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PubMed1999

Inflammation does not decrease intraluminal pH in chronic inflammatory bowel disease.

Intestinal inflammation may influence intraluminal pH. Profiles of the gastrointestinal pH were evaluated in 15 patients with active Crohn's disease of the ileocecal area. In addition, five patients with moderate (1) or severe (4) ulcerative colitis were studied. Fifteen healthy subjects served as controls. Intraluminal pH of the different parts of the gastrointestinal tract was measured by a free-floating pH-sensitive telemetering capsule. A metal sphere was attached to the capsule for exact localization by a metal detector. Physiological patterns of pH were maintained throughout the gastrointestinal tract including the inflamed segments. Median pH in the terminal ileum of the patients with Crohn's disease was 7.5 vs. 7.7 and in the rectum in ulcerative colitis 7.8 vs. 7.2 in the controls. In conclusion, intraluminal pH is not decreased by inflammatory changes in Crohn's disease and ulcerative colitis, allowing eudragit-coated pH-controlled-release formulations of mesalazine to dissolve in diseased areas also.

Acid-Base Equilibrium↗
PubMed2005

Therapeutic potential of follistatin for colonic inflammation in mice.

BACKGROUND AND AIMS: Activins belong to the transforming growth factor-beta superfamily. Recent studies have shown that activin and its natural antagonist, follistatin, are involved in tissue repair and inflammatory processes. The aim of this study was to determine whether neutralization of activins with follistatin would have an in vivo anti-inflammatory effect in several murine models of colitis. METHODS: We assessed activin levels in the colitis induced by intracolonic administration of trinitrobenzene sulfonic acid (TNBS). We subsequently tested the effects of an intraperitoneal injection of follistatin before or after induction of TNBS colitis. We also examined the established colitis induced by oral dextran sulfate sodium (DSS) as well as the spontaneous colitis that develops in interleukin (IL)-10 gene-deficient (IL-10 -/- ) mice. RESULTS: Levels of activin transcripts in the colon during the acute phase of TNBS colitis were up-regulated. Epithelial cells, infiltrating macrophages (Mvarphi), and endothelial cells produced excess activin betaA. Pretreatment with follistatin increased the survival rate of mice with TNBS colitis from 33% to 82% and decreased the plasma levels of IL-6 and amyloid A. Administration of follistatin also reduced the histologic score and tissue myeloperoxidase activity in established TNBS and DSS colitis and reduced the severity of the colitis in IL-10 -/- mice. Based on results obtained from 3 mouse models and from in vitro experiments, follistatin promoted the proliferation of colonic epithelial cells. CONCLUSIONS: Neutralization of activins by follistatin promoted epithelial cell division and tissue repair, clearly suggesting a treatment modality for intestinal inflammation.

Animals↗
PubMed2025

Parabacteroides goldsteinii mitigates parkinsonism in LRRK2 mutant mice by reducing neuroinflammation through Gut-Brain axis.

