Improve Gut Barrier Function Research Articles

Heat-Inactivated Akkermansia muciniphila Improves Gut Permeability but Does Not Prevent Development of Non-Alcoholic Steatohepatitis in Diet-Induced Obese Ldlr-/-.Leiden Mice.

The development of non-alcoholic steatohepatitis (NASH) has been associated with alterations in gut microbiota composition and reduced gut barrier function. Akkermansia muciniphila is a gut microbe that is thought to have health-promoting properties, including the ability to improve gut barrier function and host metabolism, both when administered live and after heat-inactivation. We questioned whether heat-inactivated A. muciniphila may reduce NASH development. Ldlr−/−.Leiden mice, a translational, diet-induced model for NASH, were fed a NASH-inducing high-fat diet (HFD) supplemented with heat-inactivated A. muciniphila. After 28 weeks, effects of the treatment on obesity and associated metabolic dysfunction in the gut (microbiota composition and permeability), adipose tissue, and liver were studied relative to an untreated HFD control. Treatment with heat-inactivated A. muciniphila did not affect body weight or adiposity and had no effect on plasma lipids, blood glucose, or plasma insulin. Heat-inactivated A. muciniphila had some minor effects on mucosal microbiota composition in ileum and colon and improved gut barrier function, as assessed by an in vivo functional gut permeability test. Epidydimal white adipose tissue (WAT) hypertrophy and inflammation were not affected, but heat-inactivated A. muciniphila did reduce hypertrophy in the mesenteric WAT which is in close proximity to the intestine. Heat-inactivated A. muciniphila did not affect the development of NASH or associated fibrosis in the liver and did not affect circulating bile acids or markers of liver fibrosis, but did reduce PRO-C4, a type IV collagen synthesis marker, which may be associated with gut integrity. In conclusion, despite beneficial effects in the gut and mesenteric adipose tissue, heat-inactivated A. muciniphila did not affect the development of NASH and fibrosis in a chronic disease setting that mimics clinically relevant disease stages.

Effect of dietary fiber on gut barrier function, gut microbiota, short-chain fatty acids, inflammation, and clinical outcomes in critically ill patients: A systematic review and meta-analysis.

Although some studies have explored the relationships between dietary fiber (DF) supplement and gut barrier function, changes of gut microbiota, and clinical outcomes in critically ill patients, the results were not consistent. The purpose was to explore the effect of DF on gut barrier function, gut microbiota, short-chain fatty acids (SCFAs), inflammation, and clinical outcomes in critically ill patients. A search was performed through five databases from inception to July 12, 2021. Data were expressed as mean difference (MD) or odds ratio (OR) with CI. Twenty-one studies involving 2084 critically ill patients were included. There was a significant reduction in intestinal permeability, demonstrated by lactulose/rhamnose ratio (MD, -0.04; 95% CI, -0.08 to -0.00; P = 0.03) on day 8, C-reactive protein on day 14 (MD, -36.66; 95% CI, -44.40 to -28.93; P < 0.001) and duration of hospital stay (MD, -3.16; 95% CI, -5.82 to -0.49; P < 0.05) after DF supplement. There were no significant differences in SCFA levels, duration of mechanical ventilation, and mortality between two groups. However, subgroup analysis results indicated significant decreases in duration of hospital stay and risk of mortality were seen in the subgroups with a supplementary fiber dose ≥20 g/day (MD, -5.62 [95% CI, -8.04 to -3.21; P < 0.0001]; OR, 0.18 [95% CI, 0.06-0.57; P = 0.004]), as well as in the medical intensive care unit (MD, -4.77 [95% CI, -7.48 to -2.07; P < 0.01]; OR, 0.13 [95% CI, 0.03-0.65; P < 0.05]). DF may improve gut barrier function, modulate intestinal microbiota, decrease systemic inflammatory response, and advance clinical outcomes in critically ill patients.

Polysaccharides from soybean residue fermented by Neurospora crassa alleviate DSS-induced gut barrier damage and microbiota disturbance in mice.

