Giovanni Latella

Fecal Lactate and Ulcerative Colitis

Impaired metabolism of short-chain fatty acids, as well as a modified fecal ionogram, have been reported in ulcerative colitis. Fecal water samples from 62 patients with ulcerative colitis were analyzed in the present investigation to evaluate changes in SCFAs and lactic acid in relation to activity and severity of disease. Short-chain fatty acid levels were high in quiescent and mild disease (162.6 +/- 63.6 and 147.8 +/- 63.2 mM/L, respectively), but significantly decreased in the severe form (64.7 +/- 46.9 mM/L). Lactate showed a progressive increase from mild colitis (3.0 +/- 1.8 mM/L) to severe colitis (21.4 +/- 18.6 mM/L). It thus appears that mild colitis displayed a fecal pattern characterized by normal pH and bicarbonate, slightly impaired electrolyte handling, high short-chain fatty acid values, and only moderately increased lactate. Severe colitis, on the other hand, was characterized by low fecal pH, bicarbonate, and potassium, high sodium and chloride, low short-chain fatty acid levels, and very high lactate levels. A critical lowering of intraluminal pH, which shifts bacterial metabolism from short-chain fatty acid to lactate production, may be responsible for the intraluminal pooling of lactate.

Cellular and molecular mechanisms of intestinal fibrosis

Fibrosis is a chronic and progressive process characterized by an excessive accumulation of extracellular matrix (ECM) leading to stiffening and/or scarring of the involved tissue. Intestinal fibrosis may develop in several different enteropathies, including inflammatory bowel disease. It develops through complex cell, extracellular matrix, cytokine and growth factor interactions. Distinct cell types are involved in intestinal fibrosis, such as resident mesenchymal cells (fibroblasts, myofibroblasts and smooth muscle cells) but also ECM-producing cells derived from epithelial and endothelial cells (through a process termed epithelial- and endothelial-mesenchymal transition), stellate cells, pericytes, local or bone marrow-derived stem cells. The most important soluble factors that regulate the activation of these cells include cytokines, chemokines, growth factors, components of the renin-angiotensin system, angiogenic factors, peroxisome proliferator-activated receptors, mammalian target of rapamycin, and products of oxidative stress. It soon becomes clear that although inflammation is responsible for triggering the onset of the fibrotic process, it only plays a minor role in the progression of this condition, as fibrosis may advance in a self-perpetuating fashion. Definition of the cellular and molecular mechanisms involved in intestinal fibrosis may provide the key to developing new therapeutic approaches.

Increased proliferation and apoptosis of colonic epithelial cells in dextran sulfate sodium-induced colitis in rats

We have evaluated morphologic alterations and epithelial cell apoptosis and proliferation of colonic mucosa in the acute and chronic phases of DSS-induced colitis. Colitis was induced in Sprague-Dawley rats by 7 days of 4% DSS oral administration followed by 7 days of tap water for one, two, and three cycles. Control rats receved tap water only. Morphological changes in colonic mucosa were evaluated and scored by light and scanning electron microscopy. Apoptosis was studied by TUNEL assay and cell proliferation by Ki-67 immunoreaction. The expression of both proapoptotic (Fas, FasL, Bax, p53) and antiapoptotic (Bcl2) cellular proteins was determined by immunohistochemistry. Morphologic assessment showed the most severe colonic epithelial lesions and inflammation in the distal colon with a trend to increasing severity from the first to the third DSS cycle. In DSS rats, the epithelial apoptotic index increased 20-fold after the first cycle and 120-fold after the second and third cycles compared with the controls; in the same way, the expression index of proapoptotic proteins (Fas, FasL, Bax, p53) dramatically increased. The proliferative index increased about 40 to 60-fold compared to controls, with no difference among the three DSS cycles. In conclusion, DSS-induced colitis in rats, which has many structural and ultrastructural features similar to those seen in human ulcerative colitis, is a suitable model for studying increased epithelial apoptosis and proliferation. Further studies employing this model will permitt two hypotheses to be tested. (1) Increased apoptosis may lead to a breakdown of the epithelial barrier function and facilitate the mucosal invasion of intraluminal microorganisms and/or antigens. (2) Abnormal and persistent epithelial hyperproliferation could be causally related to the development of colorectal cancers in the setting of chronic colonic inflammation.