INTRODUCTION: Alterations in the gut microbiota accompanied by intestinal inflammation are early features of Parkinson's disease (PD). Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene represent a common genetic risk factor for PD and inflammatory bowel disease. Parabacteroides goldsteinii has been reported to alleviate intestinal and systemic inflammation. However, whether modulation of the gut microenvironment at early disease stage can attenuate PD progression remains unclear. OBJECTIVE: To investigate the impact of P. goldsteinii colonization prior to the onset of motor dysfunction on PD progression. METHODS: We established a germ-free PD mouse model carrying the LRRK2 G2019S mutation and administered P. goldsteinii orally at the pre-symptomatic stage to evaluate its effects on motor performance and PD-related neuropathology. Spatial and bulk RNA transcriptomic analyses of brain tissue, together with cytokine profiling, were conducted to assess central changes. To investigate gut immunomodulatory mechanisms, we performed intestinal bulk and single-cell RNA sequencing, spectral flow cytometry as well as cellular bioenergetic analyses. RESULTS: Germ-free conditions partially alleviated PD-like phenotypes in LRRK2 G2019S mice. Colonization with P. goldsteinii at 5-months of age, prior to motor symptom onset, further improved locomotor performance, reduced neuronal α-synuclein aggregations, and mitigated microglial activation and dopaminergic neurodegeneration. Neuroprotection was mediated through enhanced noncanonical neuronal IL-12 receptor-dependent neurotrophic support without activating the canonical STAT4 phosphorylation pathway, along with suppression of microglial activation and downregulation of LRRK2 kinase activity. At the intestinal level, P. goldsteinii suppressed TLR4-driven inflammation, expanded anti-inflammatory intraepithelial CD4+CD8αα+ T cells, promoted dendritic cell and macrophage differentiation, upregulated epithelial tight-junction genes, and improved mitochondrial bioenergetics in intestinal cells. CONCLUSION: P. goldsteinii colonization attenuates the progression of LRRK2-associated parkinsonism by restoring intestinal homeostasis and reducing neuroinflammation. These findings underscore the therapeutic potential of modulating the gut-immune-brain axis during the prodromal stage of PD.

Animals↗
PubMed2005

Combined effect of 25-hydroxycholesterol and IL-1beta on IL-8 production in human colon carcinoma cell line (Caco-2).

Interleukin-1 beta (IL-1beta) is an important mediator in intestinal inflammation. IL-1beta promotes IL-8 production, which can be modulated by a number of factors, including oxidative stress. Interestingly, oxysterols, which are thought to contribute to inflammation in atherosclerotic plaques, are also produced by intestinal epithelial cells. Thus, we investigated the effect of oxysterols, including 25-hydroxycholesterol and 7beta-hydroxycholesterol, on IL-1beta-induced IL-8 production in Caco-2 cells (a human colon carcinoma cell line). Pre-treatment of Caco-2 cells with 25-hydroxycholesterol significantly enhanced IL-1beta-induced IL-8 expression at both mRNA and protein levels. However, 7beta-hydroxycholesterol showed very little effect on IL-8 production. Furthermore, pre-treatment with 25-hydroxycholesterol, followed by IL-1beta stimulation, enhanced IL-8 promoter activity beyond that observed with IL-1beta alone. These results suggest that 25-hydroxycholesterol enhances IL-1beta-induced IL-8 production, possibly by enhancing promoter activity.

Adenocarcinoma↗
PubMed1995

The 5-lipoxygenase pathway in cultured human intestinal epithelial cells.

Leukotrienes (LTs), the 5-lipoxygenase (5-LOX) metabolites of arachidonic acid, have roles in many biological processes relevant to the gastrointestinal tract, including intestinal inflammation. We screened two well-known human intestinal epithelial cell lines, HT29 and Caco-2, for evidence of LT-associated enzyme transcripts and LT synthesis. Northern blot analysis of total RNA from both intestinal lines demonstrated high levels of transcripts for LTA4 hydrolase, a multisubstrate enzyme that converts the 5-LOX metabolite, LTA4, to LTB4. With total RNA, the 5-LOX transcript was detected only in HT29. Caco-2 failed to show 5-LOX message even with poly A-containing RNA, although the transcript could be amplified with the polymerase chain reaction. Messenger RNA for FLAP, the 5-lipoxygenase-activating protein, was detectable in both cell lines, but only with poly A-containing RNA. In a sonicated cell preparation, HT29, but not Caco-2, revealed detectable levels of 5-HETE and LTB4. These results suggest that certain intestinal epithelial cells possess a limited capacity to synthesize LTs.

5-Lipoxygenase-Activating Proteins↗
PubMed2006

Regulation of early and delayed radiation responses in rat small intestine by capsaicin-sensitive nerves.

