Recommendations for the Use of Dietary Fiber to Improve Blood Pressure Control.

According to several international, regional, and national guidelines on hypertension, lifestyle interventions are the first-line treatment to lower blood pressure (BP). Although diet is one of the major lifestyle modifications described in hypertension guidelines, dietary fiber is not specified. Suboptimal intake of foods high in fiber, such as in Westernized diets, is a major contributing factor to mortality and morbidity of noncommunicable diseases due to higher BP and cardiovascular disease. In this review, we address this deficiency by examining and advocating for the incorporation of dietary fiber as a key lifestyle modification to manage elevated BP. We explain what dietary fiber is, review the existing literature that supports its use to lower BP and prevent cardiovascular disease, describe the mechanisms involved, propose evidence-based target levels of fiber intake, provide examples of how patients can achieve the recommended targets, and discuss outstanding questions in the field. According to the evidence reviewed here, the minimum daily dietary fiber for adults with hypertension should be >28 g/day for women and >38 g/day for men, with each extra 5 g/day estimated to reduce systolic BP by 2.8 mm Hg and diastolic BP by 2.1 mm Hg. This would support a healthy gut microbiota and the production of gut microbiota-derived metabolites called short-chain fatty acids that lower BP. Awareness about dietary fiber targets and how to achieve them will guide medical teams on better educating patients and empowering them to increase their fiber intake and, as a result, lower their BP and cardiovascular disease risk.

Carvacrol improves blood lipid and glucose in rats with type 2 diabetes mellitus by regulating short-chain fatty acids and the GPR41/43 pathway.

Type 2 diabetes mellitus (T2DM) is characterized by hyperglycemia and dyslipidemia. Carvacrol (CAR) has demonstrated the potential to mitigate dyslipidemia. This study aims to investigate whether CAR can modulate blood glucose and lipid levels in a T2DM rat model by regulating short-chain fatty acids (SCFAs) and the GPR41/43 pathway. The T2DM rat model was induced by a high-fat diet combined with low-dose streptozocin injection and treated with oral CAR and/or mixed antibiotics. Fasting blood glucose, oral glucose tolerance, and insulin tolerance tests were assessed. Serum lipid parameters, hepatic and renal function indicators, tissue morphology, and SCFAs were measured. In vitro, high glucose (HG)-induced IEC-6 cells were treated with CAR, and optimal CAR concentration was determined. HG-induced IEC-6 cells were treated with SCFAs or/and GPR41/43 agonists. CAR significantly reduced blood lipid and glucose levels, improved tissue damage, and increased SCFA levels in feces and GPR41/43 expression in colonic tissues of T2DM rats. CAR also attenuated HG-induced apoptosis of IEC-6 cells and enhanced GPR41/43 expression. Overall, these findings suggest that CAR alleviates blood lipid and glucose abnormalities in T2DM rats by modulating SCFAs and the GPR41/43 pathway.

Short-Chain Fatty Acids Attenuate Renal Fibrosis and Enhance Autophagy of Renal Tubular Cells in Diabetic Mice Through the HDAC2/ULK1 Axis.

BACKGRUOUND: This study investigated the effect of short-chain fatty acids (SCFAs) on diabetes in a mouse model. METHODS: Autophagy in Akita mice and streptozocin (STZ)-induced diabetic C57BL/6 mice was determined by Western blots and immunohistochemistry (IHC). Western blots, IHC, hematoxylin and eosin staining, Masson staining, periodic acid-Schiff staining, and picrosirius red staining were conducted to detect whether autophagy and renal function improved in Akita mice and STZ-induced diabetic C57BL/6 mice after treatment of SCFAs. Western blots, IHC, and chromatin immunoprecipitation were performed to determine whether SCFAs affected diabetic mice via the histone deacetylase (HDAC2)/unc-51 like autophagy activating kinase 1 (ULK1) axis. Diabetic mice with kidney-specific knockout of HDAC2 were constructed, and IHC, Masson staining, and Western blots were carried out to detect whether the deletion of endogenous HDAC2 contributed to the improvement of autophagy and renal fibrosis in diabetic mice. RESULTS: Reduced autophagy and severe fibrosis were observed in Akita mice and STZ-induced diabetic C57BL/6 mice. Increased autophagy and reduced renal cell fibrosis were found in SCFA-treated Akita diabetic mice and STZ-induced diabetic C57BL/6 mice. Diabetic mice treated with SCFAs had lower HDAC2 expression and more enriched binding of ULK1 promoter sequences to H3K27Ac. Endogenous knockout of HDAC2 caused enhanced autophagy and decreased renal fibrosis in diabetic mice treated with SCFAs. CONCLUSION: SCFAs enhanced autophagy of renal tubular cells and attenuated renal fibrosis in diabetic mice through the HDAC2/ULK1 axis.

Zinc Deficiency Elevates Fecal Protein, But Not Electrolyte and Short-Chain Fatty Acid, Levels in Enterotoxigenic Escherichia coli-Induced Diarrhea in Rats.

