The Mexican consensus on probiotics in gastroenterology. / Consenso mexicano sobre probióticos en gastroenterología.

INTRODUCTION: Probiotics are frequently prescribed in clinical practice. Their efficacy in treating gastrointestinal disorders is supported by a significant number of clinical trials. However, the correct prescription of these agents is hampered due to a lack of knowledge of the scientific evidence and to the different presentations and microbial compositions of the probiotics that are currently available. AIM: To provide the clinician with a consensus review of probiotics and recommendations for their use in gastroenterology. MATERIALS AND METHODS: Controlled clinical trials, meta-analyses, and systematic reviews published up to 2015 were selected, using the MESH terms: probiotics, gastrointestinal diseases, humans, adults, AND children. The Delphi method was employed. Eighteen gastroenterologists treating adult patients and 14 pediatric gastroenterologists formulated statements that were voted on until agreement>70% was reached. The level of evidence based on the GRADE system was evaluated for each statement. RESULTS AND CONCLUSIONS: Eleven statements on the general concepts of probiotics and 27 statements on the use of probiotics in gastrointestinal diseases in both adults and children were formulated. The consensus group recommends the use of probiotics under the following clinical conditions: the prevention of diarrhea associated with antibiotics, the treatment of acute infectious diarrhea, the prevention of Clostridium difficile infection and necrotizing enterocolitis, the reduction of adverse events from Helicobacter pylori eradication therapy, relief from irritable bowel syndrome symptoms, the treatment of functional constipation in the adult, and the induction and maintenance of remission in patients with ulcerative colitis and pouchitis, and the treatment of covert and overt hepatic encephalopathy.

Influence of colectomy on hydrogen excretion in breath.

INTRODUCTION: Hydrogen breath test is the most commonly used method to analyze carbohydrate absorption and diagnose carbohydrate malabsorption. The result of the H(2) breath test is influenced by different factors, which are mostly related to quantitative or qualitative aspects of colonic flora. A scarcely studied variable is the effect of colonic anatomical integrity on H(2) excretion in breath. PURPOSE: The present study aims to determine whether loss of colonic integrity reduces H(2) excretion capacity after an oral load of an unabsorbable carbohydrate. METHODS: An observational study was conducted in three patient groups: controls with preserved colon, patients with partial colectomy, and patients with complete colectomy and ileostomy. H(2) concentration in breath was measured by gas chromatography every 10 min for 3 h after oral lactulose administration. RESULTS: Twenty-two patients with partial colectomy, 18 controls with preserved colon, and seven patients with ileostomy were included. H(2) excretion after lactulose did not differ between patients with partial colectomy and controls (basal excretion = 8.5 vs 4 ppm; delta increase = 50.0 vs 47.5 ppm; area under the curve = 4,480.0 vs 4,710.5 ppm/min). In contrast, H(2) excretion was significantly lower in the ileostomy group. CONCLUSIONS: Partial colectomy does not influence the capacity for H(2) excretion after oral unabsorbable carbohydrate administration.

Inflammatory disease processes and interactions with nutrition.

Inflammation is a stereotypical physiological response to infections and tissue injury; it initiates pathogen killing as well as tissue repair processes and helps to restore homeostasis at infected or damaged sites. Acute inflammatory reactions are usually self-limiting and resolve rapidly, due to the involvement of negative feedback mechanisms. Thus, regulated inflammatory responses are essential to remain healthy and maintain homeostasis. However, inflammatory responses that fail to regulate themselves can become chronic and contribute to the perpetuation and progression of disease. Characteristics typical of chronic inflammatory responses underlying the pathophysiology of several disorders include loss of barrier function, responsiveness to a normally benign stimulus, infiltration of inflammatory cells into compartments where they are not normally found in such high numbers, and overproduction of oxidants, cytokines, chemokines, eicosanoids and matrix metalloproteinases. The levels of these mediators amplify the inflammatory response, are destructive and contribute to the clinical symptoms. Various dietary components including long chain omega-3 fatty acids, antioxidant vitamins, plant flavonoids, prebiotics and probiotics have the potential to modulate predisposition to chronic inflammatory conditions and may have a role in their therapy. These components act through a variety of mechanisms including decreasing inflammatory mediator production through effects on cell signaling and gene expression (omega-3 fatty acids, vitamin E, plant flavonoids), reducing the production of damaging oxidants (vitamin E and other antioxidants), and promoting gut barrier function and anti-inflammatory responses (prebiotics and probiotics). However, in general really strong evidence of benefit to human health through anti-inflammatory actions is lacking for most of these dietary components. Thus, further studies addressing efficacy in humans linked to studies providing greater understanding of the mechanisms of action involved are required.

