The Food Additive Maltodextrin Promotes Endoplasmic Reticulum Stress-Driven Mucus Depletion and Exacerbates Intestinal Inflammation.

BACKGROUND & AIMS: Food additives, such as emulsifiers, stabilizers, or bulking agents, are present in the Western diet and their consumption is increasing. However, little is known about their potential effects on intestinal homeostasis. In this study we examined the effect of some of these food additives on gut inflammation. METHODS: Mice were given drinking water containing maltodextrin (MDX), propylene glycol, or animal gelatin, and then challenged with dextran sulfate sodium or indomethacin. In parallel, mice fed a MDX-enriched diet were given the endoplasmic reticulum (ER) stress inhibitor tauroursodeoxycholic acid (TUDCA). Transcriptomic analysis, real-time polymerase chain reaction, mucin-2 expression, phosphorylated p38 mitogen-activated protein (MAP) kinase quantification, and H&E staining was performed on colonic tissues. Mucosa-associated microbiota composition was characterized by 16S ribosomal RNA sequencing. For the in vitro experiments, murine intestinal crypts and the human mucus-secreting HT29-methotrexate treated cell line were stimulated with MDX in the presence or absence of TUDCA or a p38 MAP kinase inhibitor. RESULTS: Diets enriched in MDX, but not propylene glycol or animal gelatin, exacerbated intestinal inflammation in both models. Analysis of the mechanisms underlying the detrimental effect of MDX showed up-regulation of inositol requiring protein 1ß, a sensor of ER stress, in goblet cells, and a reduction of mucin-2 expression with no significant change in mucosa-associated microbiota. Stimulation of murine intestinal crypts and HT29-methotrexate treated cell line cells with MDX induced inositol requiring protein 1ß via a p38 MAP kinase-dependent mechanism. Treatment of mice with TUDCA prevented mucin-2 depletion and attenuated colitis in MDX-fed mice. CONCLUSIONS: MDX increases ER stress in gut epithelial cells with the downstream effect of reducing mucus production and enhancing colitis susceptibility.

Recent advances in understanding Crohn's disease.

Crohn's disease is a chronic inflammatory bowel disorder resulting from an inappropriate innate and acquired immune response to commensal microorganisms in genetically susceptible individuals. This disease has a fluctuating course, with alternating periods of remission and relapses, and it is characterized by a remarkable clinical heterogeneity; it may be complicated by perianal fistulas, abscesses, and intestinal strictures leading to obstructions, besides several systemic manifestations. However, a complete resolution of the disease is currently not possible, yet Crohn's disease can be managed with established and novel therapies, which achieve long-term remission and acceptable quality of life. This review is focused on novel advances in basic and clinical aspects of Crohn's disease, although it also deals with new trends in diagnosis and treatment.

Recent advances in understanding ulcerative colitis.

Ulcerative colitis, one of the two main forms of inflammatory bowel disease, is characterized by inflammation of the large bowel with constant involvement of the rectum, and a possible continuous retrograde distribution up to the cecum. Typical macroscopic lesions are mucosal ulcerations, with immune cell infiltration and cryptic abscesses at histology. Ulcerative colitis usually manifests with bloody diarrhea, is associated with a number of extra-intestinal manifestations, and may be acutely complicated by toxic megacolon. Longstanding disease may predispose to the development of colorectal cancer. Therapeutic options include mesalazine, corticosteroids, immunomodulators and biologic agents; however, if these treatments fail, the only available therapeutic choice remaining is the surgical removal of the colon. This review emphasizes novel concepts in the basic aspects of ulcerative colitis, and, in addition to the current clinical and diagnostic knowledge, it also describes new treatment options for this condition.

Matrix metalloproteinases in necrotising enterocolitis.

Elevated cytokines, especially TNF-alpha, have been implicated in the pathogenesis of necrotising enterocolitis (NEC). We have previously shown that TNF-alpha drives the production of matrix degrading enzymes, the matrix metalloproteinases (MMPs), in the gut wall. In this study we have therefore investigated the role of MMPs in the pathogenesis of NEC in neonates. Nine newborn infant nonnecrotic resected bowels with confirmed NEC were studied and 8 newborn infants with neonatal bowel obstructions were used as controls. Immunostaining was used to identify the numbers of monocytes, macrophages, neutrophils, and T cells in the tissue. We used quantitative, competitive RT-PCR to analyze the number of TNF-alpha, IFN-gamma, MMP, and TIMP mRNA transcripts and western blotting to analyze MMP and TIMP protein production. Double labeling (immunostaining and in situ hybridization) was used to identify the phenotype of MMP mRNA expressing cells. We found increased numbers of monocytes, macrophages, and neutrophils in NEC tissue compared with controls. The number of T cells was unexpectedly low in NEC as was the number of IFN-gamma transcripts in comparison with the control samples. Increased numbers of transcripts for TNF-alpha were detected in NEC tissue, as was mRNA expression and protein production for stromelysin-1 and TIMP-1 but not collagenase, gelatinases, or TIMP-2. The cellular source of stromelysin-1 in NEC was alpha-smooth muscle actin positive cells. These results suggest that stromelysin-1, which has the ability to degrade the mucosal extra-cellular matrix, may be responsible for the extensive tissue injury in infants with NEC.