Secretion of insulinotropic proteins by commensal bacteria: rewiring the gut to treat diabetes.
Ontology highlight
ABSTRACT:
SUBMITTER: Duan F
PROVIDER: S-EPMC2592943 | biostudies-literature | 2008 Dec
REPOSITORIES: biostudies-literature
Publications
Secretion of insulinotropic proteins by commensal bacteria: rewiring the gut to treat diabetes.
Duan Faping F Curtis Katherine L KL March John C JC
Applied and environmental microbiology 20081003 23
Here, we show that commensal bacteria can stimulate intestinal epithelial cells to secrete insulin in response to glucose. Commensal strains were engineered to secrete the insulinotropic proteins GLP-1 and PDX-1. Epithelia stimulated by engineered strains and glucose secreted up to 1 ng ml(-1) of insulin with no significant background secretion. ...[more]
Similar Datasets
Project description:The gut microbiota is essential for maintenance and repair of the intestinal epithelial barrier. As shifts in both intestinal epithelial barrier function and microbiota composition are found in inflammatory bowel disease patients, it is critical to understand the role of distinct bacteria in regulating barrier repair. We identified a mouse commensal E. coli isolate, GDAR2-2, that protects mice from Citrobacter rodentium infection and dextran sulfate sodium-induced colitis. Colonization with GDAR2-2 in mice resulted in expansion of CX3CR1+ mononuclear phagocytes, including CX3CR1+ macrophages/dendritic cells and monocytes, along with IL-22-secreting type 3 innate lymphoid cells and improved epithelial barrier function. In vitro co-culture of macrophages with GDAR2-2 resulted in IL-1β production. In vivo, protection after GDAR2-2 colonization was lost after depletion of CX3CR1+ MNPs, or blockade of IL-1β or IL-22. We further identified human commensal E. coli isolates that similarly protect mice from C. rodentium infection through CX3CR1+ MNP and IL-1β production. Together, these findings demonstrate an unexpected role for commensal bacteria in promoting IL-1β secretion to support intestinal barrier repair.
| S-EPMC8741296 | biostudies-literature
Project description:The influence of the microbiota on viral transmission and replication is well appreciated. However, its impact on retroviral pathogenesis outside of transmission/replication control remained unknown. Using Murine Leukemia Virus (MuLV), we found that some commensal bacteria promoted the development of leukemia induced by this retrovirus. The promotion of leukemia development by commensals was due to suppression of the adaptive immune response through upregulation of several negative regulators of immunity. These negative regulators included Serpinb9b and Rnf128, which are associated with a poor prognosis of some spontaneous human cancers. Upregulation of Serpinb9b was mediated by sensing of bacteria by NOD1/NOD2/RIPK2 pathway. This work describes a novel mechanism by which the microbiota enhances tumorigenesis within gut-distant organs and points at potential new targets for cancer therapy.
2022-07-29 | GSE209752 | GEO
Project description:Aim: Microbial colonization of the intestine in newborns is a critical event that regulates host physiology with lifelong consequences. However, there is a need to identify microbial molecules and mechanisms that play a role in this process. We aimed to elucidate the effects of flagellin, an important immunomodulatory component involved in bacterial motility, on intestinal epithelial functions. Methods: Germfree mice were colonized with synthetic bacterial communities, including a flagellated mouse gut isolate of Escherichia coli or a ΔfliC mutant thereof that lacks flagella. The offspring of these mice were studied at 7 days of age by single-cell RNA sequencing of epithelial cells isolated from the small intestine. Results: Enterococcus faecalis was the most dominant species in the small intestine of newborn mice. Blautia pseudococcoides was detected at low relative abundances. Colonization by either E. coli strain reduced the relative abundance of E. faecalis to 10% on average, and E. coli became the dominant member, with no substantial differences between mice colonized with the wildtype or mutant strain. The distribution of cell types within the small intestinal epithelium was skewed toward specialized cells (goblet, enteroendocrine, stem cells) at the expense of enterocytes in mice colonized with flagellated bacteria. These mice were characterized by higher expression of genes involved in cell-cell interactions (Npl, Epcam) and responses to infection (Ctsl) in enterocytes and enhanced translation (ribosomal proteins) in stem cells. In contrast, genes involved in lipid homeostasis (transport and metabolism; Apoc 2/4, Dgat2, Fabp 1/2, Mttp) in all cell types and inflammatory and androgen-related pathways in specialized cell types were less expressed in epithelial cells exposed to wildtype E. coli. Conclusion: These findings suggest that early life exposure to flagellated commensal bacteria influences cellular processes underlying tissue metabolism and remodeling in the small intestine.
