Altered profiles of fecal metabolites correlate with visceral hypersensitivity and may contribute to symptom severity of diarrhea-predominant irritable bowel syndrome

BACKGROUND Fecal metabolites are associated with gut visceral sensitivity, mucosal immune function and intestinal barrier function, all of which have critical roles in the pathogenesis of irritable bowel syndrome(IBS). However, the metabolic profile and pathophysiology of IBS are still unclear. We hypothesized that altered profiles of fecal metabolites might be involved in the pathogenesis of IBS with predominant diarrhea(IBS-D).AIM To investigate the fecal metabolite composition and the role of metabolites in IBSD pathophysiology.METHODS Thirty IBS-D patients and 15 age-and sex-matched healthy controls(HCs)underwent clinical and psychological assessments, including the IBS Symptom Severity System(IBS-SSS), an Italian modified version of the Bowel Disease Questionnaire, the Bristol Stool Form Scale(BSFS), the Hospital Anxiety and Depression Scale, and the Visceral Sensitivity Index. Visceral sensitivity to rectal distension was tested using high-resolution manometry system by the same investigator. Fecal metabolites, including amino acids and organic acids, weremeasured by targeted metabolomics approaches. Correlation analyses between these parameters were performed.RESULTS The patients presented with increased stool water content, more psychological symptoms and increased visceral hypersensitivity compared with the controls. In fecal metabolites, His [IBS-D: 0.0642(0.0388, 0.1484), HC: 0.2636(0.0780, 0.3966), P= 0.012], Ala [IBS-D: 0.5095(0.2826, 0.9183), HC: 1.0118(0.6135, 1.4335), P = 0.041],Tyr [IBS-D: 0.1024(0.0173, 0.4527), HC: 0.5665(0.2436, 1.3447), P = 0.018], Phe[IBS-D: 0.1511(0.0775, 0.3248), HC: 0.3967(0.1388, 0.7550), P = 0.028], and Trp[IBS-D: 0.0323(0.0001, 0.0826), HC: 0.0834(0.0170, 0.1759), P = 0.046] were decreased in IBS-D patients, but isohexanoate [IBS-D: 0.0127(0.0060, 0.0246), HC:0.0070(0.0023, 0.0106), P = 0.028] was significantly increased. Only Tyr was mildly correlated with BSFS scores in all subjects(r =-0.347, P = 0.019). A possible potential biomarker panel was identified to correlate with IBS-SSS score(R2 Adjusted= 0.693, P 0.001). In this regression model, the levels of Tyr, Val, hexanoate,fumarate, and pyruvate were significantly associated with the symptom severity of IBS-D. Furthermore, visceral sensation, including abdominal pain and visceral hypersensitivity, was correlated with isovalerate, valerate and isohexanoate.CONCLUSION Altered profiles of fecal metabolites may be one of the origins or exacerbating factors of symptoms in IBS-D via increasing visceral sensitivity.     

Short chain fatty acids are effective in short-term treatment of chronic radiation proctitis

PURPOSE: Short chain fatty acids are the main energy source of coloncytes and their use may be impaired in chronic radiation proctitis. The aim of the present study was to evaluate the therapeutic effect of short chain fatty acid enemas in patients with chronic radiation proctitis. METHODS: A prospective, randomized, double-blind trial comparing short chain fatty acid enemas with placebo was conducted in 19 patients with chronic radiation proctitis. Short chain fatty acid enemas contained 60 mM sodium acetate, 30 mM sodium propionate, and 40 mM sodium butyrate. The treatment period lasted five weeks and patients were followed up for six months. RESULTS: On admission, both groups were similar regarding all parameters evaluated. After five weeks short chain fatty acid-treated patients showed a significant decrease in the number of days with rectal bleeding from the previous week (4.4±1.8 to 1.4±2.2;P=0.001) and an improvement of endoscopic score (4.8±1.4 to 2.2±1.2;P=0.001). Hemoglobin values were also significantly higher in short chain fatty acid-treated patients (13.1±0.9 g/dlvs. 10.7±2.1 g/dl;P=0.02). Mucosal DNA and protein concentrations decreased in both groups but significantly so only in placebotreated patients (P=0.05). Changes in histologic parameters were not significant in either group. Although short chain fatty acid-treated patients did not get worse in the next six months, placebo-treated ones gradually improved, and at the end of six months, differences between the two groups were no longer observed. CONCLUSIONS: Short chain fatty acid enemas can accelerate the process of healing in chronic radiation proctitis, but treatment has to be continuous if a complete and sustained clinical, endoscopic, and histologic response is to be obtained.Presented in part at The Digestive Disease Week Scientific Sessions, New Orleans, Louisiana, May 15 to 18, 1994.     