Oral oligofructose-enriched inulin supplementation in acute ulcerative colitis is well tolerated and associated with lowered faecal calprotectin.

BACKGROUND: Inulin and oligofructose promote selective growth of saccharolytic bacteria with low inflammatory potential. OBJECTIVE: To test the effect of oligofructose-enriched inulin in patients with active ulcerative colitis. DESIGN: Prospective, randomized, placebo controlled pilot trial. Eligible patients had been previously in remission with mesalazine as maintenance therapy or no drug, and presented with a relapse of mild to moderate activity. They were treated with mesalazine (3 g/day) and randomly allocated to receive either oligofructose-enriched inulin (12 g/day, p.o., n = 10) or placebo (12 g/day of maltodextrin, p.o., n = 9) for 2 week. Primary endpoint was the anti-inflammatory effect as determined by reduction of calprotectin and human DNA in faeces. RESULTS: Rachmilewitz score decreased in both groups, reaching statistical significance at day 14 (P < 0.05). Oligofructose-enriched inulin was well-tolerated and dyspeptic symptoms scale decreased significantly with active treatment but not with placebo. At day 7, an early significant reduction of calprotectin was observed in the group receiving oligofructose-enriched inulin (day 0: 4377 +/- 659 microg/g; day 7: 1033 +/- 393 microg/g, P < 0.05) but not in the placebo group (day 0: 5834 +/- 1563 microg/g; day 7: 4084 +/- 1395 microg/g, n.s.). Changes in faecal concentration of human DNA were not significant. CONCLUSION: In active ulcerative colitis, dietary supplementation with oligofructose-enriched inulin is well tolerated and is associated with early reduction in faecal calprotectin.

Colonic gas homeostasis: Mechanisms of adaptation following HOST-G904 galactooligosaccharide use in humans.

BACKGROUND: We have shown that a galactooligosaccharide prebiotic administration (HOST-G904) initially increased intestinal gas production and this increase declined back to baseline after 2 week administration. Our aim was to determine the mechanism of microbiota adaptation; i.e., to determine whether the net reduction is due to decreased overall production or increased gas consumption. METHODS: In 10 healthy subjects, intestinal gas production and intraluminal disposal was measured before, at the beginning and after 2 week of HOST-G904 prebiotic administration. Anal gas was collected for 4 hour after a probe meal. Paired studies were performed without and with high-rate infusion of exogenous gas (24 mL/min) into the jejunum to wash-out the endogenous gas produced by bacterial fermentation. The exogenous gas infused was labeled (5% SF6 ) to calculate the proportion of endogenous gas evacuated. KEY RESULTS: The volume of intestinal gas produced i.e., endogenous gas washed-out, increased by 37% at the beginning of HOST-G904 administration (P=.049 vs preadministration) and decreased down to preadministration level after 2 week administration (P=.030 vs early administration). The proportion of gas eliminated from the lumen before reaching the anus tended to increase after 2-week administration (87±3% vs 78±5% preadministration; P=.098). CONCLUSIONS & INFERENCES: Adaptation to regular consumption of HOST-G904 prebiotic involves a shift in microbiota metabolism toward low-gas producing pathways, with a non-significant increase in gas-consuming activity. Hence, regular consumption of HOST-G904 regulates intestinal gas metabolism: less gas is produced and a somewhat larger proportion of it is consumed.

Metabolic adaptation of colonic microbiota to galactooligosaccharides: a proof-of-concept-study.