Soluble polysaccharides derived from microbial fermentation of agricultural by-products were considered as potential functional ingredients, primarily having probiotic properties. Herein, soluble polysaccharides (FSRP) were isolated from soybean residue fermented by Neurospora crassa, and FSRP mainly contained rhamnose, arabinose, fucose, mannose, glucose, and galactose, according to GC-MS analysis. To further investigate the protective effect of FSRP against colitis, dextran sulfate sodium induction (DSS)-treated mice were orally gavaged with FSRP (200 mg kg-1 d-1) or inulin (400 mg kg-1 d-1, a positive control) for 7 d. The results showed that DSS-treated mice displayed symptoms of body weight loss, atrophy, and histopathological changes of colon, as well as gut barrier damage, which were recovered after FSRP supplementation (similar to inulin). Furthermore, the beneficial effects of FSRP were linked to a decreased inflammatory response and increased protein expression of E-cadherin, claudin-1 and ZO-1. Illumina-MiSeq sequencing analysis revealed that FSRP increased microbial diversity and altered community structure. Specifically, FSRP could modulate the abundance of inflammation-related bacteria (such as Tenericutes, Clostridia, and Bacilli) to ameliorate colitis symptoms. Therefore, FSRP can relieve DSS-induced colitis, which is closely associated with reduced levels of inflammatory factors, improved gut barrier function and gut microbiota homeostasis.

Methionine Restriction Improves Gut Barrier Function by Reshaping Diurnal Rhythms of Inflammation-Related Microbes in Aged Mice.

Age-related gut barrier dysfunction and dysbiosis of the gut microbiome play crucial roles in human aging. Dietary methionine restriction (MR) has been reported to extend lifespan and reduce the inflammatory response; however, its protective effects on age-related gut barrier dysfunction remain unclear. Accordingly, we focus on the effects of MR on inflammation and gut function. We found a 3-month methionine-restriction reduced inflammatory factors in the serum of aged mice. Moreover, MR reduced gut permeability in aged mice and increased the levels of the tight junction proteins mRNAs, including those of occludin, claudin-1, and zona occludens-1. MR significantly reduced bacterial endotoxin lipopolysaccharide concentration in aged mice serum. By using 16s rRNA sequencing to analyze microbiome diurnal rhythmicity during 24 h, we found MR moderately recovered the cyclical fluctuations of the gut microbiome which was disrupted in aged mice, leading to time-specific enhancement of the abundance of short-chain fatty acid-producing and lifespan-promoting microbes. Moreover, MR dampened the oscillation of inflammation-related TM7-3 and Staphylococcaceae. In conclusion, the effects of MR on the gut barrier were likely related to alleviation of the oscillations of inflammation-related microbes. MR can enable nutritional intervention against age-related gut barrier dysfunction.

Latilactobacillus sakei WIKIM31 Decelerates Weight Gain in High-Fat Diet-Induced Obese Mice by Modulating Lipid Metabolism and Suppressing Inflammation.

Obesity and related metabolic diseases are major problems worldwide. Some probiotics are currently considered potential therapeutic strategies for obesity. We aimed to investigate the antiobesity efficacy of Latilactobacillus sakei WIKIM31 in obese mice induced by a high fat diet. The administration of a high-fat diet with L. sakei WIKIM31 reduced body weight gain, epididymal fat mass, triglyceride and total cholesterol levels in the blood, and remarkably decreased the expression of lipogenesis-related genes in the epididymal adipose tissue and liver. Interestingly, intake of L. sakei WIKIM31 improved gut barrier function by increasing the gene expression of tight junction proteins and suppressing the inflammatory responses. Additionally, L. sakei WIKIM31 enhanced the production of short-chain fatty acids, such as butyrate and propionate, in the intestinal tract. These results showed that L. sakei WIKIM31 can be used as a potential therapeutic probiotic for obesity.

Development of Anti-inflammatory Probiotic Limosilactobacillus reuteri EFEL6901 as Kimchi Starter: in vitro and In vivo Evidence.

