Sulfonolipids as novel metabolite markers of Alistipes and Odoribacter affected by high-fat diets.

The gut microbiota generates a huge pool of unknown metabolites, and their identification and characterization is a key challenge in metabolomics. However, there are still gaps on the studies of gut microbiota and their chemical structures. In this investigation, an unusual class of bacterial sulfonolipids (SLs) is detected in mouse cecum, which was originally found in environmental microbes. We have performed a detailed molecular level characterization of this class of lipids by combining high-resolution mass spectrometry and liquid chromatography analysis. Eighteen SLs that differ in their capnoid and fatty acid chain compositions were identified. The SL called "sulfobacin B" was isolated, characterized, and was significantly increased in mice fed with high-fat diets. To reveal bacterial producers of SLs, metagenome analysis was acquired and only two bacterial genera, i.e., Alistipes and Odoribacter, were revealed to be responsible for their production. This knowledge enables explaining a part of the molecular complexity introduced by microbes to the mammalian gastrointestinal tract and can be used as chemotaxonomic evidence in gut microbiota.

High-Loading Dose of Microencapsulated Gliclazide Formulation Exerted a Hypoglycaemic Effect on Type 1 Diabetic Rats and Incorporation of a Primary Deconjugated Bile Acid, Diminished the Hypoglycaemic Antidiabetic Effect.

BACKGROUND AND OBJECTIVE: Gliclazide is a drug commonly used in type 2 diabetes mellitus. Recently, gliclazide has shown desirable pharmacological effects such as immunoregulatory and anti-clotting effects, which suggests potential applications in type 1 diabetes mellitus (T1DM). Gliclazide has variable absorption after oral administration, and thus using targeted-delivery techniques, such as microencapsulation, may optimise gliclazide absorption and potential applications in T1DM. Bile acids such as cholic acid have shown microcapsule-stabilising and controlled-release effects, and thus their incorporation into gliclazide microcapsules may further optimise gliclazide release, absorption and antidiabetic effects. Accordingly, this study aimed to examine the hypoglycaemic effects of gliclazide microcapsules with and without cholic acid, in a rat model of T1DM. METHODS: Thirty-five alloxan-induced T1DM rats were randomly divided into five equal groups and gavaged a single dose of empty microcapsules, gliclazide, gliclazide microcapsules, gliclazide-cholic acid or gliclazide-cholic acid microcapsules. Blood samples were collected over 10 h post-dose and analysed for blood glucose and gliclazide serum concentrations. RESULTS: Gliclazide microcapsules exerted a hypoglycaemic effect in the diabetic rats, and cholic acid incorporation diminished the hypoglycaemic effects, which suggests the lack of synergistic effects between gliclazide and cholic acid. In addition, neither microencapsulation nor cholic acid incorporation optimised gliclazide absorption which suggests that hypoglycaemic effects of gliclazide are independent of its absorption and serum concentrations. This also suggests that hypoglycaemic effects of gliclazide may be associated with gut-metabolic activation rather than gut-targeted delivery and systemic absorption. CONCLUSION: Gliclazide microcapsules exerted hypoglycaemic effects in T1DM rats independent of insulin and thus may have potentials in treatment of T1DM.

Dysbiotic gut microbiota causes transmissible Crohn's disease-like ileitis independent of failure in antimicrobial defence.

