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Acute pancreatitis (AP) is a common abdominal inflammatory disorder and one of the leading causes of hospital admission for gastrointestinal disorders. No specific pharmacological or nutritional therapy is available but highly needed. Inulin-type fructans (ITFs) are capable of modifying gut immune and barrier homeostasis in a chemistry-dependent manner and hence potentially applicable for managing AP, but their efficacy in AP has not been demonstrated yet. The current study aimed to examine and compare modulatory effects of ITFs with different degrees of fermentability on pancreatic-gut immunity and barrier function during experimentally induced AP in mice. BALB/c mice were fed short (I)- or long (IV)-chain ITFs supplemented diets for up to 3 days before AP induction by caerulein. Attenuating effects on AP development were stronger with ITF IV than with ITF I. We found that long-chain ITF IV attenuated the severity of AP, as evidenced by reduced serum amylase levels, lipase levels, pancreatic myeloperoxidase activity, pancreatic edema, and histological examination demonstrating reduced pancreatic damage. Short-chain ITF I demonstrated only partial protective effects. Both ITF IV and ITF I modulated AP-associated systemic cytokine levels. ITF IV but not ITF I restored AP-associated intestinal barrier dysfunction by upregulating colonic tight junction modulatory proteins, antimicrobial peptides, and improved general colonic histology. Additionally, differential modulatory effects of ITF IV and ITF I were observed on pancreatic and gut immunity: ITF IV supplementation prevented innate immune cell infiltration in the pancreas and colon and tissue cytokine production. Similar effects were only observed in the gut with ITF I and not in the pancreas. Lastly, ITF IV but not ITF I downregulated AP-triggered upregulation of IL-1 receptor-associated kinase 4 (IRAK-4) and phosphor-c-Jun N-terminal kinase (p-JNK), and a net decrease of phosphor-nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) p65 (p-NF-κB p65) nuclear translocation and activation in the pancreas. Our findings demonstrate a clear chain length-dependent effect of inulin on AP. The attenuating effects are caused by modulating effects of long-chain inulin on the pancreatic-gut immunity via the pancreatic IRAK-4/p-JNK/p-NF-κBp65 signaling pathway and on prevention of disruption of the gut barrier.

Intestinal microflora plays a key role in maintaining the homeostasis between immune and host health. Here, we reported the fluoride-induced changes of rectal structure and microflora in mice. The morphology of rectal tissue was observed by hematoxylin and eosin staining. The rectal development parameters (the thickness of mucosa, intestinal gland and muscle layer) were evaluated. The proliferation of rectal epithelial cells was evaluated via BrdU labeling. The distribution of goblet, glycoprotein and mast cell were evaluated by specific staining. Rectal microflora was detected using 16S rRNA high-throughput sequencing. The results showed that the rectal structure was seriously damaged and the proliferation of rectal epithelial cells was significantly inhibited by fluoride. The distribution of goblet cells, glycoprotein and mast cells decreased significantly after fluoride exposure. The relative richness of microfloras was changed after fluoride treatment, such as increased Bacteroidetes and decreased Firmicutes. In summary, this study indicated that excessive fluoride damages the intestinal structure, disturbs the intestinal micro-ecology and causes intestinal microflora disorder in mice. Findings mentioned in the present study enrich a new scope for elucidating fluoride toxicity from intestinal homeostasis.

“Dietary fiber” (DF) refers to a type of carbohydrate that cannot be digested fully. DF is not an essential nutrient, but it plays an important part in enhancing digestive capacity and maintaining intestinal health. Therefore, DF supplementation in the daily diet is highly recommended. Inulin is a soluble DF, and commonly added to foods. Recently, several studies have found that dietary supplementation of inulin can improve metabolic function and regulate intestinal immunity. Inulin is fermented in the colon by the gut microbiota and a series of metabolites is generated. Among these metabolites, short-chain fatty acids provide energy to intestinal epithelial cells and participate in regulating the differentiation of immune cells. Inulin and its intestinal metabolites contribute to host immunity. This review summarizes the effect of inulin and its metabolites on intestinal immunity, and the underlying mechanisms of inulin in preventing diseases such as type 2 diabetes mellitus, inflammatory bowel disease, chronic kidney disease, and certain cancer types.