BACKGROUND: Prebiotics have been shown to reduce abdominal symptoms in patients with functional gut disorders, despite that they are fermented by colonic bacteria and may induce gas-related symptoms. AIM: To investigate changes in the metabolic activity of gut microbiota induced by a recognised prebiotic. METHODS: Healthy subjects (n = 20) were given a prebiotic (2.8 g/day HOST-G904, HOST Therabiomics, Jersey, Channel Islands) for 3 weeks. During 3-day periods immediately before, at the beginning and at the end of the administration subjects were put on a standard diet (low fibre diet supplemented with one portion of high fibre foods) and the following outcomes were measured: (i) number of daytime gas evacuations for 2 days by means of an event marker; (ii) volume of gas evacuated via a rectal tube during 4 h after a test meal; and (iii) microbiota composition by faecal Illumina MiSeq sequencing. RESULTS: At the beginning of administration, HOST-G904 significantly increased the number of daily anal gas evacuations (18 ± 2 vs. 12 ± 1 pre-administration; P < 0.001) and the volume of gas evacuated after the test meal (236 ± 23 mL vs. 160 ± 17 mL pre-administration; P = 0.006). However, after 3 weeks of administration, these effects diminished (11 ± 2 daily evacuations, 169 ± 23 mL gas evacuation). At day 21, relative abundance of butyrate producers (Lachnospiraceae) correlated inversely with the volume of gas evacuated (r = -0.52; P = 0.02). CONCLUSION: The availability of substrates induces an adaptation of the colonic microbiota activity in bacterial metabolism, which produces less gas and associated issues. Clinical trials.gov NCT02618239.

Effect of inulin and fructo-oligosaccharide on the prevention of acute radiation enteritis in patients with gynecological cancer and impact on quality-of-life: a randomized, double-blind, placebo-controlled trial.

BACKGROUND/OBJECTIVES: The pathogenesis of enteritis after abdominal radiotherapy (RT) is unknown, although changes in fecal microbiota may be involved. Prebiotics stimulate the proliferation of Lactobacillus spp and Bifidobacterium spp, and this may have positive effects on the intestinal mucosa during abdominal RT. SUBJECTS/METHODS: We performed a randomized, double-blind, placebo-controlled trial involving patients with gynecological cancer who received abdominal RT after surgery. Patients were randomized to receive prebiotics or placebo. The prebiotic group received a mixture of fiber (50 inulin and 50% fructo-oligosaccharide), and the placebo group received 6 g of maltodextrin twice daily from 1 week before to 3 weeks after RT. The number of bowel movements and stool consistency was recorded daily. Diarrhea was evaluated according to the Common Toxicity Criteria of the National Cancer Institute. Stool consistency was assessed using the 7-point Bristol scale. Patients' quality-of-life was evaluated at baseline and at completion of RT using the EORTC-QLQ-C30 (European Organization for Research and Treatment of Cancer quality-of-life Questionnaire C30) test. RESULTS: Thirty-eight women with a mean age of 60.3±11.8 years participated in the study. Both groups (prebiotic (n=20) and placebo (n=18)) were comparable in their baseline characteristics. The number of bowel movements per month increased in both groups during RT. The number of bowel movements per day increased in both groups. The number of days with watery stool (Bristol score 7) was lower in the prebiotic group (3.3±4.4 to 2.2±1.6) than in the placebo group (P=0.08). With respect to quality-of-life, the symptoms with the highest score in the placebo group were insomnia at baseline and diarrhea toward the end of the treatment. In the prebiotic group, insomnia was the symptom with the highest score at both assessments, although the differences were not statistically significant. CONCLUSIONS: Prebiotics can improve the consistency of stools in gynecologic cancer patients on RT. This finding could have important implications in the quality-of-life of these patients during treatment.

Simbiosis en el tracto gastrointestinal humano / Symbiosis in the human gastrointestinal tract

El cuerpo humano es un planeta poblado por miríadas de microorganismos en toda su superficie y en las cavidades conectadas con el exterior. La investigación experimental y clínica está demostrando que los colonizadores microbianos constituyen parte funcional y no prescindible del organismo humano. El ecosistema microbiano que se aloja en el tracto gastrointestinal aporta un "metagenoma": genes y funciones adicionales a los recursos genéticos de la especie, que participan en múltiples procesos fisiológicos (desarrollo somático, nutrición, inmunidad, etc.). El intestino humano alberga estructuras linfoides especializadas en la inducción y regulación de la inmunidad adaptativa. Asimismo, la interacción de la microbiota intestinal con el sistema inmunitario de la mucosa digestiva juega un papel clave para la homeostasis del individuo con el mundo exterior. Algunas enfermedades inflamatorias crónicas no transmisibles de la sociedad desarrollada se asocian a disbiosis: pérdida de riqueza de especies en la microbiota intestinal y desviación del entorno microbiano ancestral. Generar y mantener diversidad en la microbiota intestinal es un nuevo objetivo clínico para la promoción de salud y prevención de enfermedades

