Even low-grade inflammation impacts on small intestinal function

Independent of the cause and location,inflammation-even when minimal-has clear effects on gastrointestinal morphology and function.These result in altered digestion,absorption and barrier function.There is evidence of reduced villus height and crypt depth,increased permeability,as well as altered sugar and peptide absorption in the small intestine after induction of inflammation in experimental models,which is supported by some clinical data.Identification of inflammatory factors which may promote the process of gastrointestinal dysfunction as well as clinical research to verify experimental observations of inflammatory modulation of gastrointestinal function are required.Moreover,nutritional strategies to support functional restitution are needed.

Probiotic intervention has strain-specific anti-inflammatory effects in healthy adults

AIM： To evaluate the effects of three potentially anti-inflammatory probiotic bacteria from three different genera on immune variables in setting based on previous in cytokine responses. healthy adults in a clinical vitro characterization of METHODS： A total of 62 volunteers participated in this randomized, double-blind and placebo-controlled parallel group intervention study. The volunteers were randomized to receive a milk-based drink containing either Lactobacillus rhamnosus GG （LGG）, Bifidobacterium animalis ssp. lactis Bb12 （Bb12）, or Propionibacterium freudenreichii ssp. shermanii JS （PJS） or a placebo drink for 3 wk. Venous blood and saliva samples were taken at baseline and on d 1, 7 and 21. Fecal samples were collected at baseline and at the end of intervention. RESULTS： The serum hsCRP expressed as the median AUC0-21 （minus baseline） was 0.018 mg/L in the placebo group, -0.240 mg/L in the LGG group, 0.090 mg/L in the Bb12 group and -0.085 mg/L in the PJS group （P = 0.014）. In vitro production of TNF-α from in vitro cultured peripheral blood mononuclear cells （PBMC） was significantly lower in subjects receiving LGG vs placebo. IL-2 production from PBMC in the Bb12 group was significantly lower compared with the other groups. CONCLUSION： In conclusion, probiotic bacteria have strain-specific anti-inflammatory effects in healthy adults.

Elevated pro-inflammatory and lipotoxic mucosal lipids characterise irritable bowel syndrome

AIM： To investigate the pathophysiology of irritable bowel syndrome （IBS） by comparing the global mucosal metabolic profiles of IBS patients with those of healthy controls. METHODS： Fifteen IBS patients fulfilling the Rome II criteria, and nine healthy volunteers were included in the study. A combined lipidomics （UPLC/MS） and metabolomics （GC × GC-TOF） approach was used to achieve global metabolic profiles of mucosal biopsies from the ascending colon. RESULTS： Overall, lipid levels were elevated in patients with IBS. The most significant upregulation was seen for pro-inflammatory lysophosphatidylcholines. Other lipid groups that were significantly upregulated in IBS patients were lipotoxic ceramides, glycosphingolipids, and di-and triacylglycerols. Among the meo tabolites, the cyclic ester 2（3H）-furanone was almost 14-fold upregulated in IBS patients compared to healthy subjects （P = 0.03）. CONCLUSION： IBS mucosa is characterised by a distinct pro-inflammatory and lipotoxic metabolic profile. Especially, there was an increase in several lipid species such as lysophospholipids and ceramides.

Local corticosterone production and angiotensin-Ⅰconverting enzyme shedding in a mouse model of intestinal inflammation

AIM: To investigate local corticosterone production and angiotensin-Ⅰ converting enzyme(ACE) protein expression and their interaction in healthy and inflamed intestine.METHODS: Acute intestinal inflammation was induced to six weeks old male Balb/c mice by administration of either 3% or 5% dextran sodium sulfate(DSS) in drinking water for 7 d(n = 12 in each group). Healthy controls(n = 12) were given tap water. Corticosterone production and ACE protein shedding were measured from ex vivo incubates of the small and large intestine using EIA and ELISA, respectively. Morphological changes of the intestinal wall were assessed in hematoxylin-eosin stained tissue preparations of jejunum and distal colon. Effects of angiotensin Ⅱ, captopril and metyrapone on corticosterone production was assessed by incubating pieces of small intestine of healthy mice in the presence of 0.1, 1 or 10 μmol/L angiotensin Ⅱ, 1, 10 or 100 μmol/L captopril or 1, 10 or 100 μmol/L metyrapone solutions and measuring corticosterone released to the incubation buffer after 90 min(n = 5 in each group).RESULTS: Both concentrations of DSS induced inflammation and morphological changes in large intestines but not in small intestines. Changes were observed as distortions of the crypt structure, mucosal erosion, immune cell infiltration to the mucosa and submucosal edema. Ex vivo corticosterone production(2.9 ± 1.0 ng/mL vs 2.0 ± 0.8 ng/mL, P = 0.034) and ACE shedding(269.2 ± 97.1 ng/m L vs 175.7 ± 52.2 ng/mL, P = 0.016) were increased in small intestines in 3% DSS group compared to the controls. In large intestine, corticosterone production was increased compared to the controls in both 3% DSS(229 ± 81 pg/mL vs 158 ± 30 pg/mL, P = 0.017) and 5% DSS groups(366 ± 163 pg/mL vs 158 ± 30 pg/mL, P = 0.002). Large intestine ACE shedding was increased in 5% DSS group(41.5 ± 9.0 ng/mL vs 20.9 ± 5.2 ng/mL, P = 0.034). Angiotensin Ⅱ treatment augmented corticosterone production in small intestine at concentration of 10 μmol/L(0.97 ± 0.21 ng/mg protein vs 0.40 ± 0.09 ng/mg protein, P = 0.036).CONCLUSION: Intestinal ACE shedding is increased by DSS-induced intestinal inflammation and parallels local corticosterone production. ACE product angiotensin Ⅱ stimulates corticosterone formation in healthy intestine.