PURPOSE: To determine the effect of zinc deficiency on fecal protein, electrolyte, and short-chain fatty acid levels in both heat-stable (ST) and heat-labile (LT) enterotoxigenic Escherichia coli (ETEC)-induced diarrhea in rats. METHODS: Albino rats, weighing 100 to 150 g, were divided into 2 groups, with 15 animals each: non-zinc and zinc-deficient. These two groups were sub-divided into three sub-groups with five rats each: control (saline); LT-ETEC; and ST-ETEC. Sodium phytate (30 mmol/L) was added to the animals' water to induce zinc deficiency, while diarrhea was induced using 5×109 ETEC cells/mL. Fecal protein levels were estimated using the Bradford method, while sodium and potassium levels were determined using atomic absorption spectrophotometry. Short-chain fatty acids were measured using gas chromatography-mass spectrometry. RESULTS: Among the non-zinc and zinc-deficient groups, there were significant increases (p=0.04), (p=0.03) in fecal protein concentrations (mg/mL) in the LT-ETEC- (4.50±0.33), (6.50±0.26) and ST-ETEC- (3.85±0.19), (5.98±0.32) induced groups compared to the control groups (2.60±0.52), (3.50±0.11) respectively. Fecal sodium and potassium levels (mg/L) were significantly (p=0.029) increased in non-zinc-deficient rats induced with LT-ETEC (9.35±0.95, 1.05±0.48), and ST-ETEC (9.96±1.02, 1.21±0.45) compared with the control group (8.07±0.44, 0.47±0.17) but the increase were not statistically significant (p=0.059) in the zinc deficient rat groups. Fecal acetate and propionate levels (mg/g) significantly (p=0.032) increased when induced with LT-ETEC and ST-ETEC in non-zinc and zinc-deficient groups compared with the control groups. CONCLUSION: Zinc deficiency among rats with ETEC-induced diarrhea elevated fecal protein loss but may not have an effect on fecal sodium, potassium and short-chain fatty acid levels.

Effects of acupuncture on nutritional status in patients in a persistent vegetative state: a prospective randomized controlled study / 针灸推拿医学（英文版）

Objective: To explore the effects of acupuncture on nutritional status in patients in a persistent vegetative state. Methods: A prospective randomized controlled trial was designed. A total of 66 patients in a persistent vegetative state were randomized into a control group and an observation group, with 33 cases in each group. The control group was given conventional treatment plus enteral nutrition support. The observation group was treated with additional Tiao Shen Jian Pi acupuncture therapy (acupuncture for spirit-regulating and spleen-invigorating) based on the same interventions in the control group. Both groups were treated for 8 weeks. The levels of total protein (TP), prealbumin (PA), albumin (Alb), and hemoglobin (Hb) were measured before and after treatment. The upper arm circumference and skinfold thickness of triceps brachii were measured. And the intestinal flora and fecal short-chain fatty acids contents were determined.Results: After treatment, the levels of TP, PA, Alb, and Hb in the control group were decreased (P<0.05), while in the observation group, compared with those before treatment, the levels of TP, PA, Alb, and Hb had no statistical differences (P>0.05), and the levels were all higher than those in the control group (P<0.05). The upper arm circumference and skinfold thickness of triceps brachii in both groups decreased (P<0.05), and the values of these two items in the observation group were higher than those in the control group (P<0.05). In the control group, the contents of Bifidobacterium and Lactobacillus in feces decreased (P<0.05), and the content of Enterococcus increased (P<0.05). In the observation group, the contents of Bifidobacterium and Lactobacillus in feces increased (P<0.05), and the content of Enterococcus decreased (P<0.05). The differences between the two groups were statistically significant (P<0.05). In the control group, the total content of fecal short-chain fatty acids and the contents of acetic acid and butyric acid in feces decreased (P<0.05). In the observation group, the total content of fecal short-chain fatty acids and the contents of acetic acid and butyric acid in feces increased (P<0.05) and were all higher than those in the control group (P<0.05). Conclusion: Acupuncture can improve nutrition-related blood indicators in patients in a persistent vegetative state and delay the decrease of upper arm circumference and skinfold thickness of triceps brachii, which may be related to the regulation of intestinal flora and fecal short-chain fatty acids contents.

Clinical significance of the determination of fecal short-chain fatty acids in patients with nonalcoholic fatty liver disease / 临床肝胆病杂志