2024-04-21 | GSE264411 | GEO
Project description:The gut epithelium's large surface area, its direct exposure to ingested nutrients, its vast stem cell population and its immunotolerogenic environment make it an excellent candidate for therapeutic cells to treat diabetes. Thus, several attempts have been made to coax immature gut cells to differentiate into insulin-producing cells by altering the expression patterns of specific transcription factors. Furthermore, because of similarities in enteroendocrine and pancreatic endocrine cell differentiation pathways, other approaches have used genetically engineered enteroendocrine cells to produce insulin in addition to their endogenous secreted hormones. Several studies support the utility of both of these approaches for the treatment of diabetes. Converting a patient's own gut cells into meal-regulated insulin factories in a safe and immunotolerogenic environment is an attractive approach to treat and potentially cure diabetes. Here, we review work on these approaches and indicate where we feel further advancements are required.
| S-EPMC4854511 | biostudies-other
Project description:The influence of the microbiota on viral transmission and replication is well appreciated. However, its impact on retroviral pathogenesis outside of transmission/replication control remains unknown. Using murine leukemia virus (MuLV), we found that some commensal bacteria promoted the development of leukemia induced by this retrovirus. The promotion of leukemia development by commensals is due to suppression of the adaptive immune response through upregulation of several negative regulators of immunity. These negative regulators include Serpinb9b and Rnf128, which are associated with a poor prognosis of some spontaneous human cancers. Upregulation of Serpinb9b is mediated by sensing of bacteria by the NOD1/NOD2/RIPK2 pathway. This work describes a mechanism by which the microbiota enhances tumorigenesis within gut-distant organs and points at potential targets for cancer therapy.
| S-EPMC10226680 | biostudies-literature
Project description:Toxoplasma gondii is a universally distributed pathogen that infects over one billion people worldwide. Host resistance to this protozoan parasite depends on a Th1 immune response with potent production of the cytokines interleukin-12 and interferon gamma. Although Toll-like receptor 11 (TLR11) plays a major role in controlling Th1 immunity to this pathogen in mice, this innate immune receptor is nonfunctional in humans, and the mechanisms of TLR11-independent sensing of T. gondii remain elusive. Here, we show that oral infection by T. gondii triggers a TLR11-independent but MyD88-dependent Th1 response that is impaired in TLR2xTLR4 double knockout and TLR9 single knockout mice. These mucosal innate and adaptive immune responses to T. gondii rely on the indirect stimulation of dendritic cells by normal gut microflora. Thus, our results reveal that gut commensal bacteria can serve as molecular adjuvants during parasitic infection, providing indirect immunostimulation that protects against T. gondii in the absence of TLR11.
| S-EPMC2746820 | biostudies-literature
Project description:The human gut is colonized by a large number of microorganisms (∼1013 bacteria) that support various physiologic functions. A perturbation in the healthy gut microbiome might lead to the development of inflammatory diseases, such as multiple sclerosis (MS). Therefore, gut commensals might provide promising therapeutic options for treating MS and other diseases. We report the identification of human gut-derived commensal bacteria, Prevotella histicola, which can suppress experimental autoimmune encephalomyelitis (EAE) in a human leukocyte antigen (HLA) class II transgenic mouse model. P. histicola suppresses disease through the modulation of systemic immune responses. P. histicola challenge led to a decrease in pro-inflammatory Th1 and Th17 cells and an increase in the frequencies of CD4+FoxP3+ regulatory T cells, tolerogenic dendritic cells, and suppressive macrophages. Our study provides evidence that the administration of gut commensals may regulate a systemic immune response and may, therefore, have a possible role in treatment strategies for MS.