Lactotripeptides Inhibiting ACE1 Elevate the Plasma Bradykinin Concentration Acutely in a Placebo-Controlled, Double-Blind, Cross-Over, 4-Week Trial in Healthy Volunteers

This placebo-controlled, double-blind, cross-over intervention with twelve normotensive healthy volunteers tested the effects of milk products containing either 5 or 50 mg of ACE1-inhibitory lactotripeptides (isolecine-proline-proline, Ile-Pro-Pro, and valine-proline-proline, Val-Pro-Pro) and placebo milk drink (with similar taste) on plasma bradykinin levels. The subjects consumed one of the three test products in a random order, double-blinded, and four-week trial. On the first day (day 1) and on the last day (day 29) i.e. after four weeks’ treatment with one of the products, the acute effect with the same single dose was assayed. Other markers of the renin-angiotensin-aldosterone system (RAAS) were measured from plasma four times on the same days when we also assessed daytime urinary excretion of biomarkers of endothelial function. Neither acute nor prolonged administration of the ACE-1 inhibiting peptide drinks significantly lowered blood pressure of the normotensive subjects. The most important finding was the dose-dependent, and linear increase in plasma bradykinin concentrations after acute dosing on the first day;it was nearly statistically significant also on the day 29 (p 0.06). Other indicators of RAAS or endothelial function did not differ from those of placebo after the acute or prolonged treatments. Our results suggest that even weak inhibitors of ACE-1, such as the lactotripeptides Ile-Pro-Pro and Val-Pro-Pro, are able to diminish the breakdown of bradykinin and therefore increase plasma bradykinin levels. This may partly explain the blood pressure lowering and vasodilatory effects of lactotripeptides, shown by us earlier in mildly hypertensive subjects.

Effect of probiotic Lactobacillus rhamnosus GG intervention on global serum lipidomic profiles in healthy adults

AIM: To investigate the effect of three weeks’ intervention with a probiotic Lactobacillus rhamnosus GG (LGG) bacteria on global serum lipidomic profiles and evaluate whether the changes in inflammatory variables (CRP, TNF-α and IL-6) are reflected in the global lipidomic profiles of healthy adults. METHODS: We performed UPLC/MS-based global lipidomic platform analysis of serum samples (n = 26) in a substudy of a randomised, double-blind, placebo- controlled 3-wk clinical intervention trial investigating the immunomodulatory effects of probiotics in healthy adults. RESULTS: A total of 407 lipids were identified, corresponding to 13 different lipid classes. Serum samples showed decreases in the levels of lysophosphatidylcholines (LysoGPCho), sphingomyelins (SM) and several glycerophosphatidylcholines (GPCho), while triacylglycerols (TAG) were mainly increased in the probiotic LGG group during the intervention. Among the inflammatory variables, IL-6 was moderatelyassociated by changes in global lipidomic profiles, with the top-ranked lipid associated with IL-6 being the proinflammatory LysoGPCho (20:4). There was a weak association between the lipidomic profiles and the two other inflammatory markers, TNF-α and CRP. CONCLUSION: This was the first study to investigate the effects of probiotic intervention on global lipidomic profiles in humans. There are indications that probiotic LGG intervention may lead to changes in serum global lipid profiles, as reflected in decreased GPCho, LysoGPCho and SM as well as mainly increased TAG.

Possible Correlation between INR and Serum Calcium

Experimental and clinical studies have shown that long term anticoagulation therapy with warfarin can induce vascular calcification which is preventable by vitamin K. Osteoporosis has been shown to be associated with vascular calcification. In the present study, we wanted to see, whether INR (International Normalized Ratio), a measure of prothrombin time, and serum calcium (corrected by albumin) correlate in laboratory data of 94 anticoagulation patients on warfarin therapy. When adjusted on age and sex, there was an inverse correlation between the two variables. Clinical relevance of this observation and explanation of lowered calcium levels in blood parallel to increase in INR-values remain to be studied further.