Objective To investigate the association of the metabolism of intestinal short-chain fatty acids (SCFAs) with the development and progression of the disease spectrum of nonalcoholic fatty liver disease (NAFLD) by determining the content of fecal SCFAs in patients with different NAFLD diseases and the change in the content of fecal SCFAs after treatment in patients at a high risk of nonalcoholic steatohepatitis (NASH). Methods A total of 90 patients who were diagnosed with NAFLD in The Affiliated Hospital of Qinghai University from July 2020 to July 2021 were enrolled and divided into simple nonalcoholic fatty liver (NAFL) group with 30 patients, NASH group with 30 patients, and nonalcoholic fatty liver fibrosis group with 30 patients, and 40 individuals who underwent physical examination during the same period of time were enrolled as control group. Related case data and fecal SCFAs content were collected for the four groups, and related clinical indices and fecal SCFAs content were collected for 10 patients at a high risk of NASH after 3 months of intervention. The analysis of variance was used for comparison of normally distributed continuous data between multiple groups, and the paired samples t -test was used for comparison within each group; the Kruskal-Wallis H test was used for comparison of non-normally distributed continuous data between multiple groups, and the paired samples Wilcoxon signed rank sum test was used for comparison within each group; a Spearman correlation analysis was used to investigate the correlation between variables; the receiver operating characteristic (ROC) curve analysis was used for diagnostic evaluation. Results Compared with the control group, the nonalcoholic fatty liver fibrosis group had significantly higher contents of valeric acid and caproic acid, and the NAFL group had significantly lower contents of valeric acid and caproic acid (all P < 0.05); the nonalcoholic fatty liver fibrosis group had significantly higher contents of valeric acid and caproic acid than the NAFL group ( P < 0.05); the nonalcoholic fatty liver fibrosis group had a significantly higher content of valeric acid than the NASH group ( P < 0.05); the NASH group had a significantly higher content of caproic acid than the NAFL group ( P < 0.05). After treatment, the high-risk patients in the NASH group had significant reductions in HbA1c, fasting plasma glucose (FPG), triglyceride (TG), total cholesterol (TC), alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), total bile acid (TBA), prothrombin time (PT), uric acid (UA), controlled attenuation parameter (CAP), and liver stiffness measurement (LSM) ( Z =-2.805, -2.703, -2.193, -2.599, -2.805, -2.701, -2.803, -1.988, -2.807, -2.803, -2.803, and -2.668, all P < 0.05); for these patients, the contents of acetic acid and propionic acid after treatment were significantly higher than those before treatment ( Z =-2.803 and -2.803, both P < 0.05), and the content of isobutyric acid after treatment was significantly lower than that before treatment ( Z =-2.803, P < 0.05). In the diagnosis of nonalcoholic fatty liver fibrosis, valeric acid had an area under the ROC curve (AUC) of 0.842, with a sensitivity of 86.7% and a specificity of 70% at the optimal cut-off value of 141.42 μg/g; caproic acid had an AUC of 0.819, with a sensitivity of 70% and a specificity of 85% at the optimal cut-off value of 6.93 μg/g. Conclusion Valeric acid and caproic acid may promote the development of NAFLD disease spectrum. Acetic acid and propionic acid may have a certain protective effect on the liver of NAFLD patients, and isobutyric acid may promote the development and progression of NASH. The protective effect of acetic acid and propionic acid on the liver may further lead to the reductions in HbA1c, FPG, TG, TC, ALT, AST, GGT, TBA, PT, UA, CAP, and LSM. Valeric acid and caproic acid have an inferior diagnostic value to PIIIP N-P and a superior diagnostic value to type IV collagen and hyaluronic acid. Valeric acid with the optimal cut-off value of 141.42 μg/g and caproic acid with the optimal cut-off value of 6.93 μg/g can be used as the auxiliary diagnostic indicators for the early diagnosis of nonalcoholic fatty liver fibrosis.

The Gut Microbiome in Hypertension: Recent Advances and Future Perspectives.

The pathogenesis of hypertension is known to involve a diverse range of contributing factors including genetic, environmental, hormonal, hemodynamic and inflammatory forces, to name a few. There is mounting evidence to suggest that the gut microbiome plays an important role in the development and pathogenesis of hypertension. The gastrointestinal tract, which houses the largest compartment of immune cells in the body, represents the intersection of the environment and the host. Accordingly, lifestyle factors shape and are modulated by the microbiome, modifying the risk for hypertensive disease. One well-studied example is the consumption of dietary fibers, which leads to the production of short-chain fatty acids and can contribute to the expansion of anti-inflammatory immune cells, consequently protecting against the progression of hypertension. Dietary interventions such as fasting have also been shown to impact hypertension via the microbiome. Studying the microbiome in hypertensive disease presents a variety of unique challenges to the use of traditional model systems. Integrating microbiome considerations into preclinical research is crucial, and novel strategies to account for reciprocal host-microbiome interactions, such as the wildling mouse model, may provide new opportunities for translation. The intricacies of the role of the microbiome in hypertensive disease is a matter of ongoing research, and there are several technical considerations which should be accounted for moving forward. In this review we provide insights into the host-microbiome interaction and summarize the evidence of its importance in the regulation of blood pressure. Additionally, we provide recommendations for ongoing and future research, such that important insights from the microbiome field at large can be readily integrated in the context of hypertension.

Sucralfate enemas reduce the oxidative tissue damage and preserves the contents of E-cadherin and Β-catenin in colonic mucosa without fecal stream

ABSTRACT Purpose: To evaluate the effects of sucralfate enemas in tissue contents of E-cadherin and ?-catenin in an experimental diversion colitis. Methods: Thirty-six male Wistar rats were submitted to a proximal colostomy and a distal mucous fistula. They were allocated into three groups: first group received daily saline enemas (2 mL/day) and the two other groups daily enemas with sucralfate at dosage of 1 or 2 g/kg/day, respectively. Six animals of each group were euthanized after two weeks and six animals after four weeks. The inflammation of the excluded mucosa was evaluated by histological analysis. The oxidative damage was quantified by measurement of malondialdehyde tissue levels. The expression of E-cadherin and ?-catenin was identified by immunohistochemistry, and its contents were quantified by computer-assisted image analysis. Results: Sucralfate enemas reduced inflammation in animals subjected to treatment with 2 g/kg/day by four weeks, and the levels of oxidative damage in mucosa without fecal stream irrespective of concentration and time of intervention. E-cadherin and ?-catenin content increased in segments without fecal stream in those animals subjected to treatment with sucralfate. Conclusions: Sucralfate reduces the inflammation and oxidative stress and increases the tissue content of E-cadherin and ?-catenin in colonic mucosa devoid to the fecal stream.

