively in the murine NOD model of diabetes it is fair to ask how well it comports with current concepts of the causation of human T1D. The consensus view of human T1D pathogenesis is that it is a disease initiated and sustained by viral infection of pancreatic beta cells, but only in individuals bearing an array of T1D susceptibility genes, most notably certain MHC class I genes and genes that license chronic viral infection and immunologic responses to such infection.3Lloyd R.F. Tamhankar M. Lernmark A. Enteroviruses and type 1 diabetes: multiple mechanisms and factors.Ann Rev Med. 2022; 73 (1–30.17): 30Crossref Scopus (1) Google Scholar The data available most clearly implicates enteroviruses, particularly Coxsackie B viruses, as the instigators of disease, but other viruses can be involved as well.4Rodriguez-Calvo T. Sabouri S. Anquetil F. et al.The viral paradigm in type 1 diabetes: who are the main suspects?.Autoimmune Rev. 2016; 15: 964-969Crossref PubMed Scopus (42) Google Scholar The viral infection of beta cells does not usually cause cell lysis but does cause cells to generate autoantigens and to produce interferon-I.5Marroqui L. Perez-Serna A.A. Babiloni-Chust I. et al.Type I interferons as key players in pancreatic β cell dysfunction in type 1 diabetes.Int Rev Cell Mol Biol. 2021; 359: 1-80Crossref PubMed Scopus (2) Google Scholar This sets the stage for autoimmune beta-cell destruction because interferon-I induces increased cell surface expression of MHC class I molecules loaded with beta-cell autoantigens and, at the same time, induces secretion of chemokines that recruit an array of cells into the islet cell milieu that mediate beta-cell cytotoxicity; importantly, these cells include effector dendritic cells capable of presenting beta-cell–derived autoantigens to cytotoxic T cells that target beta cells expressing the aforementioned MHC class I/beta-cell autoantigens.6Li Y. Sun F. Yue T.T. et al.Revisiting the antigen-presenting function of β cells in T1D pathogenesis.Front Immunol. 2021; 12690783Crossref PubMed Scopus (2) Google Scholar,7Knip M. Siljander H. The role of the intestinal microbiota in type 1 diabetes mellitus.Nat Rev Endocrinol. 2016; : 154-167Crossref PubMed Scopus (215) Google Scholar Note that this disease scenario does not mention or require that gut epithelial cells function as the initial sources of interferon-I or as the main inducers of effector dendritic cells that mediate beta-cell destruction. Thus, the role of such epithelial cell activity, highlighted in the Liang report,1Liang W, Enée E, Andre-Vallee C, et al. Intestinal cathelicidin antimicrobial peptide shapes a protective neonatal gut microbiota against pancreatic autoimmunity. Gastroenterology Dec 21 [Epub ahead of print].Google Scholar may be more critical to diabetes development in the NOD mouse than to human T1D because the NOD mouse develops diabetes in the absence of a viral infection. This said, there is an extensive body of studies establishing the fact that gut microbiome dysbiosis such as that observed in the Liang study is a common feature of NOD mice and, indeed, in prediabetic humans who go on to develop diabetes.6Li Y. Sun F. Yue T.T. et al.Revisiting the antigen-presenting function of β cells in T1D pathogenesis.Front Immunol. 2021; 12690783Crossref PubMed Scopus (2) Google Scholar,7Knip M. Siljander H. The role of the intestinal microbiota in type 1 diabetes mellitus.Nat Rev Endocrinol. 2016; : 154-167Crossref PubMed Scopus (215) Google Scholar That this contributes to T1D pathogenesis is shown by the fact that the incidence of T1D is influenced by factors that directly affect the initial composition of the microbiome such as the mode of fetal delivery and the occurrence of early antibiotic treatment.7Knip M. Siljander H. The role of the intestinal microbiota in type 1 diabetes mellitus.Nat Rev Endocrinol. 