The use of probiotic starters can improve the sensory and health-promoting properties of fermented foods. In this study, we developed an anti-inflammatory probiotic starter, Limosilactobacillus reuteri EFEL6901, for use in kimchi fermentation. The EFEL6901 strain was safe for use in foods and was stable under human gastrointestinal conditions. In in vitro experiments, EFEL6901 cells adhered well to colonic epithelial cells and decreased nitric oxide production in lipopolysaccharide-induced macrophages. In in vivo experiments, oral administration of EFEL6901 to DSS-induced colitis mice models significantly alleviated the observed colitis symptoms, prevented body weight loss, lowered the disease activity index score, and prevented colon length shortening. Analysis of these results indicated that EFEL6901 played a probiotic role by preventing the overproduction of pro-inflammatory cytokines, improving gut barrier function, and up-regulating the concentrations of short-chain fatty acids. In addition, EFEL6901 made a fast growth in a simulated kimchi juice and it synthesized similar amounts of metabolites in nabak-kimchi comparable to a commercial kimchi. This study demonstrates that EFEL6901 can be used as a suitable kimchi starter to promote gut health and product quality.

Outcome of Lactoferrin Supplementation In Critically Ill Septic Children With Acute Gut Failure

Abstract Background Sepsis is a clinical syndrome caused by many infections. Septic patients may suffer from Gut failure resulting in severe complications. To improve Gut function, the effect of lactofferin supplementation has been studied. Objective To test the effect of lactoferrin supplementation on improving gut barrier function by using plasma citrulline level as a marker of functional enterocytic mass. Patients and Methods This double armed single blinded therapeutic clinical trial study was conducted on 40 children admitted to (PICUs) of Ain Shams University Hospitals. By diagnosis sepsis and gut failure, twenty of them weren't supplemented with LF (group 1) and the other twenty were supplemented (group 2). All critically ill septic patients diagnosed with acute gut failure admitted from October 2018 to 2019 were subjected to citrulline level measurement by (ELISA). Results We found that citrulline concentration was significantly lower in patients (9.52 nmol/L) than control group (122 nmol/L) and lowered in non survivors (5.13 nmol/L) than survivors (30.68 nmol/L) with p value of 0.027 and 0.034 respectively and a cut off value ≤ 7.82 mmol/L. There was no significant difference between the groups 1 and 2 in treatment of sepsis with gut failure. Conclusion (1) Citrulline level can be used as a predictor of intestinal failure severity and mortality. (2) Lactoferrin supplementation was not beneficial in pediatric septic patient with gut failure and did not improve outcome or prognosis of patients.

Corchorus olitorius L. ameliorates alcoholic liver disease by regulating gut-liver axis

• Water-soluble extract from molokhia leaves (WM) were extracted and characterized. • WM ameliorates alcohol-induced metabolic disorder parameters. • WM ameliorates alcohol-induced inflammation and lipid accumulation in liver. • WM regulates gut microbial composition and ameliorates gut barrier function. Gut microbial dysbiosis, induced by alcohol consumption, disrupts the gut-liver axis, leading to the development and progression of alcoholic liver disease. In this study, we investigated the protective effects of the water-soluble extract from molokhia ( Corchorus olitorius L.) leaves (WM) on the alcohol-induced disruption of the gut-liver axis in mice. The administration of 50 and 100 mg/kg WM reduced the levels of serum biomarkers for liver injury. Moreover, WM treatment ameliorated the alcohol-induced increase in hepatic inflammation and lipogenic protein levels. WM improved the gut microbial composition disrupted by alcohol, which suggests the effects of WM in mediating the gut-liver axis. WM also improved gut barrier function via the regulation of gut permeability and tight junction protein expression. These results indicate that WM can be used as a food supplement to improve alcohol-induced liver damage by regulating the gut-liver axis.

S3356 Microbial-Derived Protein SG-2-0776 Improves Gut Barrier Function and Prevents Fibrosis by Interacting With the Extracellular Matrix During GI Injury

S3356 Microbial-Derived Protein SG-2-0776 Improves Gut Barrier Function and Prevents Fibrosis by Interacting With the Extracellular Matrix During GI Injury

Estimation of D lactat level as amarker of bacterial translocation in gut failure incritically ill pediatric patients