Two mesalazine regimens in the prevention of the post-operative recurrence of Crohn's disease: a pragmatic, double-blind, randomized controlled trial

Background : The role of mesalazine in preventing the clinical recurrence of Crohns disease after surgery has been shown in a meta‐analysis of all published studies. No clear relationship, however, has been shown between dosage and response.

Crucial steps in the natural history of inflammatory bowel disease

Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohns disease (CD), are chronic, progressive and disabling disorders. Over the last few decades, new therapeutic approaches have been introduced which have led not only to a reduction in the mortality rate but also offered the possibility of a favorable modification in the natural history of IBD. The identification of clinical, genetic and serological prognostic factors has permitted a better stratification of the disease, thus allowing the opportunity to indicate the most appropriate therapy. Early treatment with immunosuppressive drugs and biologics has offered the opportunity to change, at least in the short term, the course of the disease by reducing, in a subset of patients with IBD, hospitalization and the need for surgery. In this review, the crucial steps in the natural history of both UC and CD will be discussed, as well as the factors that may change their clinical course. The methodological requirements for high quality studies on the course and prognosis of IBD, the true impact of environmental and dietary factors on the clinical course of IBD, the clinical, serological and genetic predictors of the IBD course (in particular, which of these are relevant and appropriate for use in clinical practice), the impact of the various forms of medical treatment on the IBD complication rate, the role of surgery for IBD in the biologic era, the true magnitude of risk of colorectal cancer associated with IBD, as well as the mortality rate related to IBD will be stressed; all topics that are extensively discussed in separate reviews included in this issue of World Journal of Gastroenterology.

Results of the 4th scientific workshop of the ECCO (I): Pathophysiology of intestinal fibrosis in IBD

The fourth scientific workshop of the European Crohns and Colitis Organization (ECCO) focused on the relevance of intestinal fibrosis in the disease course of inflammatory bowel disease (IBD). The objective was to better understand the pathophysiological mechanisms of intestinal fibrosis, to identify useful markers and imaging modalities of fibrosis in order to assess its presence and progression, and, finally, to point out possible approaches for the prevention and the treatment of fibrosis. The results of this workshop are presented in three separate manuscripts. This first section describes the most important mechanisms that contribute to the initiation and progression of intestinal fibrosis in IBD including the cellular and molecular mediators, the extracellular matrix molecules and matrix metalloproteinases/tissue inhibitors of metalloproteinases-system, the microbiota products, the role of fat, genetic and epigenetic factors, as well as the currently available experimental models. Furthermore, it identifies unanswered questions in the field of intestinal fibrosis and provides a framework for future research.

Targeted disruption of Smad3 confers resistance to the development of dimethylnitrosamine-induced hepatic fibrosis in mice

Background: Hepatic fibrosis is characterized by a progressive accumulation of fibrillar extracellular matrix (ECM) proteins including collagen, which occurs in most types of chronic liver diseases. Transforming growth factor‐β (TGF‐β)/Smad3 signalling plays a central role in tissue fibrogenesis, acting as a potent stimulus of ECM accumulation.

Prevention of Fibrosis in Experimental Colitis by Captopril: the Role of tgf-β1

Background & Aims:There is a body of evidence to suggest that the local activation of angiotensin II (ANG II) plays a pivotal role in fibrogenic response involving the kidney, heart, lung, pancreas and liver. In such conditions, fibrosis is mediated, at least partially, through ANG II induction of the cytokine transforming growth factor-beta1 (TGF-β1). Both ANG II and TGF-β1 also seem to be involved in intestinal fibrosis and stenosis, particularly in Crohn’s disease.The aim of the present study was, firstly, to determine the effects of the angiotensin-converting enzyme inhibitor, captopril, on colonic fibrosis in experimental colitis in rats and, secondly, to check the role of TGF-β1 on these effects. Methods:Colitis was induced in rats by intracolonic administration of TNBS. Colonic fibrosis was assessed 21 days later by macroscopic and microscopic evaluation. Levels of collagen &agr;1 gene expression, hydroxyproline, angiotensin II and TGF-β1 proteins, and TGF-β1 mRNA were measured on the colonic tissue. Results: In chronic colitis, captopril significantly reduced the score of macroscopic and histologic lesions, as well as the colonic tissue levels of collagen &agr;1, hydroxyproline, ANG II and TGF-β1 proteins, and TGF-β1 mRNA. Conclusions:These data demonstrate for the first time that the prophylactic administration of captopril is effective in preventing colonic fibrosis in TNBS-induced colitis. The antifibrotic action of captopril could be due to the blockade of TGFβ-1 overexpression, and/or to a direct down-regulation of TGFβ-1 transcript.