| S-EPMC5763484 | biostudies-literature
Project description:Scientific studies focused on the role of the human microbiome over human health have generated billions of gigabits of genetic information during the last decade. Nowadays integration of all this information in public databases and development of pipelines allowing us to biotechnologically exploit this information are urgently needed. Prediction of the potential bioactivity of the products encoded by the human gut microbiome, or metaproteome, is the first step for identifying proteins responsible for the molecular interaction between microorganisms and the immune system. We have recently published the Mechanism of Action of the Human Microbiome (MAHMI) database (http://www.mahmi.org), conceived as a resource compiling peptide sequences with a potential immunomodulatory activity. Fifteen out of the 300 hundred million peptides contained in the MAHMI database were synthesized. These peptides were identified as being encrypted in proteins produced by gut microbiota members, they do not contain cleavage points for the major intestinal endoproteases and displayed high probability to have immunomodulatory bioactivity. The bacterial peptides FR-16 and LR-17 encrypted in proteins from Bifidobacterium longum DJ010A and Bifidobacterium fragilis YCH46 respectively, showed the higher immune modulation capability over human peripheral blood mononuclear cells. Both peptides modulated the immune response toward increases in the Th17 and decreases in the Th1 cell response, together with an induction of IL-22 production. These results strongly suggest the combined use of bioinformatics and in vitro tools as a first stage in the screening of bioactive peptides encrypted in the human gut metaproteome.
| S-EPMC5596104 | biostudies-literature
Project description:Bacteria generally live in species-rich communities, such as the gut microbiota. Yet little is known about bacterial evolution in natural ecosystems. Here, we followed the long-term evolution of commensal Escherichia coli in the mouse gut. We observe the emergence of mutation rate polymorphism, ranging from wild-type levels to 1,000-fold higher. By combining experiments, whole-genome sequencing, and in silico simulations, we identify the molecular causes and explore the evolutionary conditions allowing these hypermutators to emerge and coexist within the microbiota. The hypermutator phenotype is caused by mutations in DNA polymerase III proofreading and catalytic subunits, which increase mutation rate by approximately 1,000-fold and stabilise hypermutator fitness, respectively. Strong mutation rate variation persists for >1,000 generations, with coexistence between lineages carrying 4 to >600 mutations. The in vivo molecular evolution pattern is consistent with fitness effects of deleterious mutations sd ≤ 10-4/generation, assuming a constant effect or exponentially distributed effects with a constant mean. Such effects are lower than typical in vitro estimates, leading to a low mutational load, an inference that is observed in in vivo and in vitro competitions. Despite large numbers of deleterious mutations, we identify multiple beneficial mutations that do not reach fixation over long periods of time. This indicates that the dynamics of beneficial mutations are not shaped by constant positive Darwinian selection but could be explained by other evolutionary mechanisms that maintain genetic diversity. Thus, microbial evolution in the gut is likely characterised by partial sweeps of beneficial mutations combined with hitchhiking of slightly deleterious mutations, which take a long time to be purged because they impose a low mutational load. The combination of these two processes could allow for the long-term maintenance of intraspecies genetic diversity, including mutation rate polymorphism. These results are consistent with the pattern of genetic polymorphism that is emerging from metagenomics studies of the human gut microbiota, suggesting that we have identified key evolutionary processes shaping the genetic composition of this community.
| S-EPMC7064181 | biostudies-literature
Project description:The evolution of new strains within the gut ecosystem is poorly understood. We used a natural but controlled system to follow the emergence of intraspecies diversity of commensal Escherichia coli, during three rounds of adaptation to the mouse gut (∼1,300 generations). We previously showed that, in the first round, a strongly beneficial phenotype (loss-of-function for galactitol consumption; gat-negative) spread to >90% frequency in all colonized mice. Here, we show that this loss-of-function is repeatedly reversed when a gat-negative clone colonizes new mice. The regain of function occurs via compensatory mutation and reversion, the latter leaving no trace of past adaptation. We further show that loss-of-function adaptive mutants reevolve, after colonization with an evolved gat-positive clone. Thus, even under strong bottlenecks a regime of strong-mutation-strong-selection dominates adaptation. Coupling experiments and modeling, we establish that reverse evolution recurrently generates two coexisting phenotypes within the microbiota that can or not consume galactitol (gat-positive and gat-negative, respectively). Although the abundance of the dominant strain, the gat-negative, depends on the microbiota composition, gat-positive abundance is independent of the microbiota composition and can be precisely manipulated by supplementing the diet with galactitol. These results show that a specific diet is able to change the abundance of specific strains. Importantly, we find polymorphism for these phenotypes in indigenous Enterobacteria of mice and man. Our results demonstrate that natural selection can greatly overwhelm genetic drift at structuring the strain diversity of gut commensals and that competition for limiting resources may be a key mechanism for maintaining polymorphism in the gut.
| S-EPMC5850726 | biostudies-literature