Abstract Background Sepsis is defined as life-threatening multi organ failure caused by a dysregulated host response to infection leading to development of gut failure, D-lactate is produced by indigenous bacteria in the gastrointestinal tract lactoferrin is important constitute of human milk and other body fluid act to improve gut function. Aim of the Work To test effect of lactoferrin supplementation for improving gut barrier function, prognosis and the outcome of septic patients using D lactate as a marker of bacterial translocation in sepsis with gut failure. Patients and Methods After ethical committee approval and informed consent from the parents, this double armed single blinded therapeutic clinical trial study was conducted on 40 Egyptian children admitted to PICUs of Ain Shams University Hospitals, by diagnosis sepsis and gut failure, twenty of them weren't supplemented with LF (group 1) and the other twenty were supplemented with it (group 2). D lactate level was measured in plasma using ELISA. Results The study show highly significant difference between Patient and control group in D lactate level, and we found no statistical difference before and after giving lactoferrin in our septic patient who weren’t in treatment of sepsis and gut failure. And we found plasma D lactate higher in non survivors with p value.048. and cut of point&amp;lt; 43.9 mmol\L Conclusion Lactoferrin supplementation was not beneficial in pediatric septic patient with gut failure and did not improve outcome or prognosis of patients, D lactate can be used as a predictor of intestinal failure severity and mortality. D lactate may be predictor of gut failure in sepsis and mortality

Fermented and Germinated Processing Improved the Protective Effects of Foxtail Millet Whole Grain Against Dextran Sulfate Sodium-Induced Acute Ulcerative Colitis and Gut Microbiota Dysbiosis in C57BL/6 Mice.

This study investigated the effects of foxtail millet whole grain flours obtained through different processing methods on alleviating symptoms and gut microbiota dysbiosis in a dextran sulfate sodium (DSS)-induced murine colitis model. Sixty C57BL/6 mice were divided into six groups (n = 10 in each group), including one control group (CTRL) without DSS treatment and five DSS-treated groups receiving one of the following diets: AIN-93M standard diet (93MD), whole grain foxtail millet flour (FM), fermented (F-FM), germinated (G-FM), and fermented-germinated foxtail millet flour (FG-FM). A comparison of the disease activity index (DAI) demonstrated that foxtail millet whole grain-based diets could alleviate the symptoms of enteritis to varying degrees. In addition, 16S rRNA gene sequencing revealed that FG-FM almost completely alleviated DSS-induced dysbiosis. Mice on the FG-FM diet also had the lowest plasma IL-6 levels and claudin2 expression levels in the colon, indicating reduced systemic inflammation and improved gut barrier function. This study suggested that foxtail millet whole grain is an attractive choice for the intervention of IBD and gut microbiota dysbiosis, and its prebiotic properties are highly affected by the processing methods.

A high potency multi-strain probiotic improves glycemic control in children with new-onset type 1 diabetes mellitus: A randomized, double-blind, and placebo-controlled pilot study.

Studies in animal models and humans with type 1 diabetes mellitus (T1DM) have shown that probiotic supplementation leads to decreased pro-inflammatory cytokines (responsible for damaging β-cells of the pancreas), improved gut barrier function, and induction of immune tolerance. To study the effect of supplementation of probiotics in children with T1DM on glycemic control, insulin dose, and plasma C-peptide levels. A single-centered, double-blinded, and randomized placebo-controlled pilot trial was conducted in children (2-12 years) with new-onset T1DM. Ninety-six children were randomized and allocated to Placebo or Intervention groups. The intervention included high dose (112.5 billion viable lyophilized bacteria per capsule) multi-strain probiotic De Simone formulation (manufactured by Danisco-Dupont) sold as Visbiome® in India. The probiotic was supplemented for 3 months and HbA1c, fasting C-peptide, blood sugar records, and insulin dose was recorded at baseline and 3 months. A total of 90 patients (45 in each group) were analyzed for outcome parameters. We found a significant decrease in HbA1c (5.1 vs. 3.8; p=0.021) and a significant decline in total and bolus insulin dose (U/kg/day; p=0.037 and 0.018, respectively) in the intervention group when compared with the placebo group. A significantly higher (p=0.023) number of children achieved remission in the treatment group. We did not notice adverse effects in either of the study groups. Children with newly diagnosed T1DM managed with standard treatment along with probiotics showed better glycemic control and a decrease in insulin requirements; however, more extensive studies are further warranted.