Local Intestinal ACE-Like Activity and Corticosterone Production in Hypertensive and Aging Rats

The renin angiotensin system (RAS) participates in inflammatory processes, as either a pro-inflammatory or an anti-inflammatory mediator. Components of RAS, such as angiotensin-converting enzyme (ACE), have been detected locally in the gut epithelium. In addition, the anti-inflammatory steroid, corticosterone, is produced in the gut. Hypertension and aging evoke a low-grade inflammatory process in the vascular endothelium. It is not known whether they induce a similar low-grade inflammation in the intestine and if the low-grade inflammation would evoke an activation of ACE and an elevation of corticosterone production. These two variables were measured in ileum and colon of 9- and 26-week old spontaneously hypertensive rats (SHR) and their normotensive Wistar-Kyoto (WK) controls. ACE-activity, measured via the formation of histidyl-leucine from hippuryl-histidyl-leucine in the tissue homogenate samples, was similar in the ileum and colon of young animals although the ileum of the young normotensive animals displayed the lowest level. In the old animals, the ACE activity was higher in the ileum than in the colon, especially in normotensive rats. Corticosterone production was measured as corticosterone concentration in the supernatants of ileum or colon after a 90-min ex vivo incubation. Corticosterone production was higher in ileum than in colon in both SHR and WK. No clear evidence was seen for age-dependency or for an effect of hypertension in the measured variables in the intestine. Thus, the putative low-grade inflammation in the intestine in aging or hypertension is not a strong enough stimulus to elevate corticosterone production or activate ACE.

Ocular renin-angiotensin system with special reference in the anterior part of the eye

The renin-angiotensin system(RAS) regulates blood pressure(BP) homeostasis, systemic fluid volume and electrolyte balance. The RAS cascade includes over twenty peptidases, close to twenty angiotensin peptides and at least six receptors. Out of these, angiotensin Ⅱ, angiotensin converting enzyme 1 and angiotensin Ⅱ type 1 receptor(AngⅡ-ACE1-AT1R) together with angiotensin(1-7), angiotensin converting enzyme 2 and Mas receptor(Ang(1-7)-ACE2-Mas R) are regarded as the main components of RAS. In addition to circulating RAS, local RA-system exists in various organs. Local RA-systems are regarded as tissue-specific regulatory system accounting for local effects and long term changes in different organs. Many of the central components such as the two main axes of RAS: AngⅡ-ACE1-AT1 R and Ang(1-7)-ACE2-Mas R, have been identified in the human eye. Furthermore, it has been shown that systemic antihypertensive RAS- inhibiting medications lower intraocular pressure(IOP). These findings suggest the crucial role of RAS not only in the regulation of BP but also in the regulation of IOP, and RAS potentially plays a role in the development of glaucoma and antiglaucomatous drugs.

Neuroprotective Effects of Mas-receptor Ligands in an Experimental Rat Glaucoma

Objectives： Ocular effects of Mas-receptor ligands were studied in an experimental rat glaucoma. Elevated IOP （intraocular pressure） was induced unilaterally by laser photocoagulation of the episcleral and limbal veins in anesthetized rats. A Mas-receptor agonist （Ang （1-7）） and an antagonist （A779） were administered intravitreally in the glaucomatous eye. lOP was measured by a rebound tonometer. Effects of the treatment on RGCL （retinal ganglion cell layer） were determined stereologically and on the axons of optic nerve by a modified Gallyas silver-staining method. Key findings： Mean IOP during the 14 days follow-up in the solvent treated glaucoma eyes （n = 18） was 28.7 -4- 1.9 mmHg vs. the fellow eyes 11.0 4- 0.3 mmHg. A significant axon damage was detected in the glaucomatous eyes vs. the fellow normotensive eye. The Mas-receptor ligands did not influence high IOP resulted by laser treatment, Despite of the ineffectiveness on lOP, Ang （1-7） protected RGCL cells as determined by stereology （P = 0.016）. No significant effects in Gallyas silver-staining were found. Summary： Intravitreally administered Ang （1-7） showed a significant protective effect against neuronal damage. The present and our previous studies suggest that stimulation of Mas-receptor may have therapeutic potential to treat glaucoma.

Effects of Vitamin K-1 and Menaquinone-7 on Vascular Function and Blood Pressure in Warfarin-Induced Calcification-Model in Rats

Given that vascular calcification is inversely correlated with the clinical intake of menaquinone, a rat model of warfarin-induced calcification may be useful for testing menaquinone and vitamin K-1 potential effects on vascular function. The aim of the present study was to investigate effects of vitamin K-1 and menaquinone-7 treatments on blood pressure and vascular function in warfarin-induced vascular calcification model during five-week intervention in normotensive Wistar-Kyoto rats. Blood pressure was measured weekly, and at the end of the intervention in vitro vascular reactivity measurements were done. Alizarin Red S and von Kossa stainings were used to record possible calcification of aortic sections. Routine clinical chemistry was done from serum and urine samples. Vascular calcification was seen only in a few warfarin-treated animals in histological staining. Warfarin-treatment did not change significantly blood pressure of the rats. Warfarin-treatment increased slightly the endothelium-dependent relaxation of aorta after the L-type calcium channels were blocked. Also the vascular relaxation improved after NOS inhibition in the aorta of the healthy controls and menaquinone-7 treated animals, indicating that the relaxation in those groups was not totally dependent on NO. Clinical chemistry from serum showed some differences in urea, creatinine as well as lipid and glucose metabolism between the healthy controls and warfarin-treated rats.