Correlation between gut microbiota, short-chain fatty acids metabolic disorder and outcomes of patients with hypertensive intracerebral hemorrhage / 国际脑血管病杂志

Objective:To investigate the metabolic disorder of gut microbiota and short-chain fatty acids (SCFAs) in patients with hypertensive intracerebral hemorrhage and their correlations with the poor outcomes.Methods:Thirty-eight patients with hypertensive intracerebral hemorrhage within 7 d of onset and 32 healthy controls were enrolled prospectively. Fecal samples were collected for 16S rRNA sequencing and SCFAs levels detection. The outcome was evaluated by the modified Rankin Scale at 90 d after the onset, and >2 points were defined as a poor outcome. Multivariate logistic regression model was used to determine the correlations between the gut microbiota and the fecal SCFAs levels and outcomes. Results:The gut microbiota of patients with hypertensive intracerebral hemorrhage was significantly different from that of healthy control group. It is manifested as a decrease in α diversity, a difference in β diversity, an increase in the abundance of potential undesirable bacteria, a decrease in the abundance of common SCFA-producing bacteria and a decrease in the fecal SCFAs levels. In patients with hypertensive intracerebral hemorrhage, compared with the good outcome group, the α diversity of the gut microbiota, the abundance of SCFA-producing bacteria such as Lacetospirillum and Bacteroides, and the total SCFAs, acetic acid and propionic acid levels decreased in the poor outcome group. Multivariate logistic regression analysis showed that after adjusting for potential confounding factors, the decrease of fecal SCFAs levels after log2 conversion was significantly and independently correlated with the poor outcomes. Conclusion:Patients with hypertensive intracerebral hemorrhage have gut microbiota and SCFAs metabolic disorder, the latter is significantly correlated with the poor outcomes. Gut microbiota and SCFAs may become an outcome marker and treatment target for patients with hypertensive intracerebral hemorrhage

Conserved and variable responses of the gut microbiome to resistant starch type 2.

Resistant starch type 2 (RS2), a dietary fiber comprised solely of glucose, has been extensively studied in clinical trials and animal models for its capacity to improve metabolic and systemic health. Because the health modulatory effects of RS2 and other dietary fibers are thought to occur through modification of the gut microbiome, those studies frequently include assessments of RS2-mediated changes to intestinal microbial composition and function. In this review, we identify the conserved responses of the gut microbiome among 13 human and 35 animal RS2 intervention studies. Consistent outcomes of RS2 interventions include reductions in bacterial α-diversity; increased production of lumenal short-chain fatty acids; and enrichment of Ruminococcus bromii, Bifidobacterium adolescentis, and other gut taxa. Different taxa are usually responsive in animal models, and many RS2-mediated changes to the gut microbiome vary within and between studies. The root causes for this variation are examined with regard to methodological and analytical differences, host genetics and age, species differences (eg, human, animal), health status, intervention dose and duration, and baseline microbial composition. The significant variation found for this single dietary compound highlights the challenges in targeting the gut microbiome to improve health with dietary interventions. This knowledge on RS2 also provides opportunities to improve the design of nutrition studies targeting the gut microbiome and to ultimately identify the precise mechanisms via which dietary fiber benefits human health.

Microbiome and Metabolome Profiles Associated With Different Types of Short Bowel Syndrome: Implications for Treatment.

BACKGROUND: The gut microbiome and metabolome may significantly influence clinical outcomes in patients with short bowel syndrome (SBS). The study aimed to describe specific metagenomic/metabolomics profiles of different SBS types and to identify possible therapeutic targets. METHODS: Fecal microbiome (FM), volatile organic compounds (VOCs), and bile acid (BA) spectrum were analyzed in parenteral nutrition (PN)-dependent SBS I, SBS II, and PN-independent (non-PN) SBS patients. RESULTS: FM in SBS I, SBS II, and non-PN SBS shared characteristic features (depletion of beneficial anaerobes, high abundance of Lactobacilaceae and Enterobacteriaceae). SBS I patients were characterized by the abundance of oxygen-tolerant microrganisms and depletion of strict anaerobes. Non-PN SBS subjects showed markers of partial FM normalization. FM dysbiosis was translated into VOC and BA profiles characteristic for each SBS cohort. A typical signature of all SBS patients comprised high saturated aldehydes and medium-chain fatty acids and reduced short-chain fatty acid (SCFA) content. Particularly, SBS I and II exhibited low protein metabolism intermediate (indole, p-cresol) content despite the hypothetical presence of relevant metabolism pathways. Distinctive non-PN SBS marker was high phenol content. SBS patients' BA fecal spectrum was enriched by chenodeoxycholic and deoxycholic acids and depleted of lithocholic acid. CONCLUSIONS: Environmental conditions in SBS gut significantly affect FM composition and metabolic activity. The common feature of diverse SBS subjects is the altered VOC/BA profile and the lack of important products of microbial metabolism. Strategies oriented on the microbiome/metabolome reconstitution and targeted delivery of key compounds may represent a promising therapeutic strategy in SBS patients.