Improvement of Gut Barrier Function by Potato Anthocyanins Is Dependent on Gut Microbiota

Abstract Objectives Ulcerative colitis (UC) is characterized by chronic colonic inflammation, impaired barrier function and gut bacterial dysbiosis. Anthocyanin-containing potatoes have been shown to maintain the intestinal barrier function in colitic mice. However, the role of gut microbiota in the anti-colitic effects of anthocyanin-containing potatoes is not clear. This study evaluated the gut barrier protective efficacy of purple- and red-fleshed potatoes using a DSS-induced murine model of colitis with the intact and antibiotic-depleted microbiota. Methods Four-week-old mice (C57BL6) were randomized into four groups, receiving a standard control diet, or a 20% purple-/red-fleshed potato (PP/RP) supplemented diet. A broad-spectrum antibiotic cocktail was used to deplete the gut bacteria. After eight weeks, mice were treated with 2% DSS in their drinking water for five days to induce colitis. The polyphenol composition of potatoes was analyzed by LC-MS/MS. Intestinal permeability was measured using FITC-dextran. Colonic myeloperoxidase (MPO) activities were determined using the o-dianisidine dihydrochloride method. The fecal short-chain fatty acids (SCFA) content of mice was measured by GC-FID. RT-PCR was used to analyze the relative gene expression levels of cytokines and bacterial abundance. Results The predominant anthocyanin detected in RP was pelargonidin (93.13%). Whereas petunidin (75.57%) and malvidin (21.05%) were the two major anthocyanins present in PP. Administration of antibiotics resulted in a reduction in fecal SCFA. Antibiotic-treated mice were more prone to the DSS-induced increase in gut permeability. Anthocyanin-containing potato diets alleviated DSS-induced colonic damage, elevation in histology score and gut permeability only in non-antibiotic mice. RP alone suppressed the elevated colonic MPO activity and the gene expression levels of MUC2 in mice with intact gut microbiota. Conclusions In summary, anthocyanin-containing potatoes alleviated colitis-associated colonic epithelial damage and increased gut permeability in intact microbiota mice but not in microbiota-ablated mice. This suggests that the gut microbiome is essential for the gut barrier protective activity of anthocyanin-containing potatoes. Funding Sources USDA-NIFA awards 2016–67,017-29,285 and 2019–67,017-29,258.

Ganoderma lucidum polysaccharide modulates gut microbiota and immune cell function to inhibit inflammation and tumorigenesis in colon

This study investigated the effects of water-soluble polysaccharide extracted from the sporoderm-removed spores of Ganoderma lucidum (GLP) against AOM/DSS-induced inflammation, tumorigenesis, and gut microbiota modification, which has never been reported before. Our data revealed that GLP (200 and 300 mg/kg) decreased AOM/DSS-induced colitis and tumorigenesis, manifested by significantly reduced disease activity index score, and total number and size of tumors. Furthermore, GLP ameliorated AOM/DSS-induced microbiota dysbiosis, increased short-chain fatty acid production, and alleviated endotoxemia by inhibiting TLR4/MyD88/NF-κB signaling. Besides, GLP profoundly improved gut barrier function as evidenced by increased numbers of goblet cells, MUC2 secretion, and tight junction protein expressions. GLP treatment inhibited macrophage infiltration and downregulated IL-1β, iNOS, and COX-2 expressions. Additionally, GLP inhibited lipopolysaccharides (LPS)-induced inflammation markers and MAPK (JNK and ERK) activation in macrophage RAW264.7, intestinal HT-29, and NCM460 cells. In conclusion, these results indicate that GLP is a promising prebiotic for the treatment of colorectal cancer.

Centrally administered butyrate improves gut barrier function, visceral sensation and septic lethality in rats

Short chain fatty acids readily crosses the gut-blood and blood–brain barrier and acts centrally to influence neuronal signaling. We hypothesized that butyrate, a short-chain fatty acid produced by bacterial fermentation, in the central nervous system may play a role in the regulation of intestinal functions. Colonic permeability and visceral sensation was evaluated in rats. Septic lethality was evaluated in a sepsis model induced by subcutaneous administration of both lipopolysaccharide and colchicine. Intracisternal butyrate dose-dependently improved colonic hyperpermeability and visceral nociception. In contrast, subcutaneous injection of butyrate failed to change it. Intracisternal orexin 1 receptor antagonist or surgical vagotomy blocked the central butyrate-induced improvement of colonic hyperpermeability. The improvement of intestinal hyperpermeability by central butyrate or intracisternal orexin-A was blocked by cannabinoid 1 or 2 receptor antagonist. Intracisternal butyrate significantly improved survival period in septic rats. These results suggest that butyrate acts in the central nervous system to improve gut permeability and visceral nociception through cannabinoid signaling. Endogenous orexin in the brain may mediate the reduction of intestinal hyperpermeability by central butyrate through the vagus nerve. We would suggest that improvement of leaky gut by central butyrate may induce visceral antinociception and protection from septic lethality.