便秘状态下肠道菌群变化对脂代谢的影响

肠道菌群的稳定在维持机体健康中发挥重要作用,当便秘引起肠道菌群失衡时,它通过干扰胆汁酸(bile acids,BAs)的合成影响脂质消化、吸收过程;肠道菌群代谢物短链脂肪酸(short chain fatty acids,SCFAs)减少可破坏肠道黏膜屏障的完整性,且SCFAs的受体不能被激活,此外,氧化三甲胺(trimethylamine oxide,TMAO)产生量增多影响脂质代谢过程中关键酶的表达,进一步影响脂质转运、清除过程.本文就便秘状态下肠道菌群通过BAs、SCFAs、TMAO的变化介导脂代谢紊乱的机制作一综述.     

短链脂肪酸对人结肠癌Caco-2细胞增殖分化的影向与临床意义

目的 离纤维素饮食对预防结肠癌有重要作用，但其具体作用环节与机制并不清楚。以人结肠癌Caco-2细胞为模型，研究3种短链脂肪酸对细胞增殖、分化和转移的影响以及高纤维素饮食抗结肠癌的作用与意义。方法 以人高分化结肠癌Caco-2为模型，分别绎细胞增殖能力对数转换法检测倍增时间、结肠癌上皮刷状缘细胞分化标忐物组蛋白酶C生化检测及转移率测定，分析短链脂肪酸对人结肠癌细胞增殖、分化与转移的影响。结果 3种短链脂肪酸均可影响人结肠癌细胞的表型，显著延长肿瘤细胞倍增时川，增强癌细胞分化标志物组蛋白酶的表达，行明显抑制癌细胞的转移。结论 高纤维素饮食所含的短链脂肪酸通过抑制癌细胞的增殖、分化及转移而起到抗肿瘤作用。提高丁酸盐／乙酸盐比率的纤维素饮食可增强其抗癌作用。     

Evaluation and comparison of short chain fatty acids composition in gut diseases

BACKGROUND An altered(dysbiosis) and unhealthy status of the gut microbiota is usually responsible for a reduction of short chain fatty acids(SCFAs) concentration.SCFAs obtained from the carbohydrate fermentation processes are crucial in maintaining gut homeostasis and their determination in stool samples could provide a faster, reliable and cheaper method to highlight the presence of an intestinal dysbiosis and a biomarker for various gut diseases. We hypothesize that different intestinal diseases, such as celiac disease(CD), adenomatous polyposis(AP) and colorectal cancer(CRC) could display a particular fecal SCFAs' signature.AIM To compare the fecal SCFAs' profiles of CD, AP, CRC patients and healthy controls, using the same analytical method.METHODS In this cross-sectional study, we defined and compared the SCFAs' concentration in fecal samples of 9 AP, 16 CD, 19 CRC patients and 16 healthy controls(HC).The SCFAs' analysis were performed using a gas-chromatography coupled with mass spectrometry method. Data analysis was carried out using Wilcoxon ranksum test to assess pairwise differences of SCFAs' profiles, partial least squaresdiscriminate analysis(PLS-DA) to determine the status membership based on distinct SCFAs' profiles, and Dirichlet regression to determine factors influencing concentration levels of SCFAs.RESULTS We have not observed any difference in the SCFAs' amount and composition between CD and healthy control. On the contrary, the total amount of SCFAs was significantly lower in CRC patients compared to HC(P = 0.044) and CD(P =0.005). Moreover, the SCFAs' percentage composition was different in CRC and AP compared to HC. In detail, HC displayed higher percentage of acetic acid(P value = 1.3 × 10~(-6)) and a lower amount of butyric(P value = 0.02192), isobutyric(P value = 7.4 × 10~(-5)), isovaleric(P value = 0.00012) and valeric(P value = 0.00014)acids compared to CRC patients. AP showed a lower abundance of acetic acid(P value = 0.00062) and higher percentages of propionic(P value = 0.00433) and isovaleric(P value = 0.00433) acids compared to HC. Moreover, AP showed higher levels of propionic acid(P value = 0.03251) and a lower level of isobutyric acid(P value = 0.00427) in comparison to CRC. The PLS-DA model demonstrated a significant separation of CRC and AP groups from HC, although some degree of overlap was observed between CRC and AP.CONCLUSION Analysis of fecal SCFAs shows the potential to provide a non-invasive means of diagnosis to detect patients with CRC and AP, while CD patients cannot be discriminated from healthy subjects.     