The human body is a planet populated by myriads of microorganisms all over its surface and in cavities connected to the outside. Experimental and clinical research is showing that microbial colonizers are a functional and essential part of the human organism. The microbial ecosystem, which is housed in the gastrointestinal tract, provides a "metagenome": genes and additional functions to the genetic resources of the species, which are involved in multiple physiological processes (somatic development, nutrition, immunity, etc.). The human intestine houses lymphoid structures specialized in the induction and regulation of adaptive immunity, and the interaction of the intestinal microbiota with the immune system of the digestive mucosa plays a key role for the individual's homeostasis with the outside world. Some chronic non-communicable inflammatory diseases in developed society are associated with dysbiosis: loss of species richness in the gut microbiota and deviation from the ancestral microbial environment. Generating and maintaining diversity in the gut microbiota is a new clinical goal for health promotion and disease prevention

Accumulative effect of food residues on intestinal gas production.

BACKGROUND: As mean transit time in the colon is longer than the interval between meals, several consecutive meal loads accumulate, and contribute to colonic biomass. Our aim was to determine the summation effect of fermentable food residues on intestinal gas production. METHODS: In eight healthy subjects, the volume of endogenous intestinal gas produced in the intestine over a 4-h period was measured by means of a wash-out technique, using an exogenous gas infusion into the jejunum (24 mL/min) and collection of the effluent via a rectal Foley catheter. The exogenous gas infused was labeled (5% SF6 ) to calculate the proportion of endogenous intestinal gas evacuated. In each subject, four experiments were performed ≥1 week apart combining a 1-day high- or low-flatulogenic diet with a test meal or fast. KEY RESULTS: Basal conditions: on the low-flatulogenic diet, intestinal gas production during fasting over the 4-h study period was 609 ± 63 mL. Effect of diet: during fasting, intestinal gas production on the high-flatulogenic diet was 370 ± 146 mL greater than on the low-flatulogenic diet (p = 0.040). Effect of test meal: on the low-flatulogenic diet, intestinal gas production after the test meal was 681 ± 114 mL greater than during fasting (p = 0.001); a similar effect was observed on the high-flatulogenic diet (599 ± 174 mL more intestinal gas production after the test meal than during fasting; p = 0.021). CONCLUSIONS & INFERENCES: Our data demonstrate temporal summation effects of food residues on intestinal gas production. Hence, intestinal gas production depends on pre-existing and on recent colonic loads of fermentable foodstuffs.

The administration of probiotics and synbiotics in immune compromised adults: is it safe?

This study aimed to systematically evaluate safety of probiotics and synbiotics in immune compromised adults (≥18 years). Safety was analysed using the Common Terminology Clinical Adverse Events (CTCAE version 4.0) classification, thereby providing an update on previous reports using the most recent available clinical data (2008-2013). Safety aspects are represented and related to number of participants per probiotic strain/culture, study duration, dosage, clinical condition and selected afflictions. Analysis of 57 clinical studies indicates that probiotic and/or synbiotic administration in immune compromised adults is safe with regard to the current evaluated probiotic strains, dosages and duration. Individuals were considered immune compromised if HIV-infected, critically ill, underwent surgery or had an organ- or an autoimmune disease. There were no major safety concerns in the study, as none of the serious adverse events (AE)s were related, or suspected to be related, to the probiotic or synbiotic product and the study products were well tolerated. Overall, AEs occurred less frequent in immune compromised subjects receiving probiotics and/or synbiotics compared to the control group. In addition, the results demonstrated a flaw in precise reporting and classification of AE in most studies. Furthermore, generalisability of conclusions are greatly limited by the inconsistent, imprecise and potentially incomplete reporting as well as the variation in probiotic strains, dosages, administration regimes, study populations and reported outcomes. We argue that standardised reporting on adverse events (CTCAE) in 'food' studies should be obligatory, thereby improving reliability of data and re-enforcing the safety profile of probiotics.