Differential Effects of Lactobacillus casei Strain Shirota on Patients With Constipation Regarding Stool Consistency in China.

BACKGROUND/AIMS: Probiotics are expected to confer benefits on patients with constipation, but how probiotics act on constipated patients with variable stool consistencies remains unclear. We investigated the effect of Lactobacillus casei strain Shirota (LcS) on constipation-related symptoms, especially stool consistency, of constipated patients. METHODS: Constipated patients meeting the Rome III criteria were divided into 3 groups according to the Bristol Stool Form Scale (BSFS): hard (hard stool [HS], BSFS ＜ 3), normal (normal stool [NS], ≤ 3 BSFS ≤ 4), and soft (soft stool [SS], 4 ＜ BSFS ≤ 5) stools. Subjects in each group consumed a probiotic beverage containing 10¹° colony-forming units of LcS daily for 28 days. RESULTS: LcS intervention significantly alleviated constipation-related symptoms and increased defecation frequency in all subjects. Four weeks of LcS supplementation softened the hard stools in HS, hardened the soft stools in SS, and did not alter the ideal stool consistency in NS. The short-chain fatty acid (SCFA) concentrations were highest in SS, followed by NS and HS. LcS intervention increased the stool SCFA levels in HS but reduced or did not alter the levels in NS and SS. LcS intervention increased the Pseudobutyrivibrio and Roseburia abundances in HS and decreased the Pseudobutyrivibrio abundance in SS. CONCLUSIONS: LcS supplementation improved the constipation-related symptoms in constipated subjects. Differences in baseline stool consistency could result in different anti-constipation effects of LcS intervention. LcS balanced the stool consistency-softened the HS and hardened the SS. These effects could be associated with modulation of the gut microbiota and SCFA production.

A Proinflammatory Gut Microbiota Increases Systemic Inflammation and Accelerates Atherosclerosis.

RATIONALE: Several studies have suggested a role for the gut microbiota in inflammation and atherogenesis. A causal relation relationship between gut microbiota, inflammation, and atherosclerosis has not been explored previously. OBJECTIVE: Here, we investigated whether a proinflammatory microbiota from Caspase1-/- ( Casp1-/-) mice accelerates atherogenesis in Ldlr-/- mice. METHOD AND RESULTS: We treated female Ldlr-/- mice with antibiotics and subsequently transplanted them with fecal microbiota from Casp1-/- mice based on a cohousing approach. Autologous transplantation of fecal microbiota of Ldlr-/- mice served as control. Mice were cohoused for 8 or 13 weeks and fed chow or high-fat cholesterol-rich diet. Fecal samples were collected, and factors related to inflammation, metabolism, intestinal health, and atherosclerotic phenotypes were measured. Unweighted Unifrac distances of 16S rDNA (ribosomal DNA) sequences confirmed the introduction of the Casp1-/- and Ldlr-/- microbiota into Ldlr-/- mice (referred to as Ldlr-/-( Casp1-/-) or Ldlr-/-( Ldlr-/-) mice). Analysis of atherosclerotic lesion size in the aortic root demonstrated a significant 29% increase in plaque size in 13-week high-fat cholesterol-fed Ldlr-/-( Casp1-/-) mice compared with Ldlr-/-( Ldlr-/-) mice. We found increased numbers of circulating monocytes and neutrophils and elevated proinflammatory cytokine levels in plasma in high-fat cholesterol-fed Ldlr-/-( Casp1-/-) compared with Ldlr-/-( Ldlr-/-) mice. Neutrophil accumulation in the aortic root of Ldlr-/-( Casp1-/-) mice was enhanced compared with Ldlr-/-( Ldlr-/-) mice. 16S-rDNA-encoding sequence analysis in feces identified a significant reduction in the short-chain fatty acid-producing taxonomies Akkermansia, Christensenellaceae, Clostridium, and Odoribacter in Ldlr-/-( Casp1-/-) mice. Consistent with these findings, cumulative concentrations of the anti-inflammatory short-chain fatty acids propionate, acetate and butyrate in the cecum were significantly reduced in 13-week high-fat cholesterol-fed Ldlr-/-( Casp1-/-) compared with Ldlr-/-( Ldlr-/-) mice. CONCLUSIONS: Introduction of the proinflammatory Casp1-/- microbiota into Ldlr-/- mice enhances systemic inflammation and accelerates atherogenesis.

Short-Chain Fatty Acid Propionate Protects From Hypertensive Cardiovascular Damage.