PURPOSE: Mast cells protect against the early manifestations of intestinal radiation toxicity, but promote chronic intestinal wall fibrosis. Intestinal sensory nerves are closely associated with mast cells, both anatomically and functionally, and serve an important role in the regulation of mucosal homeostasis. This study examined the effect of sensory nerve ablation on the intestinal radiation response in an established rat model. METHODS AND MATERIALS: Rats underwent sensory nerve ablation with capsaicin or sham ablation. Two weeks later, a localized segment of ileum was X-irradiated or sham irradiated. Structural, cellular, and molecular changes were examined 2 weeks (early injury) and 26 weeks (chronic injury) after irradiation. The mast cell dependence of the effect of sensory nerve ablation on intestinal radiation injury was assessed using c-kit mutant (Ws/Ws) mast cell-deficient rats. RESULTS: Capsaicin treatment caused a baseline reduction in mucosal mast cell density, crypt cell proliferation, and expression of substance P and calcitonin gene-related peptide, two neuropeptides released by sensory neurons. Sensory nerve ablation strikingly exacerbated early intestinal radiation toxicity (loss of mucosal surface area, inflammation, intestinal wall thickening), but attenuated the development of chronic intestinal radiation fibrosis (collagen I accumulation and transforming growth factor beta immunoreactivity). In mast cell-deficient rats, capsaicin treatment exacerbated postradiation epithelial injury (loss of mucosal surface area), but none of the other aspects of radiation injury were affected by capsaicin treatment. CONCLUSIONS: Ablation of capsaicin-sensitive enteric neurons exacerbates early intestinal radiation toxicity, but attenuates development of chronic fibroproliferative changes. The effect of capsaicin treatment on the intestinal radiation response is partly mast cell dependent.

Animals↗
PubMed2003

Role of bacteria in experimental colitis.

Epidemiology suggests some relationship between the establishment of the gut flora and the risk of developing inflammatory bowel disease. Unrestrained activation of the immune system against commensal bacteria appears to be responsible for the chronicity of these diseases. In animal models, broad-spectrum antibiotics reduce the bacterial load and militate against intestinal inflammation. Several bacterial species found in of the common microflora, including anaerobes, are able to invade the colonic wall when there is dysfunction of the colonic mucosal barrier. Most aerobes provoke focal areas of acute inflammation, but some anaerobes in the predominant flora induce diffuse a fibrogenic transmural response. Current research aims to identify the probiotics that might act against these bacteria. Colonization with specific probiotic strains, including a bacterium genetically engineered to secrete interleukin-10, prevents spontaneous colitis in susceptible mice. Certain lactobacilli exhibit anti-inflammatory properties naturally, i.e. without previous genetic manipulation. Prebiotics may increase colonization by lactobacilli and can prevent mucosal inflammation. Modulation of the gut flora with probiotics may prove useful in the prevention and control of inflammatory bowel diseases.

Animals↗
PubMed2003

The genetics of inflammatory bowel disease.

The inflammatory bowel diseases (IBD) comprise complex genetic disorders, with multiple contributing genes. Linkage studies have implicated several genomic regions as likely containing IBD susceptibility genes, with some observed uniquely in Crohn's disease (CD) or ulcerative colitis (UC), and others common to both disorders. The best replicated linkage region, IBD1, on chromosome 16q contains the CD susceptibility gene, NOD2/CARD15. NOD2/CARD15 is expressed in peripheral blood monocytes and is structurally related to the plant R proteins, which mediate host resistance to microbial pathogens. Three major coding region polymorphisms within NOD2/CARD15 have been highly associated with CD among patients of European descent. Having one copy of the risk alleles confers a 2-4-fold risk for developing CD, whereas double-dose carriage increases the risk 20-40-fold. All 3 major CD variants exhibit a deficit in NF-kappaB activation in response to bacterial components. Carriage of NOD2/CARD15 risk alleles is associated with ileal location, earlier disease onset, and stricturing phenotype. Other IBD genomic regions include IBD2 on chromosome 12q (observed more in UC), and IBD3, containing the major histocompatibility complex region. A short genomic region has been associated with CD on chromosome 5q, but the precise contributing gene is as yet unidentified. The characterization of additional IBD susceptibility genes could potentially lead to the identification of novel therapeutic agents for IBD, make possible a molecular reclassification of disease, and increase understanding of the contribution of environmental factors (notably, tobacco and the intestinal microbial milieu) to intestinal inflammation.