Safety of probiotics and synbiotics in children under 18 years of age.

This study aimed to systematically evaluate safety of probiotics and synbiotics in children ageing 0-18 years. This study is the third and final part in a safety trilogy and an update is provided using the most recent available clinical data (2008-2013) by means of the Common Terminology Clinical Adverse Events (CTCAE version 4.0) classification. Safety aspects are represented and related to number of participants per probiotic strain/culture, study duration, dosage, clinical condition and selected afflictions. Analysis of 74 clinical studies indicated that probiotic and/or synbiotic administration in children is safe with regard to the specific evaluated strains, dosages and duration. The population of children include healthy, immune compromised and obese subjects, as well as subjects with intestinal disorders, infections and inflammatory disorders. This study revealed no major safety concerns, as the adverse events (AEs) were unrelated, or not suspected to be related, to the probiotic or synbiotic product. In general the study products were well tolerated. Overall, AEs occurred more frequent in the control arm compared to children receiving probiotics and/or synbiotics. Furthermore, the results indicate inadequate reporting and classification of AEs in the majority of the studies. In addition, generalizability of conclusions are greatly limited by the inconsistent, imprecise and potentially incomplete reporting as well as the variation in probiotic strains, dosages, administration regimes, study populations and reported outcomes.

Antiinflammatory effects of enterically coated amoxicillin-clavulanic acid in active ulcerative colitis.

The inflammatory activity of colonic mucosal lesions may be stimulated by intraluminal bacteria. Our aim was to investigate whether administration of broad-spectrum antibiotics decreases inflammatory activity in ulcerative colitis. To this end, we performed a randomized, 5-day study with either oral enterically coated amoxicillin-clavulanic acid (1 g + 250 mg, t.i.d.); i.v. methylprednisolone (40 mg/day) and oral placebo (t.i.d.); or both i.v. methylprednisolone and oral amoxicillin-clavulanic acid as above, in 30 patients with clinically active ulcerative colitis. Before and after 5 days of treatment, intestinal inflammation was assessed by the quantification of mucosal release of eicosanoids and interleukin-8 by rectal dialysis in each patient. Breath H2 excretion after oral lactulose was determined as an index of metabolic activity of colonic flora. The total release of (IL-8) interleukin-8 and eicosanoids significantly decreased in patients treated with antibiotic or steroids and antibiotic. Antibiotic treatment, but not steroids, markedly inhibited breath H2 excretion. In conclusion, short-term treatment with enteric-coated amoxicillin-clavulanic acid decreases the intraluminal release of IL-8 and other inflammatory mediators.

Stimulation of mucosal inflammatory activity by the normal fecal flora in a rat model of colitis.

SUMMARY: : Bacteria and their products stimulate inflammatory responses and may play a role in the pathogenesis of inflammatory bowel diseases. We investigated interactions between fecal flora and injured colonic mucosa using the trinitrobenzenesulfonic acid model of colitis in the rat. First, we tested the effects of broad-spectrum antibiotics administered at different times after induction of colitis. Second, in rats pretreated with antibiotics, we studied the effects of reintroduction of fecal flora on the release of inflammatory mediators and on the morphology of colonic lesions. Antibiotics reduced colonic lesion scores when started on day 1 after induction of colitis, but had no significant effect when started on day 7. In antibiotic-treated rats, intracolonic administration of a suspension of fecal contents 6 h after induction of colitis enhanced mucosal inflammatory activity and aggravated lesion scores. This effect was not observed when the suspension was administered 3 days after induction. Sonication of the suspension inhibited bacterial growth in aerobic and anaerobic cultures, and abolished its effect on colonic inflammation. In this model, bacteria of the common flora stimulate inflammatory activity and play a role in the induction of colonic mucosal lesions.

Induction of chronic pancreatic disease by trinitrobenzene sulfonic acid infusion into rat pancreatic ducts.