Prebiotic Effect of Berberine and Curcumin Is Associated with the Improvement of Obesity in Mice.

Berberine and curcumin, used as food additives or food supplements, possess interesting anti-inflammatory and antioxidant properties. We tested the potential protective effect of both phytochemicals in genetically obese mice and we determined whether these effects can be related to the modulation of gut functions and microbiota. Ob/ob mice were fed a standard diet supplemented with or without 0.1% berberine and/or 0.3% curcumin for 4 weeks. By using targeted qPCR, we found that cecal content of Bifidobacterium spp. and Akkermansia spp. increased mainly upon berberine supplementation. Genes involved in innate immunity (Pla2g2a), mucus production (Muc2) and satietogenic peptide production (Gcg and Pyy) were upregulated in the colon of mice treated with both phytochemicals. Berberine supplementation alone reduced food intake, body weight gain, hypertriglyceridemia and hepatic inflammatory and oxidative stress markers, thus lessening hepatic injury. The increase in Bifidobacterium spp. and Akkermansia spp. was correlated with the improvement of gut barrier function and with the improvement of hepatic inflammatory and oxidative stresses in obese mice. These data support the fact that non-carbohydrate phytochemicals may modulate the gut microbiota in obesity and related gut and hepatic alterations.

Effects of supplemental calcium gluconate embedded in a hydrogenated fat matrix on lactation, digestive, and metabolic variables in dairy cattle

There is growing evidence suggesting that by improving gut integrity and function, less energy is partitioned toward immune responses related to xenobiotic infiltration, sparing energy for productive purposes. Gluconic acid and its salts have previously shown prebiotic effects in the lower gut of nonruminant animals, where they serve as a precursor for butyrate, although evidence in ruminants is limited. Butyrate and its fermentative precursors have demonstrated multiple beneficial effects to gastrointestinal ecology, morphology, and function, such as the stimulation of epithelial cell proliferation and improvement of gut barrier function and ecology. The objective of this study was to evaluate changes in milk production, milk fatty acid composition, and fecal and blood parameters in lactating dairy cattle fed a hydrogenated fat-embedded calcium gluconate (HFCG) supplement designed to target the hindgut for calcium gluconate delivery. In addition, the effects of a compound feed processing method (i.e., incorporated into a mash or an extruded pellet) were tested to evaluate the effect of extrusion on product efficacy. Forty-five lactating Holstein cows at approximately 165 d in milk were used in a 3 × 3 Latin square consisting of three 28-d periods, during which animals were offered a basal ration mixed with 3 different compound feeds: a negative control in mash form containing no HFCG, or the HFCG supplement fed at a target rate of 16 g/d, delivered in either a mash or pelleted form. Supplementation of HFCG tended to increase yields of milk fat and fat- and energy-corrected milk. Total yields and concentrations of milk fatty acids ≥18 carbons in length tended to increase in response to HFCG. Plasma nonesterified fatty acids and milk urea increased in HFCG treatments. No differences were observed in fecal pH or fecal concentrations of volatile fatty acids, with the exception of isobutyrate, which decreased in HFCG-fed cows. Changes in milk fatty acid profile suggest that increased milk fat yield was driven by increased incorporation of preformed fatty acids, supported by increased circulating nonesterified fatty acid. Future research investigating the mode of action of HFCG at the level of the hindgut epithelium is warranted, as measured fecal parameters showed no response to treatment.

Membrane Permeant Inhibitor of Myosin Light Chain Kinase Worsens Survival in Murine Polymicrobial Sepsis.