OBJECTIVES: Dysbiosis of the intestinal microbiota is associated with Crohn's disease (CD). Functional evidence for a causal role of bacteria in the development of chronic small intestinal inflammation is lacking. Similar to human pathology, TNF(deltaARE) mice develop a tumour necrosis factor (TNF)-driven CD-like transmural inflammation with predominant ileal involvement. DESIGN: Heterozygous TNF(deltaARE) mice and wildtype (WT) littermates were housed under conventional (CONV), specific pathogen-free (SPF) and germ-free (GF) conditions. Microbial communities were analysed by high-throughput 16S ribosomal RNA gene sequencing. Metaproteomes were measured using LC-MS. Temporal and spatial resolution of disease development was followed after antibiotic treatment and transfer of microbial communities into GF mice. Granulocyte infiltration and Paneth cell function was assessed by immunofluorescence and gene expression analysis. RESULTS: GF-TNF(deltaARE) mice were free of inflammation in the gut and antibiotic treatment of CONV-TNF(deltaARE) mice attenuated ileitis but not colitis, demonstrating that disease severity and location are microbiota-dependent. SPF-TNF(deltaARE) mice developed distinct ileitis-phenotypes associated with gradual loss of antimicrobial defence. 16S analysis and metaproteomics revealed specific compositional and functional alterations of bacterial communities in inflamed mice. Transplantation of disease-associated but not healthy microbiota transmitted CD-like ileitis to GF-TNF(deltaARE) recipients and triggered loss of lysozyme and cryptdin-2 expression. Monoassociation of GF-TNF(deltaARE) mice with the human CD-related Escherichia coli LF82 did not induce ileitis. CONCLUSIONS: We provide clear experimental evidence for the causal role of gut bacterial dysbiosis in the development of chronic ileal inflammation with subsequent failure of Paneth cell function.

The influence of chronic intake of saccharin on rat hepatic and pancreatic function and morphology: gender differences.

There are opposite hypotheses on the effect of saccharin. Our aim was reviewing the influence of chronically ingested saccharin on the function and histological structure of liver and pancreas and all this in light of gender differences. The rats were divided into control group - (Group C) and saccharin-treated group - (Group S) which was given a normal diet and 0.0005% saccharin in drinking water for 6 weeks. Liver and pancreas were histologically processed and quantitative histological analysis was performed. Glucose blood levels and plasma activities of aspartate transaminase (AST) and alanine transaminase (ALT), body weight, and food intake were analyzed. Quantitative histological analysis determined that the values of diameter and volume density of both Langerhans islets and exocrine acini were significantly higher in S group, especially in males. AST levels were significantly higher in treated group. Glucose levels were higher in treated group, mainly due to the values of the female subgroup. Food intake was significantly higher in control group, while weight gain was higher in treated group. Treated males had significantly higher food intake and weight gain in comparison with treated females. The data presented here suggests that chronic saccharin intake affects the examined parameters. Reported facts reflect various metabolic, hormonal and neural responses in males and females.

[Outpatient utilization of non-steroidal anti-inflammatory drugs in three largest municipalities in South Backa district].

INTRODUCTION: Nonsteroidal anti-inflammatory drugs (NSAIDs) are used in the treatment of musculoskeletal system diseases (MSD) and are associated with numerous adverse effects. OBJECTIVE: To determine the amount and structure of outpatient consumption of NSAIDs and its correlation with musculoskeletal system diseases in three municipalities in South Backa district with different levels of health care. To examine whether the cost of drugs and the level of health care influence the choice of drugs. METHODS: Data on the quarterly consumption of NSAIDs have been collected from all pharmacies in Novi Sad, Vrbas and Backa Palanka. Data are presented by the number of defined daily dosage (DDD) per 1000 inhabitants. Cost (in RSD)/DDD was also calculated. The drug utilization 90% (DU90%) methodology was used. Data on the incidence of MSD from the three municipalities were obtained from the Institute of Public Health of Vojvodina and were presented as the number of patients/1000 inhabitants. RESULTS: The highest total outpatient consumption of NSAIDs was recorded in Backa Palanka, a municipality with the highest prevalence of MSD. The lowest NSAIDs consumption and the lowest number of patients were observed in Vrbas. Diclofenac was NSAID with the highest consummation in all three municipalities, while ibuprofen, meloxicam and nimesulide were dispensed in much smaller amounts. The cheapest NSAIDs were found to be piroxicam and naproxen, diclofenac was the third in terms of price/DDD, while ibuprofen was the sixth. CONCLUSION: In order to improve prescription practice and the profile of drug usage in the population, it is important to educate health care professionals, and to inform general population about the risks of inappropriate drug use.