Animals↗
PubMed1992

Gastrointestinal accumulation of indium-111 labelled granulocytes in reactive arthritis.

Six patients with reactive arthritis (ReA) were examined for gastrointestinal accumulation of Indium-111 labelled granulocytes. Abnormal scintigrams were found in three of six patients all of which showed early (less than 4 h) accumulation of indium-111 labelled granulocytes which may represent small intestinal inflammation. Our findings may indicate that the small intestine is involved in ReA, and that indium-111 granulocyte scintigraphy is a useful method for demonstrating inflammatory changes in the small intestine in reactive arthritis (ReA).

Adult↗
PubMed2005

Neurotensin stimulates interleukin-8 expression through modulation of I kappa B alpha phosphorylation and p65 transcriptional activity: involvement of protein kinase C alpha.

Neurotensin (NT) is released in the gastrointestinal tract and participates in the pathophysiology of colonic inflammation. We have shown that NT mediates acute intestinal inflammation in vivo and stimulates nuclear factor-kappaB-dependent interleukin (IL)-8 expression in nontransformed human colonocytes in vitro. However, the exact mechanisms by which NT induces IL-8 expression have not been elucidated. In this study, we first show that NT stimulates IkappaBalpha phosphorylation and degradation and p65 phosphorylation and transcriptional activity. Inhibition of protein kinase C (PKC) activation significantly attenuates NT-induced IL-8 expression. This effect seems to be mediated through inhibition of IkappaBalpha phosphorylation and degradation and by p65 phosphorylation and transcriptional activity. We also show that intracellular calcium mobilization is necessary for NT-induced phosphorylation of IkappaBalpha and p65, suggesting that a conventional PKC is involved. Furthermore, transfection of a dominant-negative form of PKCalpha significantly reduces NT-induced IL-8 promoter activity. These results indicate that the conventional PKCalpha is an important mediator in the proinflammatory signaling pathway elicited by NT at the colonocyte level.

Animals↗
PubMed2003

Induction of proinflammatory responses in the human monocytic cell line THP-1 by Campylobacter jejuni.

Campylobacter jejuni can cause an enteritis that is associated with an acute inflammatory response at the gut epithelial surface. The signals inducing inflammation are unknown. C. jejuni can penetrate the intestinal epithelial barrier and may then interact with leucocytes, potentially inducing proinflammatory responses. To investigate this, we studied the interaction of C. jejuni with the human monocytic cell line THP-1 and show that a range of proinflammatory cytokines and chemokines is induced. These include interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-6, IL-8, and tumor necrosis factor alpha. Responses can be induced by killed Campylobacter as well as live bacteria and do not depend on the cytolethal distending toxin. C. jejuni infection of THP-1 cells triggers both nuclear translocation of functional NF-kappa B and stimulation of IL-1 alpha, indicating that NF-kappa B-dependent and -independent stimulation is occurring. The extent of proinflammatory cytokine stimulation suggests that monocytes might significantly contribute to intestinal inflammation and disease pathology.

Bacterial Toxins↗
PubMed1995

Effect of gliadin and other food peptides on expression of MHC class II molecules by HT-29 cells.