Despite being a common disease in humans, little is known about the etiopathogenesis of and effective therapeutic approaches to chronic pancreatitis, due mainly to the fact that few simple animal models suitable to study inflammatory and fibrogenetic processes have been described in the pancreas. Trinitrobenzene sulfonic acid (TNBS) induces chronic colitis and cholangitis in the rat. We hypothesized that TNBS instillation into the pancreatic ducts could also result in the development of a chronic pancreatic disease. The biliopancreatic duct of rats was cannulated and tied close to the liver. TNBS [0.4 ml of 2% TNBS in phosphate-buffered saline (PBS)-10% ethanol, pH 8] was infused into the pancreas under a continuous controlled-pressure system. Control rats underwent the same procedure using vehicle only. Pathology assessment of TNBS-treated rats examined at 48 h was consistent with severe acute necrotizing pancreatitis, having a morality rate of 31% and serum amylase activity of 37.4 +/- 8.8 U/ml at 24 h and 13.3 +/- 1.7 U/ml at 48 h (p < 0.01 for both time points compared to PBS/ethanol-treated rats). Groups of 10 rats each were killed at 3, 4, and 6 week after the surgical procedure. Morphological examination revealed changes mimicking features of chronic pancreatitis in humans in 80% (32 of 40) of TNBS-treated rats, consisting in various degrees of periductal and lobular fibrosis, duct stenosis, patchy acute and chronic inflammatory cell infiltrates, and signs of gland atrophy. Animals developing chronic disease had a weight gain rate significantly lower than that of control rats. Serum amylase, fasting glucose, and a glucose tolerance test were not different in diseased or control rats. In conclusion, we were able to induce chronic fibrogenetic inflammatory disease in the pancreas after a single pulse instillation of TNBS into the pancreatic ducts. This might be a useful animal model to study the pathophysiology of inflammatory, fibrogenetic, and reparative processes in pancreatic tissue.

Effects of calcium and parathyroid hormone on prostacyclin synthesis by vascular tissue.

Prostacyclin generation by rat aortic rings was studied at different calcium concentrations. Extracellular calcium influenced prostacyclin synthesis, as reflected by the release of 6-keto-PGF1 alpha into the medium, in a concentration-dependent fashion. Calcium levels beyond the physiological range (1.12-1.25 mM unbound calcium) markedly stimulated 6-keto-PGF1 alpha production when compared with calcium-free solutions. On the other hand, addition of purified parathyroid hormone did not change 6-keto-PGF1 alpha production at any calcium concentration tested. These data suggest that parathyroid hormone has no direct effect on prostacyclin synthesis by vascular tissue, although it might influence prostacyclin generation through changes in extracellular calcium levels.

Effects of thromboxane synthase inhibition on in vivo release of inflammatory mediators in chronic ulcerative colitis.

OBJECTIVE: To evaluate the effects of a thromboxane inhibitor on the production of eicosanoids by the colonic mucosa of patients with chronic ulcerative colitis. PATIENTS AND METHODS: Fourteen patients with active left-sided ulcerative colitis were divided into in two treatment groups. Seven patients received oral ridogrel (300 mg twice daily) and seven 5-aminosalicylic acid (5-ASA; 1 g twice daily) for 4 weeks. Intracolonic eicosanoid and elastase release were measured using a colonic double-lumen perfusion technique. An isotonic solution was infused 50 cm from the anal verge at the rate of 5 ml/min, and recovered by siphonage 30 cm distally. Effluents were assayed for thromboxane B2 (TXB2), prostaglandin E2 (PGE2), and leukotriene B4 (LTB4) by radioimmunoassay (RIA), and for polymorphonuclear elastase by immunoactivation. Clinical and colonoscopic criteria were used to determine activity before and after treatment. RESULTS: Four of the seven patients in the ridogrel group and five of the seven in the 5-ASA group showed clinical and colonoscopic improvement. Intraluminal elastase release decreased in every responding patient in the 5-ASA group (P < 0.05) and in three out of seven responders in the ridogrel group. Basal eicosanoid release was similar in both groups. In the responders, 5-ASA significantly reduced the release of the three eicosanoids (P < 0.05). Ridogrel reduced the release of TXB2 to 31% of basal levels (P < 0.01) but the release of PGE2 and LTB4 was not affected. CONCLUSIONS: These results suggest that ridogrel is an oral active selective inhibitor of thromboxane synthetase, which modifies the pattern of colonic eicosanoid generation in patients with chronic ulcerative colitis. Oral ridogrel may be a useful treatment for patients with non-severe ulcerative colitis, although specific indications require further studies.