The gut microbiota influences the health of the host, especially with regard to gut immune homeostasis and the intestinal immune response. In addition to serving as a nutrient enhancer, L-tryptophan (Trp) plays crucial roles in the balance between intestinal immune tolerance and gut microbiota maintenance. Recent discoveries have underscored that changes in the microbiota modulate the host immune system by modulating Trp metabolism. Moreover, Trp, endogenous Trp metabolites (kynurenines, serotonin, and melatonin), and bacterial Trp metabolites (indole, indolic acid, skatole, and tryptamine) have profound effects on gut microbial composition, microbial metabolism, the host's immune system, the host-microbiome interface, and host immune system-intestinal microbiota interactions. The aryl hydrocarbon receptor (AhR) mediates the regulation of intestinal immunity by Trp metabolites (as ligands of AhR), which is beneficial for immune homeostasis. Among Trp metabolites, AhR ligands consist of endogenous metabolites, including kynurenine, kynurenic acid, xanthurenic acid, and cinnabarinic acid, and bacterial metabolites, including indole, indole propionic acid, indole acetic acid, skatole, and tryptamine. Additional factors, such as aging, stress, probiotics, and diseases (spondyloarthritis, irritable bowel syndrome, inflammatory bowel disease, colorectal cancer), which are associated with variability in Trp metabolism, can influence Trp-microbiome-immune system interactions in the gut and also play roles in regulating gut immunity. This review clarifies how the gut microbiota regulates Trp metabolism and identifies the underlying molecular mechanisms of these interactions. Increased mechanistic insight into how the microbiota modulates the intestinal immune system through Trp metabolism may allow for the identification of innovative microbiota-based diagnostics, as well as appropriate nutritional supplementation of Trp to prevent or alleviate intestinal inflammation. Moreover, this review provides new insight regarding the influence of the gut microbiota on Trp metabolism. Additional comprehensive analyses of targeted Trp metabolites (including endogenous and bacterial metabolites) are essential for experimental preciseness, as the influence of the gut microbiota cannot be neglected, and may explain contradictory results in the literature.

The complex interplay between the gut microbiota, the intestinal barrier, the immune system and the liver is strongly influenced by environmental and genetic factors that can disrupt the homeostasis leading to disease. Among the modulable factors, diet has been identified as a key regulator of microbiota composition in patients with metabolic syndrome and related diseases, including the metabolic dysfunction-associated fatty liver disease (MAFLD). The altered microbiota disrupts the intestinal barrier at different levels inducing functional and structural changes at the mucus lining, the intercellular junctions on the epithelial layer, or at the recently characterized vascular barrier. Barrier disruption leads to an increased gut permeability to bacteria and derived products which challenge the immune system and promote inflammation. All these alterations contribute to the pathogenesis of MAFLD, and thus, therapeutic approaches targeting the gut-liver-axis are increasingly being explored. In addition, the specific changes induced in the intestinal flora may allow to characterize distinctive microbial signatures for non-invasive diagnosis, severity stratification and disease monitoring.

The physical barrier of the intestine and associated mucosal immunity maintains a delicate homeostatic balance between the host and the external environment by regulating immune responses to commensals, as well as functioning as the first line of defense against pathogenic microorganisms. Understanding the orchestration and characteristics of the intestinal mucosal immune response during commensal or pathological conditions may provide novel insights into the mechanisms underlying microbe-induced immunological tolerance, protection, and/or pathogenesis. Over the last decade, our knowledge about the interface between the host intestinal mucosa and the gut microbiome has been dominated by studies focused on bacterial communities, helminth parasites, and intestinal viruses. In contrast, specifically how commensal and pathogenic protozoa regulate intestinal immunity is less well studied. In this review, we provide an overview of mucosal immune responses induced by intestinal protozoa, with a major focus on the role of different cell types and immune mediators triggered by commensal ( Blastocystis spp. and Tritrichomonas spp.) and pathogenic ( Toxoplasma gondii , Giardia intestinalis , Cryptosporidium parvum ) protozoa. We will discuss how these various protozoa modulate innate and adaptive immune responses induced in experimental models of infection that benefit or harm the host.