The outpatient utilization of non-steroidal anti-inflammatory drugs in South Backa District, Serbia.

OBJECTIVE: To evaluate the utilization of non-steroidal anti-inflammatory drugs (NSAIDs) in South Backa District (SBD), Serbia. SETTING: State-owned and private pharmacies in SBD, a northern district of Serbia, with 605,720 inhabitants (according to the 2008 census). METHOD: Data on the number of packages, size of packages, and retail price of NSAIDs (Anatomical Therapeutic Chemical (ATC) group M01A) from 1 January to 31 March 2008 were obtained from all state-owned and private pharmacies in SBD. This included NSAIDs bought without prescription and those issued by prescription (on the Health Insurance Companies List for Reimbursement). The number of defined daily doses/1000 inhabitants/day (DDD/1000 inh/day) was calculated. Within the DU90% (drug utilization 90%) segment, the proportion of high-, medium- and low-risk NSAIDs with respect to the risk of gastrointestinal (GI) bleeding was determined. Price/DDD was also calculated. MAIN OUTCOME MEASURE: Consumption of drugs expressed as DDD/1000 inh/day. RESULTS: The total consumption of NSAIDs over a 3-month period was 48.31 DDD/1000 inh/day. Only four drugs were within DU90%: diclofenac, ibuprofen, nimesulide and meloxicam (62.14, 19.87, 5.77, and 5.73% of total NSAID consumption, respectively). All dispensed NSAIDs within the DU90% segment except nimesulide (which was exclusively purchased without prescription) were nearly equally purchased without prescription and issued by prescription. The average price per DDD within the DU90% segment was 0.17 Euro/DDD, whereas it was 0.30 Euro/DDD for NSAIDs beyond the DU90% segment. The pattern of use of NSAIDs according to their GI risk showed that medium-risk diclofenac accounted for 66.45%, whereas low-risk ibuprofen was estimated to be 21.25% within the DU90% segment. CONCLUSION: Factors other than evidence-based medicine (such as poor health education in the past that led to long-lasting consequences on the cultural behaviour of the general population as well as on the prescribing habits of physicians) have a dominating impact on the use of NSAIDs in SBD. Targeted education from independent sources in the prescribing, dispensing and use of drugs is required to improve the quality of prescription and use of NSAIDs in Serbia.

Consumption of non-steroidal anti-inflammatory drugs in Serbia: a comparison with Croatia and Denmark during 2005-2008.

PURPOSE: To analyze the amount and pattern of use of non-steroidal anti-inflammatory drugs (NSAIDs) in Serbia and to compare these parameters with those in Croatia and Denmark. The prescribing pattern of NSAIDs in Serbia as a direct indicator of physicians' knowledge of these agents was also assessed. METHODS: The use of NSAIDs in Serbia, Croatia, and Denmark was analyzed during a 4-year period (2005-2008). Data were retrieved from the annual reports of the Agency for Drugs and Medical Devices of Serbia, Croatia, and Denmark. Data on prescribing behavior were obtained from the Health Insurance Fund of Serbia and represent NSAIDs issued by prescription between 2005 and 2008. Results were expressed as the number of defined daily doses/1000 inhabitants/day. The drug utilization 90% method was also used. RESULTS: The total consumption of NSAIDs in Serbia was higher than that in Croatia and Denmark. Diclofenac accounted for approximately 50% of NSAID consumption during the observation period, followed (in much smaller quantities) by ibuprofen. The most commonly prescribed medicine was diclofenac, followed, in much smaller amounts, by ibuprofen. There was no trend of a reduced consumption of diclofenac or of an increased use of ibuprofen during the study period CONCLUSIONS: These data suggest that factors other than evidence-based medicine have a dominant effect on the use of NSAIDs in Serbia. Targeted education from independent sources in the prescribing, dispensing, and use of drugs is important to improve the quality of the prescribing behavior and the use of NSAIDs.