Maintaining Gut Homeostasis Research Articles

A PGC-1 Tale: Healthier Intestinal Stem Cells, Longer Life

PGC-1 regulates energy homeostasis and mitochondrial activity. In this issue, Rera etal. (2011) show that dPGC-1 overexpression in Drosophila intestinal stem cells and their immediate progeny extends organismal life span and protects against age-related loss of intestinal homeostasis and integrity, thereby establishing a link between mitochondria, tissue stem cells, and aging.

Enteric Commensal Bacteria Induce Extracellular Signal-regulated Kinase Pathway Signaling via Formyl Peptide Receptor-dependent Redox Modulation of Dual Specific Phosphatase 3

The normal microbial occupants of the mammalian intestine are crucial for maintaining gut homeostasis, yet the mechanisms by which intestinal cells perceive and respond to the microbiota are largely unknown. Intestinal epithelial contact with commensal bacteria and/or their products has been shown to activate noninflammatory signaling pathways, such as extracellular signal-related kinase (ERK), thus influencing homeostatic processes. We previously demonstrated that commensal bacteria stimulate ERK pathway activity via interaction with formyl peptide receptors (FPRs). In the current study, we expand on these findings and show that commensal bacteria initiate ERK signaling through rapid FPR-dependent reactive oxygen species (ROS) generation and subsequent modulation of MAP kinase phosphatase redox status. ROS generation induced by the commensal bacteria Lactobacillus rhamnosus GG and the FPR peptide ligand, N-formyl-Met-Leu-Phe, was abolished in the presence of selective inhibitors for G protein-coupled signaling and FPR ligand interaction. In addition, pretreatment of cells with inhibitors of ROS generation attenuated commensal bacteria-induced ERK signaling, indicating that ROS generation is required for ERK pathway activation. Bacterial colonization also led to oxidative inactivation of the redox-sensitive and ERK-specific phosphatase, DUSP3/VHR, and consequent stimulation of ERK pathway signaling. Together, these data demonstrate that commensal bacteria and their products activate ROS signaling in an FPR-dependent manner and define a mechanism by which cellular ROS influences the ERK pathway through a redox-sensitive regulatory circuit.

Mucosal Injuries due to Ribosome-Inactivating Stress and the Compensatory Responses of the Intestinal Epithelial Barrier

Ribosome-inactivating (ribotoxic) xenobiotics are capable of using cleavage and modification to damage 28S ribosomal RNA, which leads to translational arrest. The blockage of global protein synthesis predisposes rapidly dividing tissues, including gut epithelia, to damage from various pathogenic processes, including epithelial inflammation and carcinogenesis. In particular, mucosal exposure to ribotoxic stress triggers integrated processes that are important for barrier regulation and re-constitution to maintain gut homeostasis. In the present study, various experimental models of the mucosal barrier were evaluated for their response to acute and chronic exposure to ribotoxic agents. Specifically, this review focuses on the regulation of epithelial junctions, epithelial transporting systems, epithelial cytotoxicity, and compensatory responses to mucosal insults. The primary aim is to characterize the mechanisms associated with the intestinal epithelial responses induced by ribotoxic stress and to discuss the implications of ribotoxic stressors as chemical modulators of mucosa-associated diseases such as ulcerative colitis and epithelial cancers.