Intestinal immunity and homeostasis are maintained through the regulation of cytokine trafficking, microbiota, necrosis and apoptosis. Intestinal immunity and homeostasis participate in host defenses and inflammatory responses locally or systemically through the gut-organ axis. NF-κB functions as a crucial transcription factor mediating the expression of proteins related to the immune responses. The activation of NF-κB involves two major pathways: canonical and non-canonical. The canonical pathway has been extensively studied and reviewed. Here, we present the current knowledge of NIK, a pivotal mediator of the non-canonical NF-κB pathway and its role in intestinal immunity and homeostasis. This review also discusses the novel role of NIK signaling in the pathogenesis and treatment of inflammatory bowel disease.

Over a long period of evolution, insects have developed unique intestinal defenses against invasion by foreign microorganisms, including physical defenses and immune responses. The physical defenses of the insect gut consist mainly of the peritrophic matrix (PM) and mucus layer, which are the first barriers to pathogens. Gut microbes also prevent the colonization of pathogens. Importantly, the immune-deficiency (Imd) pathways produce antimicrobial peptides to eliminate pathogens; mechanisms related to reactive oxygen species are another important pathway for insect intestinal immunity. The janus kinase/STAT signaling pathway is involved in intestinal immunity by producing bactericidal substances and regulating tissue repair. Melanization can produce many bactericidal active substances into the intestine; meanwhile, there are multiple responses in the intestine to fight against viral and parasitic infections. Furthermore, intestinal stem cells (ISCs) are also indispensable in intestinal immunity. Only the coordinated combination of the intestinal immune defense system and intestinal tissue renewal can effectively defend against pathogenic microorganisms.

Hesperidin, found in citrus fruits, has shown a wide range of biological properties. Nonetheless, a more in-depth investigation is required on the effects on the immune system, and in particular, on the gut-associated lymphoid tissue, together with its relationship with the gut microbiota. Therefore, we aimed to establish the influence of oral hesperidin administration on the intestinal lymphoid tissue and on the gut microbiota composition in healthy animals. Lewis rats were orally administrated 100 or 200 mg/kg hesperidin three times per week for four weeks. Microbiota composition and IgA-coated bacteria were determined in caecal content. Mesenteric lymph node lymphocyte (MLNL) composition and functionality were assessed. IgA, cytokines, and gene expression in the small intestine were quantified. Hesperidin administration resulted in a higher number of bacteria and IgA-coated bacteria, with changes in microbiota composition such as higher Lactobacillus proportion. Hesperidin was also able to increase the small intestine IgA content. These changes in the small intestine were accompanied by a decrease in interferon-γ and monocyte chemotactic protein-1 concentration. In addition, hesperidin increased the relative proportion of TCRαβ+ lymphocytes in MLNL. These results show the immunomodulatory actions of hesperidin on the gut-associated lymphoid tissue and reinforce its role as a prebiotic.

Crohn’s disease (CD) is a chronic relapsing disorder of the gastrointestinal tract and represents one of the main entities of inflammatory bowel disease (IBD). CD affects genetically susceptible patients that are influenced by environmental factors and the intestinal microbiome, which results in excessive activation of the mucosal immune system and aberrant cytokine responses. Various studies have implicated the pro-inflammatory cytokines IL17 and IL23 in the pathogenesis of CD. IL23 is a member of the IL12 family of cytokines and is able to enhance and affect the expansion of pathogenic T helper type 17 (Th17) cells through various mechanisms, including maintenance of Th17 signature genes, upregulation of effector genes or suppression of repressive factors. Moreover, IL17 and IL23 signaling is able to induce a cascade of pro-inflammatory molecules like TNF, IFNγ, IL22, lymphotoxin, IL1β and lipopolysaccharide (LPS). Here, IL17A and TNF are known to mediate signaling synergistically to drive expression of inflammatory genes. Recent advances in understanding the immunopathogenetic mechanisms underlying CD have led to the development of new biological therapies that selectively intervene and inhibit inflammatory processes caused by pro-inflammatory mediators like IL17 and IL23. Recently published data demonstrate that treatment with selective IL23 inhibitors lead to markedly high response rates in the cohort of CD patients that failed previous anti-TNF therapy. Macrophages are considered as a main source of IL23 in the intestine and are supposed to play a key role in the molecular crosstalk with T cell subsets and innate lymphoid cells in the gut. The following review focuses on mechanisms, pathways and specific therapies in Crohn’s disease underlying the IL23/IL17 pathway.