Expression of major histocompatibility (MHC) class II molecules by enterocytes is known to be enhanced in coeliac disease and other disorders characterised by intestinal inflammation--an effect thought to be mediated via intestinal lymphocytes. To investigate if food peptides can exert direct effects on class II expression, the influence of gliadins, casein, and beta lactoglobulin on an intestinal epithelial cell line (HT-29) was examined in the absence of immune cells. Class II expression was determined by flow cytometry and immunofluorescence microscopy using antibodies against the beta chain of all products of the gene subregions DR, DQ, and DP. MHC expression was low in HT-29 cells but could be stimulated by interferon gamma. Tryptin digested gliadin had no effect on class II expression. In the presence of interferon gamma, however, it was able to amplify MHC class II expression to mean (SEM) 150 (4)%. Casein exerted a similar effect (160 (14)%), but undigested gliadin, tryptin digested casein, and beta lactoglobulin had no influence. The observations suggest that within the concert of cytokine mediated interactions between enterocytes and lymphocytes, some dietary peptides could upregulate the presentation of food antigens, leading to a more efficient stimulation of lymphocytes, which in the case of coeliac disease might result in damage to the enterocytes.

Adenocarcinoma↗
PubMed2004

Genetic aspects of intestinal permeability in inflammatory bowel disease.

There is a long-standing belief that disruption of the intestinal barrier function may lead to systemic and local intestinal disease. The role of increased intestinal permeability in Crohn's disease is reviewed here. What is not in doubt is that intestinal permeability in patients with Crohn's disease is increased proportional to disease activity; it can be used to predict clinical relapse of disease and prognosis; and a small proportion of first-degree relatives have increased intestinal permeability. This last finding has been subject to much speculation. In particular it has been suggested that it represents a genetically determined abnormality. If so it might play an important pathogenic process in the disease. However this permeability change in relatives does not conform to a classical inheritance pattern and in some studies it is found in the patients' spouses. This suggests an environmental cause for the changes. However proponents of an environmental factor have been singularly inactive in attempting to identify this agent(s). In view of recent research it seems likely that the increased intestinal permeability in relatives of Crohn's patients may be secondary to sub-clinical intestinal inflammation. This inflammation conforms to an inherited additive trait. The genetic basis for this inflammation is being studied.

Crohn Disease↗
PubMed1995

Desensitization of platelet-activating factor receptors, induced by inflammation in guinea pig ileal smooth muscle cells.

BACKGROUND/AIMS: Platelet-activating factor (PAF) is involved in the pathophysiology of motility changes induced by intestinal inflammation. The aim of this study was to evaluate a possible desensitization of PAF receptors in guinea pig intestinal smooth muscle cells after experimental inflammation induced by trinitrobenzenesulfonic acid (TNB). METHODS: Saline or TNB (80 mg/kg) was injected in the intestinal lumen, and the animals were killed 6 days later. Smooth muscle cells from the circular layer were isolated, and cell contraction induced by PAF was measured. RESULTS: In cells from saline-treated animals, PAF induced a maximal cell contraction at 10 nmol/L and half-maximal contraction (EC50) was 9 +/- 0.2 pmol/L. After TNB injection, the maximal contraction induced by PAF was observed at 1000 nmol/L and EC50 was 300 +/- 70 pmol/L, indicating a 2 logmol/L right shift of the concentration-response curve of PAF. When animals were treated with the PAF antagonist, 20 mg/kg BN52021, or with 2 mg/kg indomethacin for the 6 days after TNB instillation, the right-sided shift of the concentration-response curve of PAF did not occur. CONCLUSIONS: Desensitization of PAF receptors occurring in intestinal smooth muscle cells after TNB instillation could be mediated in vivo by PAF itself via a prostaglandin-dependent pathway.

Acetylcholine↗
PubMed2005

Involvement of innate immunity in the development of inflammatory and autoimmune diseases.