Inflamed gut mucosa: downstream of interleukin‐10

Interleukin-10 is a pleiotropic cytokine, whose main function is limitation and ultimately termination of immune responses. This is especially true for environmental interfaces such as the gastrointestinal tract. IL-10 acts as a key mediator for maintaining gut homeostasis. IL-10 knockout mice are well established as a genetic model for inflammatory bowel disease (IBD), and sequence variants in the IL-10 locus contribute to ulcerative colitis (UC). This review covers the significance of IL-10 signalling in the intestinal immune response both in health and disease. It explains the biological role of IL-10, its deregulation in IBD and its contribution to intestinal inflammation via endoplasmic reticulum stress response. Many IBD susceptibility genes have been discovered in the past years, linking fundamental biological systems, like innate and adaptive immunity, stress responses, autophagy and mucosal barrier to the pathogenesis of Crohn's disease (CD) and UC. IL-10 has long been known for its substantial role in regulating gut immunity, but its contribution to IBD was somewhat elusive. A recent study identified mutations in either IL-10 receptor subunits that are associated with early-onset enterocolitis, a severe phenotype of IBD. Other than genetic variants of IL-10 receptors, IL-10 and STAT3 genes are also associated with IBD, emphasizing the involvement of the IL-10 signalling cascade in the pathogenesis of CD and UC. The discovery of inherited deregulations in the IL-10 signalling cascade is not only considered the missing link between IL-10 and intestinal homeostasis, but also demonstrates how findings made in animal models help explaining human disease.

Fibroblast Growth Factor Receptor-3 (FGFR-3) Regulates Expression of Paneth Cell Lineage-specific Genes in Intestinal Epithelial Cells through both TCF4/β-Catenin-dependent and -independent Signaling Pathways

Fibroblast growth factor receptor-3 (FGFR-3) expression in the developing intestine is restricted to the undifferentiated epithelial cells within the lower portion of the crypt. We previously showed that mice lacking functional FGFR-3 have a significant decrease in the number of Paneth cells in the small intestine. Here, we used Caco2 cells to investigate whether FGFR-3 signaling can directly modulate expression of Paneth cell differentiation markers through its effects on TCF4/β-catenin or through other signaling pathways downstream of this receptor. Caco2 cells treated with FGFR-3 ligands or expressing FGFR-3(K650E), a constitutively active mutant, resulted in a significantly increased expression of genes characteristic of mature Paneth cells, including human α-defensins 5 and 6 (HD5 and HD6) and Paneth cell lysozyme, whereas enterocytic differentiation markers were reduced. Activation of FGFR-3 signaling sustained high levels of β-catenin mRNA expression, leading to increased TCF4/β-catenin-regulated transcriptional activity in Caco2 cells. Sustained activity of the TCF4/β-catenin pathway was required for the induction of Paneth cell markers. Activation of the MAPK pathway by FGFR-3 is also required for the induction of Paneth cell markers in addition to and independent of the effect of FGFR-3 on TCF4/β-catenin activity. These studies suggest that coordinate activation of multiple independent signaling pathways downstream of FGFR-3 is involved in regulation of Paneth cell differentiation.

Glycosylated Chitinase 3-Like 1 Protein and Chitin-Binding Motif of Potentially Pathogenic E. coli Play a Critical Role in Host-Microbial Interactions

response to ATP (5 mM) than control group after 3h (291 ± 4.6 versus 55.85 ± 1.9, respectively, p < 0.0001). IL-β secretion was completely abrogated when ATP was preincubated with cIAP (200 units/ml) for 2 h. Conclusions: We hypothesize that IAP could play a role in protecting the host against excessive gut inflammation induced by extracellular danger signals like ATP. These processes are critical to the fundamental understanding of the gut mucosal enzyme defense system which maintains gut homeostasis. IAP could represent a novel therapy for human IBD.

Unveiling an abundant core microbiota in the human adult colon by a phylogroup-independent searching approach

The potential presence of widespread and stable bacterial core phylogroups in the human colon has promoted considerable attention. Despite major efforts, no such phylogroups have yet been identified. Therefore, using a novel phylogroup- and tree-independent approach, we present a reanalysis of 1,114,722 V2 region and 71,550 near full-length 16S rRNA sequences from a total of 210 human beings, with widespread geographic origin, ethnic background and diet, in addition to a wide range of other mammals. We found two highly prevalent core phylogroups (cores 1 and 2), belonging to the clostridial family Lachnospiraceae. These core phylogroups showed a log-normal distribution among human individuals, while non-core phylogroups showed more skewed distributions towards individuals with low levels compared with the log-normal distribution. Molecular clock analyses suggest that core 2 co-evolved with the radiation of vertebrates, while core 1 co-evolved with the mammals. Taken together, the stability, prevalence and potential functionality support the fact that the identified core phylogroups are pivotal in maintaining gut homeostasis and health.