2016; : 154-167Crossref PubMed Scopus (215) Google Scholar In studies defining the dysbiosis related to T1D, it was shown that children genetically predisposed to T1D studied between the time of first appearance of autoantibodies (at “seroconversion”) and the time of onset of frank diabetes exhibit an increased abundance of commensal organisms that can function as pathobionts capable of inducing inflammatory responses; in addition, this was accompanied by a decreased abundance of bacteria that evoke anti-inflammatory responses or are less capable of producing short chain fatty acids, the latter substances shown to favor Treg development.9Kostic A.D. Gevers D. Siljander H. et al.The dynamics of the human infant gut microbiome in development and in progression toward type 1 diabetes.Cell Host Microb. 2015; 17: 260-273Abstract Full Text Full Text PDF PubMed Scopus (575) Google Scholar, 10Stewart C.J. Ajami N.J. O’Brian J.L. et al.Temporal development of the gut microbiome in early childhood from the TEDDY study.Nature. 2018; 562: 583-588Crossref PubMed Scopus (501) Google Scholar, 11Vatanen T. Franzosa E.A. Schwager R. et al.The human gut microbiome in early-onset type 1 diabetes from the TEDDY Study.Nature. 2018; 562: 589-594Crossref PubMed Scopus (269) Google Scholar Studies in NOD mice suggest that a bacterial constellation of this kind leads to decreased stimulation of mucosal dendritic cells necessary for generation of mucosal Tregs with the ability to traffic to pancreatic islets and thus counter the function of effector cells causing beta-cell loss at this site.12Goncalves Miranda M.C. Pires Oliveira R. Torres L. et al.Abnormalities in the gut mucosa of non-obese diabetic mice precede the onset of type 1 diabetes.J Leuk Biol. 2019; 106: 513-529Crossref PubMed Scopus (23) Google Scholar A similar decrease in Treg generation resulting from dysbiosis is thought to occur in human T1D, but this has less experimental support than in mouse models of diabetes because of the relative inaccessibility of relevant tissues in humans.13Bettini M. Bettini M.L. Function, failure, and the future potential of Tregs in type 1 diabetes.Diabetes. 2021; 70: 1211-1219Crossref PubMed Scopus (2) Google Scholar Nevertheless, the possibility that such loss of Treg generation occurs in humans as well as in experimental mice is compelling because dysbiosis hinders extrathymic induction of beta-cell antigen-specific Tregs at a site, the gastrointestinal mucosa, that is the logical repository of autoantigens originating from targeted beta-cells in the pancreatic islets. On this basis, the general thrust of the Liang study has considerable merit because it advocates for the prevention of human T1D by fostering a mucosal environment that allows mucosal Treg generation. The CRAMP equivalent in humans, known as LL-37, is a widely studied AMP implicated in the pathogenesis of several human inflammatory states.14Pahar B. Madonna S. Das A. et al.Immunomodulatory role of the antimicrobial LL-37 peptide in autoimmune disease and viral infections.Vaccines. 2020; 8: 517-536Crossref Scopus (20) Google Scholar However, there is little or no evidence (as yet) indicating that epithelial cells in neonatal humans at risk for diabetes are deficient in the production of LL-37 or an equivalent AMP. This finding, coupled with evidence that full-blown dysbiosis does not make its appearance in prediabetic children until diabetic autoimmunity occurs (at the time of seroconversion), suggests that the administration of an intestinal AMP appropriate to humans at the time of occurrence of incipient T1D may be the most relevant approach to control of T1D via maintenance of a physiologic microbiome, free of dysbiosis. 8Abdellatif A.M. Sarvetnick N.E. Current understanding of the role of gut dysbiosis in type 1 diabetes.J Diabetes. 2019; 11: 632-644Crossref PubMed Scopus (26) Google Scholar. Intestinal Cathelicidin Antimicrobial Peptide Shapes a Protective Neonatal Gut Microbiota Against Pancreatic AutoimmunityGastroenterologyPreviewExploring the intestinal environment in a newborn mouse model of autoimmune diabetes, the protective role of the cathelicidin antimicrobial peptide was uncovered through its ability to set a healthy microbiota. Full-Text PDF Open Access