BACKGROUND: Arterial hypertension and its organ sequelae show characteristics of T cell-mediated inflammatory diseases. Experimental anti-inflammatory therapies have been shown to ameliorate hypertensive end-organ damage. Recently, the CANTOS study (Canakinumab Antiinflammatory Thrombosis Outcome Study) targeting interleukin-1ß demonstrated that anti-inflammatory therapy reduces cardiovascular risk. The gut microbiome plays a pivotal role in immune homeostasis and cardiovascular health. Short-chain fatty acids (SCFAs) are produced from dietary fiber by gut bacteria and affect host immune homeostasis. Here, we investigated effects of the SCFA propionate in 2 different mouse models of hypertensive cardiovascular damage. METHODS: To investigate the effect of SCFAs on hypertensive cardiac damage and atherosclerosis, wild-type NMRI or apolipoprotein E knockout-deficient mice received propionate (200 mmol/L) or control in the drinking water. To induce hypertension, wild-type NMRI mice were infused with angiotensin II (1.44 mg·kg-1·d-1 subcutaneous) for 14 days. To accelerate the development of atherosclerosis, apolipoprotein E knockout mice were infused with angiotensin II (0.72 mg·kg-1·d-1 subcutaneous) for 28 days. Cardiac damage and atherosclerosis were assessed using histology, echocardiography, in vivo electrophysiology, immunofluorescence, and flow cytometry. Blood pressure was measured by radiotelemetry. Regulatory T cell depletion using PC61 antibody was used to examine the mode of action of propionate. RESULTS: Propionate significantly attenuated cardiac hypertrophy, fibrosis, vascular dysfunction, and hypertension in both models. Susceptibility to cardiac ventricular arrhythmias was significantly reduced in propionate-treated angiotensin II-infused wild-type NMRI mice. Aortic atherosclerotic lesion area was significantly decreased in propionate-treated apolipoprotein E knockout-deficient mice. Systemic inflammation was mitigated by propionate treatment, quantified as a reduction in splenic effector memory T cell frequencies and splenic T helper 17 cells in both models, and a decrease in local cardiac immune cell infiltration in wild-type NMRI mice. Cardioprotective effects of propionate were abrogated in regulatory T cell-depleted angiotensin II-infused mice, suggesting the effect is regulatory T cell-dependent. CONCLUSIONS: Our data emphasize an immune-modulatory role of SCFAs and their importance for cardiovascular health. The data suggest that lifestyle modifications leading to augmented SCFA production could be a beneficial nonpharmacological preventive strategy for patients with hypertensive cardiovascular disease.

Enemas with mesalazine increase the tissue contents of mucins in the colonic mucosa devoid of fecal stream

Abstract Purpose: To evaluate the inflammatory reaction and measure the content of mucins, in the colonic mucosa without fecal stream submit to intervention with mesalazine. Methods: Twenty-four rats were submitted to a left colostomy and a distal mucous fistula and divided into two groups according to euthanasia to be performed two or four weeks. Each group was divided into two subgroups according daily application of enemas containing saline or mesalazine at 1.0 g/kg/day. Colitis was diagnosed by histological analysis and the inflammatory reaction by validated score. Acidic mucins and neutral mucins were determined with the alcian-blue and periodic acid of Schiff techniques, respectively. Sulfomucin and sialomucin were identified by high iron diamine-alcian blue technique. The tissue contents of mucins were quantified by computer-assisted image analysis. Mann-Whitney test was used to analyze the results establishing the level of significance of 5%. Results: Enemas with mesalazine in colonic segments without fecal stream decreased the inflammation score and increased the tissue content of all subtypes of mucins. The increase of tissue content of neutral, acid and sulfomucin was related to the time of intervention. Conclusion: Mesalazine enemas reduce the inflammatory process and preserve the content of mucins in colonic mucosa devoid of fecal stream.

Differential Effects of Lactobacillus casei Strain Shirota on Patients With Constipation Regarding Stool Consistency in China

BACKGROUND/AIMS: Probiotics are expected to confer benefits on patients with constipation, but how probiotics act on constipated patients with variable stool consistencies remains unclear. We investigated the effect of Lactobacillus casei strain Shirota (LcS) on constipation-related symptoms, especially stool consistency, of constipated patients. METHODS: Constipated patients meeting the Rome III criteria were divided into 3 groups according to the Bristol Stool Form Scale (BSFS): hard (hard stool [HS], BSFS < 3), normal (normal stool [NS], ≤ 3 BSFS ≤ 4), and soft (soft stool [SS], 4 < BSFS ≤ 5) stools. Subjects in each group consumed a probiotic beverage containing 1010 colony-forming units of LcS daily for 28 days. RESULTS: LcS intervention significantly alleviated constipation-related symptoms and increased defecation frequency in all subjects. Four weeks of LcS supplementation softened the hard stools in HS, hardened the soft stools in SS, and did not alter the ideal stool consistency in NS. The short-chain fatty acid (SCFA) concentrations were highest in SS, followed by NS and HS. LcS intervention increased the stool SCFA levels in HS but reduced or did not alter the levels in NS and SS. LcS intervention increased the Pseudobutyrivibrio and Roseburia abundances in HS and decreased the Pseudobutyrivibrio abundance in SS. CONCLUSIONS: LcS supplementation improved the constipation-related symptoms in constipated subjects. Differences in baseline stool consistency could result in different anti-constipation effects of LcS intervention. LcS balanced the stool consistency—softened the HS and hardened the SS. These effects could be associated with modulation of the gut microbiota and SCFA production.