Altered innate immunity contributes to the development of colitis in PI3K p110d mutant mice

The phosphoinositide‐3 kinase (PI3K) pathway is an important negative regulator of innate immune signaling. Initial characterization of mice with a targeted mutation in the p110δ subunit of PI3K revealed chronic, focal colitis. However, immunomodulatory effects of PI3K p110δ in innate immunity remain unclear. We demonstrate that PI3K p110δ mutant macrophages (splenic, bone marrow derived &amp; intestinal) are hyperresponsive to TLR signaling, producing increased levels of IL‐12 p40, IL‐12 p70, and IL‐23. Likewise, increased colonic IL‐12/23, IFN‐γ, and IL‐17 are detected, indicating that aberrant regulation of innate immune signaling could contribute to the development of Th1/Th17 mediated colitis. An innate mucosal inflammatory response is essential for clearance of enteric microorganisms that breach the epithelial barrier. However, excessive and prolonged activation of these inflammatory pathways is detrimental to the host and may contribute to the pathogenesis of IBD. We therefore sought to determine the role of PI3K p110δ signaling in killing of intracellular enteric bacteria by macrophages. P13K p110δ mutant macrophages display significantly decreased killing of intracellular K12 E. coli compared to wild type macrophages. In addition, decreased bacterial killing was associated with marked increases in IL‐12 p40 production in p110δ mutant macrophages as compared to wild type macrophages (mutant vs. wild type, p= 0.05, n=3). In conclusion, PI3K p110δ plays an important role in dampening innate immune responses necessary for maintaining gut homeostasis.

Commensal bacteria exert immunomodulatory activities on human intestinal immune cells

Aims: Intestinal epithelial cells (IEC) and dendritic cells (DC) play a crucial role in antigen sampling and maintaining gut homeostasis. Here we investigated the responses of these gut cells to commensal and pathogenic bacteria.

Immunologic effects of probiotics and human health

The human gastrointestinal tract (GIT) harbours an extremely complex and diverse microbial ecosystem representing over 500 different species. While a majority of indigenous bacteria are benign or beneficial, some possess the potential to cause disease; in healthy individuals, a balance exists between these populations. In addition to nutritional and barrier functions, the intestinal microflora plays an important role in guiding the development of a balanced immune system and maintaining gut homeostasis. Perturbations in the microbial homeostasis due to factors such as antibiotic therapy, stress and infection enhances predisposition to increased risk of infectious diseases, cancers and immunoinflammatory disorders.

Isobutyl cinnamate

The gut microbiota acts as a real organ. The symbiotic interactions between the living microorganisms and the digestive tract contribute greatly to maintaining gut homeostasis. However, alterations to the microbiota caused by environmental changes (e.g., infection, diet, and/or lifestyle) can disturb this relationship, altering the healthy status and promoting disease, such as different types of inflammatory bowel diseases and cancer. Regarding the latter, it is noteworthy that it is already proven that this alteration in microbiota is implicated in the occurrence and development of colorectal cancer (CRC).Despite progress being made, CRC continues to be one of the deadliest cancer types with different molecular phenotypes, a strong resistance to therapies, and a very high mortality rate. In recent years, clinical data show that the incidence of CRC decreased slightly among adults aged ≥ 50 years. In contrast, the incidence increased by about 20% among adults aged < 50 years, with mortality increasing by about 10%. These changes seem to show that some factors, different to genetic predisposition and related with lifestyle, have started to influence the early apparition of disease.Due to the advances produced in the knowledge of the microbiota composition and its role in CRC, an interesting need in identifying new markers for the diagnosis, prevention, and even treatment has emerged. This has been possible due to the advances produced in sequencing technologies, which through the analysis of the 16S bacterial region on fecal samples have allowed; for example, characterize some microbial markers.