A Computer Model Simulating the Intestinal Absorption of Bile Acids

Mathematical models were developed for assessment of the absorption kinetics of compounds passing down the length of a perfused intestinal segment. The models considered the intestinal segment as a cylinder composed of a large number of very small (infinitesimal) cylinders and described the concentration decline of the compound in situations with active, passive and combined active and passive transport. The maximal velocity of active transport, V_max, the Michaëlis-Menten constant, K_m and the permeability coefficient, P, were calculated. A computer program was developed to operate the mathematical expressions. The models were validated by jejunal and ileal perfusions of various bile acids in six healthy volunteers. The fit between the mathematical models and the actually measured data showed an average standard deviation of 0.14mmol/l (substrate infusion concentration ranging from 0.25 mmol/1 to 3.0 mmol/1). It was concluded that the computer models were feasible for practical purposes. Moreover, the models reduced the number of perfusions necessary to determine the absorption kinetics of a given bile acid.     

Beneficial effects of nutritional supplements on intestinal epithelial barrier functions in experimental colitis models in vivo

Acute and chronic colitis affect a huge proportion of the population world-wide.The etiology of colitis cases can be manifold,and diet can significantly affect onset and outcome of colitis.While many forms of acute colitis are easily treatable,chronic forms of colitis such as ulcerative colitis and Crohn’s disease(summarized as inflammatory bowel diseases)are multifactorial with poorly understood pathogenesis.Inflammatory bowel diseases are characterized by exacerbated immune responses causing epithelial dysfunction and bacterial translocation.There is no cure and therapies aim at reducing inflammation and restoring intestinal barrier function.Unfortunately,most drugs can have severe side effects.Changes in diet and inclusion of nutritional supplements have been extensively studied in cell culture and animal models,and some supplements have shown promising results in clinical studies.Most of these nutritional supplements including vitamins,fatty acids and phytochemicals reduce oxidative stress and inflammation and have shown beneficial effects during experimental colitis in rodents induced by dextran sulphate sodium or 2,4,6-trinitrobenzene sulfonic acid,which remain the gold standard in pre-clinical colitis research.Here,we summarize the mechanisms through which such nutritional supplements contribute to epithelial barrier stabilization.     

经动脉药盒化疗治疗转移性黑色素瘤病人的护理

[目的]总结经动脉药盒化疗治疗转移性黑色素瘤病人的护理。[方法]对10例转移性黑色素瘤病人行动脉药盒植入术,利用动脉药盒进行化疗,并做好治疗前、中、后的护理。[结果]10例病人中1例出现化疗药物外渗终止治疗,其余均能按计划完成治疗。[结论]掌握动脉药盒植入后的护理操作方法是行动脉灌注化疗的关键,有利于治疗的顺利进行。     

短链脂肪酸在2型糖尿病发病机制中的作用

短链脂肪酸(SCFA)是由肠道菌群发酵膳食纤维产生的代谢产物,饮食结构变化通过改变肠道菌群结构与功能,影响SCFA的产生.近来研究发现,SCFA通过调节胃肠道激素分泌、胰岛素敏感性及糖、脂代谢,参与了2型糖尿病的发生、发展.对SCFA的深入研究,为阐明2型糖尿病发病机制及其预防和治疗提供了新的思路和靶点.     