Evaluation of enemas containing sucralfate in tissue content of muc-2 protein in experimental model of diversion colitis / Avaliação de enemas com sucralfato no conteúdo tecidual da proteina muc-2 em colite de exclusão experimental

ABSTRACT Background: The effects of topical application of sucralfate (SCF) on the tissue content of MUC-2 protein have not yet been evaluated in experimental models of diversion colitis. Aim: To measure the tissue content of MUC-2 protein in the colonic mucosa diverted from fecal stream submitted to the SCF intervention. Methods: Thirty-six rats underwent derivation of intestinal transit through proximal colostomy and distal mucous fistula. The animals were divided into three groups which were submitted application of enemas with saline, SCF 1 g/kg/day and SCF 2 g/kg/day. Each group was divided into two subgroups, according to euthanasia was done after two or four weeks. The colitis diagnosis was established by histopathological study and the inflammatory intensity was evaluated by previously validated scale. The MUC-2 protein was identified by immunohistochemistry and the tissue content was measured computerized morphometry). Results: The application of enemas with SCF in the concentration of 2 g/kg/day reduced inflammatory score of the segments that were diverted from fecal stream. The content of MUC-2 in diverted colon of the animals submitted to the intervention with SCF, independently of intervention period and the used concentration, was significantly greater than animals submitted to the application of enemas containing saline (p< 0.01). The content of MUC-2 after the intervention with SCF in the concentration of 2 g/kg/day was significantly higher when compared to the animals submitted to the application containing SCF at concentration of 1.0 g/kg/day (p<0.01). The tissue content of MUC-2 reached the highest values after intervention with SCF in the concentration of 2 g/kg/day for four weeks (p<0.01). Conclusion: The preventive application of enemas containing SCF reduces the inflammatory score and avoids the reduction of tissue content of MUC-2, suggesting that the substance is a valid therapeutic strategy to preserve the mucus layer that covers the intestinal epithelium.

RESUMO Racional: Os efeitos da aplicação tópica de sucralfato (SCF) no conteúdo tecidual da proteína mucina-2 (MUC-2) ainda não foram avaliados em modelos experimentais de colite de exclusão. Objetivo: Mensurar o conteúdo tecidual da proteína MUC-2 na mucosa cólica sem trânsito intestinal submetida à intervenção com SCF. Método: Trinta e seis ratos foram submetidos à derivação intestinal por colostomia proximal terminal e fístula mucosa distal. Foram divididos em três grupos segundo recebessem clisteres contendo solução fisiológica (SF), SCF 1 g/kg/dia e SCF 2 g/kg/dia. Cada grupo foi dividido em dois subgrupos, segundo a eutanásia ser realizada após duas ou quatro semanas. O diagnóstico de colite foi estabelecido por estudo histopatológico e a intensidade inflamatória foi avaliada por escala validada. A expressão tecidual da MUC-2 foi identificada por imunoistoquímica e seu conteúdo mensurado por morfometria computadorizada. Resultados: A aplicação de clisteres com SCF na concentração de 2 g/kg/dia reduziu a intensidade inflamatória no cólon sem trânsito fecal. O conteúdo tecidual de MUC-2 no cólon sem trânsito dos animais submetidos à intervenção com SCF, independente do tempo de intervenção e da concentração utilizada, foi maior quando comparado aos animais tratados com SF (p<0,01). O conteúdo de MUC-2 após a intervenção com SCF na concentração de 2 g/kg/dia foi maior quando comparado aos animais submetidos à intervenção com concentração menor (p<0,01). O conteúdo de MUC-2 foi maior após intervenção com SCF na concentração de 2 g/kg/dia por quatro semanas (p<0,01). Conclusão: A aplicação preventiva de clisteres com SCF reduz o grau de inflamação e preserva o conteúdo tecidual de MUC-2, em segmentos desprovidos de trânsito intestinal, mostrando-se uma estratégia terapêutica válida para preservar a camada de muco que recobre o epitélio intestinal.

[retracted article]: evaluation of enemas containing sucralfate in tissue content of muc-2 protein in experimental model of diversion colitis / [artigo retratado]: avaliação de enemas com sucralfato no conteúdo tecidual da proteina muc-2 em colite de exclusão experimental

ABSTRACT Background: The effects of topical application of sucralfate (SCF) on the tissue content of MUC-2 protein have not yet been evaluated in experimental models of diversion colitis. Aim: To measure the tissue content of MUC-2 protein in the colonic mucosa diverted from fecal stream submitted to the SCF intervention. Methods: Thirty-six rats underwent derivation of intestinal transit through proximal colostomy and distal mucous fistula. The animals were divided into three groups which were submitted application of enemas with saline, SCF 1 g/kg/day and SCF 2 g/kg/day. Each group was divided into two subgroups, according to euthanasia was done after two or four weeks. The colitis diagnosis was established by histopathological study and the inflammatory intensity was evaluated by previously validated scale. The MUC-2 protein was identified by immunohistochemistry and the tissue content was measured computerized morphometry). Results: The application of enemas with SCF in the concentration of 2 g/kg/day reduced inflammatory score of the segments that were diverted from fecal stream. The content of MUC-2 in diverted colon of the animals submitted to the intervention with SCF, independently of intervention period and the used concentration, was significantly greater than animals submitted to the application of enemas containing saline (p< 0.01). The content of MUC-2 after the intervention with SCF in the concentration of 2 g/kg/day was significantly higher when compared to the animals submitted to the application containing SCF at concentration of 1.0 g/kg/day (p<0.01). The tissue content of MUC-2 reached the highest values after intervention with SCF in the concentration of 2 g/kg/day for four weeks (p<0.01). Conclusion: The preventive application of enemas containing SCF reduces the inflammatory score and avoids the reduction of tissue content of MUC-2, suggesting that the substance is a valid therapeutic strategy to preserve the mucus layer that covers the intestinal epithelium.