Sepsis-induced intestinal hyperpermeability is mediated by disruption of the epithelial tight junction, which is closely associated with the peri-junctional actin-myosin ring. Genetic deletion of myosin light chain kinase (MLCK) reverses intestinal hyperpermeability and improves survival in a murine model of intra-abdominal sepsis. In an attempt to determine whether these findings could be translated using a more clinically relevant strategy, this study aimed to determine if pharmacologic inhibition of MLCK using the membrane permeant inhibitor of MLCK (PIK) improved gut barrier function and survival following sepsis. C57BL/6 mice underwent cecal ligation and puncture to induce sepsis and were then randomized to receive either PIK or vehicle. Unexpectedly, PIK significantly worsened 7-day survival following sepsis (24% vs. 62%). The three pathways of intestinal permeability were then interrogated by orally gavaging septic mice with creatinine (6Å), FD-4 (28Å), and rhodamine70 (120Å) and assaying their appearance in the bloodstream. PIK led to increased permeability in the leak pathway with higher levels of FD-4 in the bloodstream compared to septic mice given vehicle. In contrast, no differences were detected in the pore or unrestricted pathways of permeability. Examination of jejunal tight junctions for potential mechanisms underlying increased leak permeability revealed that mice that received PIK had increased phosphorylated MLC without alterations in occludin, ZO-1, or JAM-A. PIK administration was not associated with significant differences in systemic or peritoneal bacterial burden, cytokines, splenic or Peyer's Patches immune cells or intestinal integrity. These results demonstrate that pharmacologic inhibition of MLCK unexpectedly increases mortality, associated with worsened intestinal permeability through the leak pathway, and suggest caution is required in targeting the gut barrier as a potential therapy in sepsis.

Modulation of the Gut Microbiota by Shen-Yan-Fang-Shuai Formula Improves Obesity Induced by High-Fat Diets.

Obesity and related metabolic disorders are associated with intestinal microbiota dysbiosis, disrupted intestinal barrier and chronic inflammation. Shen-Yan-Fang-Shuai formula (SYFSF) is a traditional Chinese herbal formula composed of Astragali Radix, Radix Angelicae Sinensis, Rheum Officinale Baill, and four other herbs. In this study, we identified that SYFSF treatment prevented weight gain, low-grade inflammation and insulin resistance in high-fat diet (HFD)-fed mice. SYFSF also substantially improved gut barrier function, reduced metabolic endotoxemia, as well as systemic inflammation. Sequencing of 16S rRNA genes obtained from fecal samples demonstrated that SYFSF attenuated HFD-induced gut dysbiosis, seen an decreased Firmicutes to Bacteroidetes ratios. Microbial richness and diversity were also higher in the SYFSF-treated HFD group. Furthermore, similar therapeutic effects and changes in gut microbiota profile caused by SYFSF could be replicated by fecal microbiota transfer (FMT). Taken together, our study highlights the efficacy of SYFSF in preventing obesity and related metabolic disorders. Its therapeutic effect is associated with the modulation of gut microbiota, as a prebiotic.

Dietary Fiber Intake Alters Gut Microbiota Composition but Does Not Improve Gut Wall Barrier Function in Women with Future Hypertensive Disorders of Pregnancy.

Pregnancy alters the inflammatory state, metabolic hormones, and gut microbiota composition. It is unclear if the lower abundance of dietary fiber-fermenting, short-chain fatty acid-producing bacteria observed in hypertension also occurs in hypertensive disorders of pregnancy (HDP). This study investigated the relationship between dietary fiber intake and the gut microbiota profile at 28 weeks gestation in women who developed HDP in late pregnancy (n = 22) or remained normotensive (n = 152) from the Study of PRobiotics IN Gestational diabetes (SPRING). Dietary fiber intake was classified as above or below the median of 18.2 g/day. Gut microbiota composition was examined using 16S rRNA gene amplicon sequencing. The gut permeability marker zonulin was measured in a subset of 46 samples. In women with future HPD, higher dietary fiber intake was specifically associated with increased abundance of Veillonella, lower abundance of Adlercreutzia, Anaerotruncus and Uncl. Mogibacteriaceae and higher zonulin levels than normotensive women. Fiber intake and zonulin levels were negatively correlated in women with normotensive pregnancies but not in pregnancies with future HDP. In women with normotensive pregnancies, dietary fiber intake may improve gut barrier function. In contrast, in women who develop HDP, gut wall barrier function is impaired and not related to dietary fiber intake.