In the intestine, multiple interactions occur with the external world. Thus, the intestinal mucosal barrier has to tolerate millions of microorganisms that commonly inhabit the gut, degrade and ...absorb food, and establish tolerance or immunity, depending on the nature of the encountered antigens. Recent findings have highlighted that intestinal epithelial cells are not simply a barrier, but also are crucial for integrating these external and internal signals and for coordinating the ensuing immune response. Here, I review these findings and show how epithelial cells harmonize information that comes from inflammatory and non-inflammatory components of the microbiota to preserve intestinal homeostasis. If dysregulated, this immunomodulatory function of epithelial cells might contribute to the development of intestinal inflammation.
The gut-liver axis refers to the bidirectional relationship between the gut and its microbiota, and the liver, resulting from the integration of signals generated by dietary, genetic and ...environmental factors. This reciprocal interaction is established by the portal vein which enables transport of gut-derived products directly to the liver, and the liver feedback route of bile and antibody secretion to the intestine. The intestinal mucosal and vascular barrier is the functional and anatomical structure that serves as a playground for the interactions between the gut and the liver, limiting the systemic dissemination of microbes and toxins while allowing nutrients to access the circulation and to reach the liver. The control of microbial communities is critical to maintaining homeostasis of the gut-liver axis, and as part of this bidirectional communication the liver shapes intestinal microbial communities. Alcohol disrupts the gut-liver axis at multiple interconnected levels, including the gut microbiome, mucus barrier, epithelial barrier and at the level of antimicrobial peptide production, which increases microbial exposure and the proinflammatory environment of the liver. Growing evidence indicates the pathogenetic role of microbe-derived metabolites, such as trimethylamine, secondary bile acids, short-chain fatty acids and ethanol, in the pathogenesis of non-alcoholic fatty liver disease. Cirrhosis by itself is associated with profound alterations in gut microbiota and damage at the different levels of defence of the intestinal barrier, including the epithelial, vascular and immune barriers. The relevance of the severe disturbance of the intestinal barrier in cirrhosis has been linked to translocation of live bacteria, bacterial infections and disease progression. The identification of the elements of the gut-liver axis primarily damaged in each chronic liver disease offers possibilities for intervention. Beyond antibiotics, upcoming therapies centred on the gut include new generations of probiotics, bacterial metabolites (postbiotics), faecal microbial transplantation, and carbon nanoparticles. FXR-agonists target both the gut and the liver and are currently being tested in different liver diseases. Finally, synthetic biotic medicines, phages that target specific bacteria or therapies that create physical barriers between the gut and the liver offer new therapeutic approaches.
Summary
Intestinal epithelial cells are fundamental to maintain barrier integrity and to participate in food degradation and absorption, but they can also decipher signals coming from the outside ...world and ‘educate’ the immune system accordingly. In particular, they interact with dendritic cells (DCs) and other intraepithelial immune cells to drive tolerogenic responses under steady state, but they can also release immune mediators to recruit inflammatory cells and to elicit immunity to infectious agents. When these interactions are deregulated, immune disorders can develop. In this review, we discuss some important features of epithelial cells and DCs and their fruitful interactions.
The intestinal barrier protects our body from external insults through specialized cells organized in a multilayered structure that evolved in symbiosis with the resident microbiota. A breach in the ...outer mucus and epithelium can be transmitted to the inner gut vascular barrier (GVB), leading to systemic dissemination of microbes or microbe-derived molecules. Several extraintestinal pathologies have been linked to gut microbiota dysbiosis that causes GVB leakage in their early phases. The consequent spreading of inflammatory stimuli to distant organs could be driven by later vascular barrier disruption at different sites, suggesting an interplay between anatomical barriers across the body. Thus, targeting the intestinal barrier holds promise for the prevention and/or therapy of several intestinal, metabolic, and neurological disorders.
The gut vascular barrier (GVB) represents the inner layer of defense in the multilayered intestinal barrier system that finely regulates the translocation of substances from the intestinal lumen to the systemic circulation.Alterations in gut microbiota barrier homeostasis can lead to the development of intestinal and extraintestinal disease induced by a leaky gut.Increased GVB permeability can lead to leakage of harmful molecules into the blood circulation, with consequent damage to other organs along the gut–liver–brain axis.Targeting the GVB and the active molecules that drive the vascular connection of the gut–liver–brain axis might provide additional therapeutic approaches to diseases affecting organs other than the intestine.
The gut mucosa is exposed to a large community of commensal bacteria that are required for the processing of nutrients and the education of the local immune system. Conversely, the gut immune system ...generates innate and adaptive responses that shape the composition of the local microbiota. One striking feature of intestinal adaptive immunity is its ability to generate massive amounts of noninflammatory immunoglobulin A (IgA) antibodies through multiple follicular and extrafollicular pathways that operate in the presence or absence of cognate T-B cell interactions. Here we discuss the role of intestinal IgA in host-commensal mutualism, immune protection, and tolerance and summarize recent advances on the role of innate immune cells in intestinal IgA production.
DCs are specialized APCs that orchestrate innate and adaptive immune responses. The intestinal mucosa contains numerous DCs, which induce either protective immunity to infectious agents or tolerance ...to innocuous antigens, including food and commensal bacteria. Several subsets of mucosal DCs have been described that display unique functions, dictated in part by the local microenvironment. In this review, we summarize the distinct subtypes of DCs and their distribution in the gut; examine how DC dysfunction contributes to intestinal disease development, including inflammatory bowel disease and celiac disease; and discuss manipulation of DCs for therapy.
In healthy individuals, the intestinal microbiota cannot access the liver, spleen, or other peripheral tissues. Some pathogenic bacteria can reach these sites, however, and can induce a systemic ...immune response. How such compartmentalization is achieved is unknown. We identify a gut-vascular barrier (GVB) in mice and humans that controls the translocation of antigens into the bloodstream and prohibits entry of the microbiota. Salmonella typhimurium can penetrate the GVB in a manner dependent on its pathogenicity island (Spi) 2-encoded type III secretion system and on decreased β-catenin-dependent signaling in gut endothelial cells. The GVB is modified in celiac disease patients with elevated serum transaminases, which indicates that GVB dismantling may be responsible for liver damage in these patients. Understanding the GVB may provide new insights into the regulation of the gut-liver axis.
The microbiota comprises the microorganisms that live in close contact with the host, with mutual benefit for both counterparts. The contribution of the gut microbiota to the emergence of ...castration-resistant prostate cancer (CRPC) has not yet been addressed. We found that androgen deprivation in mice and humans promotes the expansion of defined commensal microbiota that contributes to the onset of castration resistance in mice. Specifically, the intestinal microbial community in mice and patients with CRPC was enriched for species capable of converting androgen precursors into active androgens. Ablation of the gut microbiota by antibiotic therapy delayed the emergence of castration resistance even in immunodeficient mice. Fecal microbiota transplantation (FMT) from CRPC mice and patients rendered mice harboring prostate cancer resistant to castration. In contrast, tumor growth was controlled by FMT from hormone-sensitive prostate cancer patients and
administration. These results reveal that the commensal gut microbiota contributes to endocrine resistance in CRPC by providing an alternative source of androgens.
DCs in the gut have specialized functions and are involved in maintaining intestinal homeostasis via tolerizing the microbiota and inducing immunity to pathogenic bacteria. Here, we summarize the ...characteristics of two major subtypes of phagocytes in the gut (CX3CR1(+) and CD103(+)) and pDCs and analyze their possible involvement in bacterial handling.
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