Initial events and effector mechanisms of most inflammatory and autoimmune diseases remain largely unknown. Dysfunction of the innate and adaptive immune systems associated with mucosae (the major interface between the organism and its environment, e.g., microbiota, food) can conceivably cause impairment of mucosal barrier function and development of localized or systemic inflammatory and autoimmune processes. Animal models help in elucidating the etiology and pathogenetic mechanisms of human diseases, such as the inflammatory bowel diseases, Crohn's disease and ulcerative colitis, severe chronic diseases affecting the gut. To study the role of innate immunity and gut microbiota in intestinal inflammation, colitis was induced by dextran sulfate sodium (DSS) in mice with severe combined immunodeficiency (SCID). Conventionally reared (microflora-colonized) SCID mice displayed severe inflammation like that seen in immunocompetent Balb/c mice, whereas only minor changes appeared in the intestinal mucosa of DSS-fed gnotobiotic germ-free SCID mice. The presence of microflora facilitates the inflammation in DSS-induced colitis that develops in immunodeficient SCID mice, that is, in the absence of T and B lymphocytes. Celiac disease, a chronic autoimmune small bowel disorder, afflicts genetically susceptible individuals with wheat gluten intolerance. We showed that, in contrast with any other food proteins, wheat gliadin and its peptic fragments activate mouse macrophages and human monocytes to produce proinflammatory cytokines through the nuclear factor-kappaB signaling pathway. Activation of innate immunity cells by food proteins or components from gut microbiota thus could participate in the impairment of intestinal mucosa and the development of intestinal and/or systemic inflammation.

Animals↗
PubMed2006

Differential pattern of inflammatory molecule regulation in intestinal epithelial cells stimulated with IL-1.

To better predict the consequences of blocking signal transduction pathways as a means of controlling intestinal inflammation, we are characterizing the pathways up-regulated by IL-1 in intestinal epithelial cells (IEC). IL-1beta induced increased mRNA levels of MIP-2, MCP-1, RANTES, inducible NO synthase (iNOS), and cyclooxygenase-2 (COX-2) in the IEC-18 cell line. IL-1beta activated NF-kappaB but not ERK or p38. Infecting cells with adenovirus expressing a mutated gene for IkappaBalpha (IkappaBAA) blocked IL-1-induced mRNA increases in MIP-2, MCP-1, and iNOS but not COX-2 or RANTES. Expression of IkappaBAA attenuated the IL-1-induced increase in COX-2 protein. Unexpectedly, RANTES mRNA increased, and protein was secreted by cells expressing IkappaBAA in the absence of IL-1. Adenovirus-expressing IkappaBAA, blocking protein synthesis, and IL-1beta all resulted in activation of JNK. The JNK inhibitor SP600125 prevented the RANTES increases by all three stimuli. A human enterocyte line was similarly examined, and both NF-kappaB and JNK regulate IL-1-induced RANTES secretion. We conclude that in IEC-18, IL-1beta-induced increases in mRNA for MIP-2, MCP-1, and iNOS are NF-kappaB-dependent, whereas regulation of RANTES mRNA is independent of NF-kappaB but is positively regulated by JNK. IL-1beta-induced mRNA increases in COX-2 mRNA are both NF-kappaB- and MAPK-independent but the translation of COX-2 protein is NF-kappaB-dependent. This pattern of signaling due to a single stimulus exposed the complexities of regulating inflammatory genes in IEC.

Cell Line↗
PubMed1994

Mast cells are not essential to inflammation in murine model of colitis.

A simple rat model of chronic intestinal inflammation was adapted to mice in order to ascertain whether mast cells play an essential role in its induction or perpetuation. Colitis was induced in C57BL mice by intrarectal administration of trinitrobenzene sulfonic acid in 50% ethanol. Higher doses of trinitrobenzene sulfonic acid per gram of body weight were required in mice than rats, with a narrower effective dose range (the upper dose limited by unacceptable mortality and the lower by decreased inflammation). Colons of treated mice were macroscopically inflamed, with transmural damage, adhesions to adjacent structures, and ulcerations. Inflammation was scored subjectively and by tissue weight and myeloperoxidase content; each index was increased dose-dependently by trinitrobenzene sulfonic acid doses of 0.3-10 mg. Six milligrams of trinitrobenzene sulfonic acid induced reproducible inflammation for up to four weeks. Trinitrobenzene sulfonic acid could induce inflammation in both mast-cell-deficient W/Wv mice and their normal +/+ littermates in a similar fashion. Thus it is possible to induce chronic colitis in the mouse. Mast cells are not essential participants in this process.

Animals↗