Role of microecology in chronic inflammatory bowel diseases.

Inflammatory bowel diseases (IBD) are chronic conditions of unknown etiology. Current therapy mitigates the severity of acute bouts of mucosal inflammation but an eradication therapy is lacking. Growing incidence of IBD is associated with social development. Epidemiology suggests a relationship between the establishment of the individual gut flora and the risk of developing IBD. Patients show an impaired tolerance towards commensal bacteria of the resident flora. Unrestrained activation of the intestinal immune system against some commensal bacteria appears to be responsible for the characteristic relapsing course of these diseases. Wide-spectrum antibiotic therapy reduces bacterial load and mitigates intestinal inflammation in human IBD and in animal models. Current research aims at the identification of probiotics for bacterial antagonism therapies. Probiotics are living microorganisms which upon ingestion in certain numbers exert health benefits beyond inherent basic nutrition. Colonization with a Lactobacillus reuteri strain can prevent the development of colitis in genetically susceptible mice. Other studies have used a bacterium genetically engineered to secrete the antiinflammatory cytokine IL-10 and demonstrated a therapeutic effect in animal models of colitis. Moreover, some probiotics may naturally exhibit antiinflammatory properties when interacting with the human gut mucosa. Prebiotics such as inulin have also been shown to prevent colonic inflammation in animal models. Preliminary clinical trials with probiotics in IBD are encouraging. Probiotics offer a valuable tool for the prevention and control of inflammatory bowel diseases.

9 beta-methylcarbacyclin, a stable prostacyclin analogue, in prevention of platelet losses during charcoal haemoperfusion.

The effect of 9 beta-methylcarbacyclin, a stable analogue of prostacyclin, as a platelet protective agent, has been investigated during in-vitro charcoal haemoperfusion with fresh heparinized human blood, a model of progressive platelet damage. There were no platelet losses over 3 h perfusion after an initial bolus (1 microgram ml-1) of 9 beta-methylcarbacyclin (101.6 +/- s.e. 1.9% of initial value) whereas in the paired control circuit there was a significant reduction in the platelet level (73.5 +/- 4.1%, P less than 0.05). Prevention of rises in plasma thromboxane B2 by 9 beta-methylcarbacyclin confirmed the lack of platelet damage and a significant, but less marked, effect on white cell losses was observed. In a second series of experiments a bolus of 9 beta-methylcarbacyclin in one circuit was compared with prostacyclin infusion in the other which demonstrated that this prostaglandin analogue was as effective as prostacyclin and on the basis of these initial results it would merit clinical evaluation.

CNS effects of platelet-activating factor on the rat stomach.

PAF has been implicated in the pathogenesis of acute gastric injury. When administered peripherally, PAF induces severe gastric mucosal damage. PAF-metabolizing enzymes are present in the brain, but the central effects of PAF on the stomach are unknown. We have investigated gastric secretory and mucosal response to i.c.v. PAF in the rat and compared it with that of i.c.v. thyrotropin-releasing hormone (TRH), a known central gastric secretagogue. Gastric acid output was markedly increased by TRH (171.6 +/- 26.3 mumol/h mean +/- SE) and by 20 micrograms/kg/h i.v. pentagastrin (107.6 +/- 23.6), as compared to controls receiving i.c.v. vehicle (20.2 +/- 7.5; p less than 0.01 for both). In contrast, acid output decreased after i.c.v. PAF (13.5 +/- 7.5). Furthermore, i.c.v. PAF markedly inhibited acid output stimulated by i.v. pentagastrin (45.1 +/- 7.03; p less than 0.05). Morphologic studies showed acute gastric mucosal erosions after i.c.v. TRH, but no damage was observed after i.c.v. PAF or vehicle. Thus, i.c.v. PAF inhibits gastric acid secretion but does not alter gastric mucosal integrity, whereas i.c.v. TRH stimulates acid secretion and induces gastric injury. The opposite effects of PAF and TRH suggest the existence of a gastric modulatory system at the central level.