GI distension in severe ulcerative colitis.

OBJECTIVES:In previous retrospective studies in patients with severe ulcerative colitis (UC), small bowel distension was found to characterize a subgroup of patients at higher risk for both toxic megacolon (TMC) and multiple organ dysfunction syndrome (MODS). In this study we prospectively evaluated the prevalence of GI distension and its relationship to clinical outcome in patients with severe UC.METHODS:Of 109 consecutive inpatients with acute UC (admitted to the GI Unit of the University of Rome during the period 1995–2000), 45 had severe colitis. Routine blood tests and acid-base balance and plain abdominal film evaluations were performed upon admission and repeated every 1–3 days. The gas content of the stomach and small and large intestines was evaluated on plain abdominal films. All patients were submitted to the standard Oxford intensive medical regimen; clinical improvement, occurrence of major complications, need for surgery, and mortality were evaluated. Statistical analysis was carried out using Students t, χ2, Fishers exact, Mann-Whitney, and Wilcoxon rank sum tests, when appropriate.RESULTS:Of 45 patients with severe UC, 24 (53%) had GI distension. Three of these 24 patients had TMC on admission (all underwent surgery and survived), 21 showed increased GI gas content (four developed TMC 1–4 days after the detection of GI distension and were operated on, two developed MODS and died, and eight did not improve but were submitted to surgery and survived). None of the 21 patients with normal GI gas content had complications; all survived (five did not improve and required surgery).CONCLUSIONS:In severe UC, persistent GI distension characterized a subgroup of patients with poor response to medical therapy and at higher risk for TMC and of need for surgery. The development of MODS was the most important predicting factor for fatal outcome.

Increased prevalence of Helicobacter pylori in patients with diabetes mellitus

BACKGROUND Whilst upper gastrointestinal disturbances are frequently observed in patients with diabetes mellitus, little is known about the prevalence of Helicobacter pylori infection and peptic disease in these patients. AIM To evaluate prevalence of Helicobacter pylori infection and peptic disease lesions in diabetics with dyspeptic symptoms. PATIENTS AND METHODS Study population comprises 74 consecutive diabetes mellitus patients with dyspepsia and 117 consecutive non diabetic dyspeptic patients. Upon enrolment, each patient completed an interview screening questionnaire to obtain information concerning presence and severity of dyspepsia. All patients underwent upper gastrointestinal endoscopy with biopsy specimens being collected from gastric antrum and body Helicobacter pylori was evaluated in each patient by rapid urease test and histology (Giemsa). Gastritis was classified according to the Sydney System. Statistical analysis was performed by chi-square, Fisher exact or t test and logistic regression analysis. A p value <0.05 was considered significant. RESULTS Prevalence of Helicobacter pylori infection was found to be significantly higher in diabetics than in controls. The prevalence rate of endoscopic lesions was comparable in the two groups, but the association between endoscopic lesions and Helicobacter pylori infection was significantly higher in diabetics. Overall, the presence of chronic gastritis, both non atrophic and atrophic, as well as intestinal metaplasia were comparable in the two groups of patients, whilst the association between chronic gastritis and Helicobacter pylori infection or gastritis activity were significantly higher in diabetics. In neither group, was any correlation found between severity of dyspepsia and presence of endoscopic lesions, chronic gastritis or Helicobacter pylori infection. CONCLUSIONS These data show a higher prevalence of Helicobacter pylori infection in diabetes mellitus patients with dyspepsia. Helicobacter pylori infection was significantly associated both with the presence of endoscopic lesions and chronic gastritis in diabetic patients, but not in the controls.