RESUMO Racional: Os efeitos da aplicação tópica de sucralfato (SCF) no conteúdo tecidual da proteína mucina-2 (MUC-2) ainda não foram avaliados em modelos experimentais de colite de exclusão. Objetivo: Mensurar o conteúdo tecidual da proteína MUC-2 na mucosa cólica sem trânsito intestinal submetida à intervenção com SCF. Método: Trinta e seis ratos foram submetidos à derivação intestinal por colostomia proximal terminal e fístula mucosa distal. Foram divididos em três grupos segundo recebessem clisteres contendo solução fisiológica (SF), SCF 1 g/kg/dia e SCF 2 g/kg/dia. Cada grupo foi dividido em dois subgrupos, segundo a eutanásia ser realizada após duas ou quatro semanas. O diagnóstico de colite foi estabelecido por estudo histopatológico e a intensidade inflamatória foi avaliada por escala validada. A expressão tecidual da MUC-2 foi identificada por imunoistoquímica e seu conteúdo mensurado por morfometria computadorizada. Resultados: A aplicação de clisteres com SCF na concentração de 2 g/kg/dia reduziu a intensidade inflamatória no cólon sem trânsito fecal. O conteúdo tecidual de MUC-2 no cólon sem trânsito dos animais submetidos à intervenção com SCF, independente do tempo de intervenção e da concentração utilizada, foi maior quando comparado aos animais tratados com SF (p<0,01). O conteúdo de MUC-2 após a intervenção com SCF na concentração de 2 g/kg/dia foi maior quando comparado aos animais submetidos à intervenção com concentração menor (p<0,01). O conteúdo de MUC-2 foi maior após intervenção com SCF na concentração de 2 g/kg/dia por quatro semanas (p<0,01). Conclusão: A aplicação preventiva de clisteres com SCF reduz o grau de inflamação e preserva o conteúdo tecidual de MUC-2, em segmentos desprovidos de trânsito intestinal, mostrando-se uma estratégia terapêutica válida para preservar a camada de muco que recobre o epitélio intestinal.

Influence of the application of enemas with oily extract of curcumin (Curcuma longa) on the tissue content of neutral and acidic mucins in the colonic mucosa without fecal stream / Influência da aplicação de clisteres contendo extrato oleoso de curcumina (Curcuma longa) no conteúdo tecidual de mucinas neutras e ácidas na mucosa cólica sem trânsito intestinal

ABSTRACT Purpose: To verify if the application of enemas containing oily extracts of curcumin preserves the tissue content of mucins in the glands of the colonic mucosa without fecal stream. Method: Thirty-six Wistar rats were submitted to diversion of the fecal stream by proximal colostomy and distal mucous fistula. The animals were subdivided into three groups, and accordingly received enemas with saline and oily extract of curcumin at concentrations of 50 mg/kg/day or 200 mg/kg/day. After two or four weeks of intervention, the irrigated colic segments were removed. Neutral and acidic mucins were identified by Periodic-acid Schiff and Alcian-Blue techniques, respectively. The content of both mucin subtypes was measured by computerized morphometry. Mann-Whitney test was used to analyze the results, adopting a significance level of 5% (p ≤ 0.05). Results: There was an increase in the tissue content of neutral mucins in animals treated with curcumin at a concentration of 50 mg/kg/day for four weeks, whereas in the group treated with 200 mg/kg/day there was an increase independent of the time of intervention. The content of acidic mucins increased in animals treated with 200 mg/kg/day regardless of the intervention time, whereas in those treated with 50 mg/kg/day an increase was observed only after four weeks. Conclusion: Enemas with curcumin preserve the content of neutral and acidic mucins in the colonic epithelium without fecal stream.

RESUMO Objetivo: Verificar se a aplicação de clisteres com extrato oleoso de curcumina preserva o conteúdo de mucinas nas glândulas da mucosa cólica sem trânsito intestinal. Método: Trinta e seis ratos Wistar foram submetidos à derivação intestinal por colostomia proximal e fístula mucosa distal. Os animais foram subdivididos em três grupos, segundo receberem clisteres com soro fisiológico 0,9%, extrato oleoso de curcumina nas concentrações de 50 mg/kg/dia ou 200 mg/kg/dia. Após duas ou quatro semanas de intervenção foram removidos os segmentos cólicos irrigados. As mucinas neutras e ácidas foram identificadas pelas técnicas do PAS e Alcian-Blue, respectivamente. O conteúdo tecidual de ambos os subtipos de mucinas foi mensurado por morfometria computadorizada. Utilizou-se teste de Mann-Whitney para análise dos resultados adotando-se nível de significância de 5% (p ≤ 0,05). Resultados: Houve aumento no conteúdo de mucinas neutras nos animais tratados com curcumina na concentração de 50 mg/kg/dia por quatro semanas, enquanto nos tratados com 200 mg/kg/dia houve aumento independente do tempo de intervenção. O conteúdo de mucinas ácidas aumentou nos animais tratados com 200 mg/kg/dia independente do tempo de intervenção, enquanto nos tratados com 50 mg/kg/dia encontrou-se aumento apenas após quatro semanas. Conclusão: Clisteres com curcumina preservam o conteúdo de mucinas neutras e ácidas no epitélio cólico sem trânsito intestinal.