Stimulation of Butyrate Absorption in the Human Rectum in Vivo

Background: Models of short-chain fatty acid absorption have focused on the stimulation of sodium absorption, an effect mainly located in the proximal colon of man. With the present efforts to utilize butyrate enemas as a treatment of ulcerative colitis, it seemed important to assess the transport in the rectum. Methods: Non-equilibrium dialysis of the rectum was applied by placing dialysis bags containing various electrolyte solutions in the rectum of volunteers for 30min. In this period changes in ion concentrations were linear with time. Net absorption and secretion rates were calculated from the change in fluid composition. Results: Sodium absorption was highest (24 ± 8 μmol/cm² h) in the presence of chloride and lowest (16 ± 2μmol/cm² h) in the presence of bicarbonate and butyrate. Butyrate (70 mmol/l) was absorbed at a high rate of 7.1 ± 2.2 μmol/cm² h, independent on the presence of chloride, and was accompanied by increased bicarbonate secretion. Butyrate absorption increased to 9.6 ± 1.8μmol/cm² h in sodium-free high-potassium media containing bicarbonate. Conclusion: The results show that it is possible to increase butyrate uptake by manipulation of the electrolyte composition in the rectal lumen. Maximal uptake occurred with an electrolyte composition that was similar to the natural rectal content. The information gathered could be useful in designing enemas for trial in ulcerative colitis, provided the findings can be confirmed in these patients.     

Conversion of Short and Medium Chain Fatty Acids into Novel Polyhydroxyalkanoates Copolymers by Aeromonas sp. AC_01

Polyhydroxyalkanoates (PHAs) production by Aeromonas sp. AC_01 was investigated using synthetic and waste derived short and medium chain fatty acids (SMCFAs). The obtained results revealed that the analyzed bacterial strain was able to grow and synthesize PHAs using SMCFAs. The highest PHA productivity was observed in the cultivation supplemented with a mixture of acetic acid and butyric acid (3.89 mg/L·h). Furthermore, SMCFAs-rich stream, derived from acidogenic mixed culture fermentation of acid whey, was found to be less beneficial for PHA productivity than its synthetic mixture, however the PHA production was favored by the nitrogen-limited condition. Importantly, Aeromonas sp. AC_01 was capable of synthesizing novel scl-mcl copolymers of 3-hydroxybutyrate (3HB), 3-hydroxyvalerate (3HV), 3-hydroxytridecanoate (3HtriD) and/or 3-hydroxytetradecaonate (3HTD) with high 3HB and 3HV fractions. They were identified with alterable monomers composition depending on the culture conditions used. Moreover, in-depth thermal analyses proved that they are highly resistant to thermal degradation regardless of their monomeric composition. The obtained results confirm that Aeromonas sp. AC_01 is a promising candidate for the biotechnological production of PHAs from SMCFAs with thermal properties that can be tuned together with their chemical composition by the corresponding adjustment of the cultivation process.     

Absorption of Short-Chain Fatty Acids from the In-Situ-Perfused Caecum and Colon of the Guinea Pig

Oltmer S, Engelhardt W v. Absorption of short-chain fatty acids from the in-situ-perfused caecum and colon of the guinea pig. Scand J Gastroenterol 1994;29:1009-1016.

Background: Short-chain fatty acids (SCFA) originate from microbial fermentation of carbohydrates in the hindgut. Mechanisms involved in SCFA absorption are not fully understood.

Methods: The caecum and proximal and distal colon of the guinea pig were perfused in situ.

