Laquinimod arrests experimental autoimmune encephalomyelitis by activating the aryl hydrocarbon receptor.

Laquinimod is an oral drug currently being evaluated for the treatment of relapsing, remitting, and primary progressive multiple sclerosis and Huntington's disease. Laquinimod exerts beneficial activities on both the peripheral immune system and the CNS with distinctive changes in CNS resident cell populations, especially astrocytes and microglia. Analysis of genome-wide expression data revealed activation of the aryl hydrocarbon receptor (AhR) pathway in laquinimod-treated mice. The AhR pathway modulates the differentiation and function of several cell populations, many of which play an important role in neuroinflammation. We therefore tested the consequences of AhR activation in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) using AhR knockout mice. We demonstrate that the pronounced effect of laquinimod on clinical score, CNS inflammation, and demyelination in EAE was abolished in AhR-/- mice. Furthermore, using bone marrow chimeras we show that deletion of AhR in the immune system fully abrogates, whereas deletion within the CNS partially abrogates the effect of laquinimod in EAE. These data strongly support the idea that AhR is necessary for the efficacy of laquinimod in EAE and that laquinimod may represent a first-in-class drug targeting AhR for the treatment of multiple sclerosis and other neurodegenerative diseases.

Bacterial population and innate immunity-related genes in rat gastrointestinal tract are altered by vitamin A-deficient diet.

Vitamin A and its derivatives have been shown to regulate the growth and differentiation of gastrointestinal epithelial cells; in addition, vitamin A deficiency has been convincingly shown to be associated with increased susceptibility to infection. The gastrointestinal mucosal barrier, which is a component of the innate immune system, is considered the first line of defense, as it provides a barrier between the external environment and the internal milieu. A disturbance in the integrity of the intestinal epithelium is one of the main factors involved in increased incidence of infections during vitamin A deficiency. In this study, the effects of vitamin A deficiency on microbial ecology and the expression of genes related to the intestinal mucosa's innate immunity were examined in a rat model. Using the 16s rDNA method, we demonstrate that a vitamin A-deficient (VAD) diet increases the total amount of bacteria in the gastrointestinal tract and alters the intestinal microflora. Results show a decrease in the relative proportion of Lactobacillus spp. and the simultaneous appearance of Escherichia coli strains. Lack of vitamin A significantly changed mucin (MUC) dynamics, as reflected by the enlarged goblet-cell "cup" area relative to controls; decreased MUC2 mRNA expression in the jejunum, ileum and colon of VAD rats and increased MUC3 mRNA expression in the ileum and colon of these rats. In addition, vitamin A deficiency down-regulated defensin 6 mRNA expression while up-regulating toll-like receptors 2 and 5 mRNA expressions. The current study indicates that vitamin A deficiency interferes with the integrity of the gastrointestinal mucosal barrier.

Therapeutic potential of two probiotics in inflammatory bowel disease as observed in the trinitrobenzene sulfonic acid model of colitis.

PURPOSE: The pathogenesis of inflammatory bowel disease is thought to be a multifactorial process. One of the leading hypotheses is that an imbalance in normal gut flora induces an excessive immune response and contributes to inflammation in the gastrointestinal tract. Administration of probiotic bacteria reduces symptoms in patients suffering from inflammatory bowel diseases, probably via both manipulation of the microflora and stimulation of the intestinal immune system. In the current study the therapeutic potential of two different probiotics-Lactobacillus GG and a mixture of Streptococcus thermophilus, Lactobacillus acidophilus, and Bifidobacterium longum (YO-MIX Y 109 FRO 1000)--in a rat model of colitis were evaluated. METHODS: Male Wistar rats were administered probiotics for three days simultaneously with colitis induction. Colonic damage was evaluated histologically and biochemically and colonic tissues, as well as fecal samples, were used for bacterial studies using 16S rRNA gene primers. RESULTS: Probiotics administration reduced the relative amounts of the pathogenic bacteria Aeromonas and Escherichia coli in the colonic tissue. However, whereas both probiotics affected colon morphology, only Lactobacillus GG administration reduced myeloperoxidase activity. CONCLUSIONS: We report the therapeutic rather than preventive potential of two different probiotics in an animal model of colitis.

Mucosal function in rat jejunum and ileum is altered by induction of colitis.

Many studies dealing with trinitrobenzene sulfonic acid (TNBS) colitis in rats have been carried out referring only to the colon. In humans, ulcerative colitis (UC) can extend a variable distance into the terminal ileum in a phenomenon known as backwash ileitis (BWI). The aim of this study was therefore to examine the effect of TNBS-induced colitis on different aspects of the rat ileum and jejunum. We hypothesized that TNBS administration would lead to a systemic influence on the small intestine. Rats were induced colitis by administration of 0.25 ml of 2,4,6-trinitrobenzene sulfonic acid and 72 h after colitis induction animals were sacrificed. Segments were taken of the colon, ileum and jejunum. In addition to mucin mRNA expression, morphological changes were observed in the jejunum and ileum. We examined the mRNA expression and biochemical activity of brush border enzyme, sucrase iso-maltase and aminopeptidase, in all three segments. The villous surface area of colitis-induced rats was smaller in jejunum and ileum compared to control. In the jejunum of TNBS-induced rats, goblet-cell volume increased and their density decreased. The relative amount of MUC2 mRNA decreased in the jejunum, ileum and colon of colitis rat. However, MUC3 mRNA expression increased in the ileum and colon of these rats. Sucrase isomaltase expression and activity decreased in the ileum of TNBS-induced rats, while aminopeptidase activity was lower in the jejunum. These observations suggest that intrarectal administration of TNBS to rats influences not only their colon and terminal ileum, but also the proximal ileum and jejunum. Involvement of the ileum and jejunum in TNBS-induced colitis may be related to the systemic reaction of the immune system and mucosa to colitis.

Multistep mechanism of probiotic bacterium, the effect on innate immune system.

The etiology and pathogenesis of inflammatory bowel disease are still not fully understood. However, evidence from both animal models and clinical observations suggests luminal bacteria as the most probable inducer of this disease. The intestinal bacterial microbiota may be modified by dietary addition of viable probiotic bacteria, thereby constituting an alternative approach to disease prevention and treatment. The aim of this study was to evaluate and compare the effects of two probiotic regiments; Lactobacillus GG and a mixture of Streptococcus thermophilus, Lactobacillus acidophilus, and Bifidobacterium lactis (YO-MIX Y 109 FRO 1000) in both normal and trinitrobenzenesulfonic acid colitis-induced rats. Colon morphology and damage were evaluated histologically; colonic tissues were used for mRNA analysis, using real-time PCR. Administration of both probiotics reduced the expression of proinflammatory cytokines tumor necrosis factor-alpha and IL-6 and increased the expression of mucin 2 in compared with colitis group and reduced the inflammatory response. These results provide additional support for the positive effect of probiotics in the gut and may shed light on the mechanism by which probiotic bacteria exert their action in an animal model.