Results: SCFA absorption per gram mucosal dry weight was highest in the proximal colon and lowest in the caecum. Owing to the large surface, quantitatively SCFA absorption was highest from the caecum. In the distal colon clearance of SCFA increased with chain length (Ac < Pr < Bu); in the caecum and proximal colon only a comparatively small or no such influence was observed. Inhibition of the proton antiport systems in the apical membrane and inhibition of the carbonic anhydrase activity diminished SCFA absorption. The diffusive and carrier components of absorption were calculated for propionate at increasing propionate concentrations.

Conclusions: Marked segmental differences in SCFA absorption are apparent in the large intestine of the guinea pig.     

Short Chain Fatty Acids,pancreatic dysfunction and type 2 diabetes

The microbiota living in gut influences the immune response, metabolism, mood and behavior. The diet plays a pivotal role in maintaining healthy gut microbiota composition and its fermentation leads to production of Short Chain Fatty Acids (SCFAs) mainly acetate, propionate and butyrate. During pancreatic dysfunction, insulin mediated suppression of glucagon is impaired leading to uncontrolled glucose production by liver and state of hyperglycemia. Insulin and glucagon balance is as important as insulin sensitivity which is reduced during Type 2 Diabetes (T2D). Glucagon like peptide-1 (GLP1) produced by Intestinal epithelial cells regulates insulin and glucagon secretion directly via GLP1 receptor on pancreatic cells or via nervous system. But half-life period of GLP1 is very short i.e. about 2 minutes, after which it is cleaved and inactivated. SCFAs are well documented to induce GLP1 but its direct effect on pancreatic dysfunction has not been reported. This review opens a new avenue to study the role of SCFAs as a treatment to pancreatic dysfunction and T2D.     

Effect of sulphonylurea administration on insulin secretion and amino acid metabolism in non-insulin-dependent diabetic patients

Sulphonylureas lower blood glucose but other metabolic effects have been little studied. In an assessment of carbohydrate and amino acid metabolism in 9 patients with non-insulin-dependent diabetes mellitus (NIDDM) before and after 3 months' therapy with gliclazide, glycaemic control was improved (mean +/- S.D. glycosylated haemoglobin 13.8 +/- 1.9% before therapy, 10.2 +/- 2.1% after therapy (p less than 0.01], but fasting amino acid levels were not altered. In contrast, postprandial levels of branched chain amino acids (BCAA) were significantly reduced: total BCAA (valine, leucine, and isoleucine) 120 mins following a standard test meal fell from 717 +/- 71 mumol/l before therapy to 600 +/- 90 mumol/l after 3 months' therapy (p less than 0.01). This finding implies an increased action of endogenous insulin on skeletal muscle to promote uptake of BCAA postprandially and, in accord with this, peripheral insulin levels were significantly increased following drug treatment (peak insulin level 55.6 +/- 20.2 mU/l before therapy, 91.3 +/- 17.9 mU/l after therapy (p less than 0.01]. Sulphonylurea drugs therefore do not simply have a hypoglycaemic action but also affect amino acid metabolism in NIDDM patients.     

Trace element status and fatty acids metabolism during healthy ageing: an example of a population from the Tunisian eastern coast

Micronutrients as well as essential fatty acids are indispensable for the correct functioning of the organism. The risk of disturbance in the associated nutrition and metabolism is expected to increase during ageing. In addition, it seems that trace elements are involved in the fatty acids metabolism. The aim of the present study was then to assess age-related changes in trace elements status and in plasma essential fatty acids composition with an emphasis on the desaturase activity estimation. Two hundred healthy Tunisian subjects (30-85 years old) were recruited and separated into two subgroups: elderly (65-85 years old) and middle-aged (30-60 years old). The findings revealed that plasma zinc and calcium concentrations significantly decreased according to age. The prevalence of zinc deficiency was therefore shown to increase in old age (over 60% of elderly subjects were deficient or at risk of deficiency). No age-related changes were obtained for copper or magnesium status. The Δ6 desaturase, involved in the EFAs conversion, was shown to decrease according to age and to be associated with the plasma zinc level. Since elderly subjects were at risk of nutritional imbalance, it would be interesting to set optimal dietary proportion. This will help to prevent age-associated alterations and diseases for a better and healthy ageing.