Gut Microbiota Dysfunction Research Articles

Puerariae lobatae Radix ameliorates chronic kidney disease by reshaping gut microbiota and downregulating Wnt/β‑catenin signaling.

Gut microbiota dysfunction is a key factor affecting chronic kidney disease (CKD) susceptibility. Puerariae lobatae Radix (PLR), a traditional Chinese medicine and food homologous herb, is known to promote the gut microbiota homeostasis; however, its role in renoprotection remains unknown. The present study aimed to investigate the efficacy and potential mechanism of PLR to alleviate CKD. An 8‑week 2% NaCl‑feeding murine model was applied to induce CKD and evaluate the therapeutic effect of PLR supplementary. After gavage for 8 weeks, The medium and high doses of PLR significantly alleviated CKD‑associated creatinine, urine protein increasement and nephritic histopathological injury. Moreover, PLR protected kidney from fibrosis by reducing inflammatory response and downregulating the canonical Wnt/β‑catenin pathway. Furthermore, PLR rescued the gut microbiota dysbiosis and protected against high salt‑induced gut barrier dysfunction. Enrichment of Akkermansia and Bifidobacterium was found after PLR intervention, the relative abundances of which were in positive correlation with normal maintenance of renal histology and function. Next, fecal microbiota transplantation experiment verified that the positive effect of PLR on CKD was, at least partially, exerted through gut microbiota reestablishment and downregulation of the Wnt/β‑catenin pathway. The present study provided evidence for a new function of PLR on kidney protection and put forward a potential therapeutic strategy target for CKD.

Prebiotic diet normalizes aberrant immune and behavioral phenotypes in a mouse model of autism spectrum disorder

Autism spectrum disorder (ASD) is a cluster of neurodevelopmental disorders characterized by deficits in communication and behavior. Increasing evidence suggests that the microbiota-gut-brain axis and the likely related immune imbalance may play a role in the development of this disorder. Gastrointestinal deficits and gut microbiota dysfunction have been linked to the development or severity of autistic behavior. Therefore, treatments that focus on specific diets may improve gastrointestinal function and aberrant behavior in individuals with ASD. In this study, we investigated whether a diet containing specific prebiotic fibers, namely, 3% galacto-oligosaccharide/fructo-oligosaccharide (GOS/FOS; 9:1), can mitigate the adverse effects of in utero exposure to valproic acid (VPA) in mice. Pregnant BALB/cByJ dams were injected with VPA (600 mg/kg, sc.) or phosphate-buffered saline (PBS) on gestational day 11 (G11). Male offspring were divided into four groups: (1) in utero PBS-exposed with a control diet, (2) in utero PBS-exposed with GOS/FOS diet, (3) in utero VPA-exposed with a control diet, and (4) in utero VPA-exposed with GOS/FOS diet. Dietary intervention started from birth and continued throughout the duration of the experiment. We showed that the prebiotic diet normalized VPA-induced alterations in male offspring, including restoration of key microbial taxa, intestinal permeability, peripheral immune homeostasis, reduction of neuroinflammation in the cerebellum, and impairments in social behavior and cognition in mice. Overall, our research provides valuable insights into the gut-brain axis involvement in ASD development. In addition, dietary interventions might correct the disbalance in gut microbiota and immune responses and, ultimately, might improve detrimental behavioral outcomes in ASD.

Sex-Specific Effect of Ethanol on Colon Content Lipidome in a Mice Model Using Nontargeted LC/MS.

Consumption of alcohol has widespread effects on the human body. The organs that are most significantly impacted are the liver and digestive system. When alcohol is consumed, it is absorbed in the intestines and processed by the liver. However, excessive alcohol use may affect gut epithelial integrity, microbiome composition, and lipid metabolism. Despite past studies investigating the effect of ethanol on hepatic lipid metabolism, the focus on colonic lipid metabolism has not been well explored. In this study, we investigated the sex-specific effect of ethanol on the colonic content lipidome in a mouse model using nontargeted liquid chromatography-mass spectrometry. Comprehensive lipidome analysis of colonic flush samples was performed using ethanol-fed (EF) and pair-fed (PF) mice of each sex. Partial least-squares discriminant analysis revealed that ethanol altered colonic lipid composition largely in male mice compared with female mice. A significant increase in free fatty acids, ceramides, and hexosylceramides and decreased phosphatidylglycerols (PG) was observed in the EF group compared to the PF group in male mice. Phosphatidylethanolamine (PE) levels were increased significantly in the EF group of both sexes compared to the PF group. The volcanic plot shows that PG (O-15:1/15:0) and PE (O-18:2/15:0) are common markers that are increased in both sexes of the EF group. In addition, decreased fatty acid esters of hydroxy fatty acids (FAHFA) were observed specifically in the EF group of female mice. Overall, a significant variation in the mice colonic content lipidome between the EF and PF groups was observed. Target pathways, such as sphingolipid metabolism in males, FAHFA in females, and PE metabolism in both sexes, were suggested. This study provides new insight into the sex-dependent lipid change associated with alcohol-induced gut-microbiota dysfunction and its potential health impacts.

Dihydroartemisinin Protects Mice from CUMS-induced Depression-like Behaviors by Regulating Gut Microbes

Depression is one of the most common forms of psychopathology, which is associated with gut microbiota dysfunction. Dihydroartemisinin (DHA) has been shown to regulate gut microbiota and ameliorate neuropathies, but whether it can be used to treat depression remains unclear. Our study found that DHA treatment raised the preference for sugar water in chronic unpredictable mild stress (CUMS)-induced mice and reduced the immobility time in open field, forced swimming and tail suspension experiments, and promoted doublecortin expression. Additionally, DHA up-regulated the diversity and richness of intestinal microbiota in depression-like mice, and restored the abnormal abundance of microbiota induced by CUMS, such as Turicibacter, Lachnospiraceae, Erysipelotrichaceae, Erysipelatoclostridium, Eubacterium, Psychrobacter, Atopostipes, Ileibacterium, Coriobacteriacea, Alistipes, Roseburia, Rikenella, Eggerthellaceae, Ruminococcus, Tyzzerella, and Clostridia. Furthermore, KEGG pathway analysis revealed that gut microbiota involved in the process of depression may be related to glucose metabolism, energy absorption and transport, and AMPK signaling pathway. These results indicated that DHA may play a protective role in CUMS-induced depression by mediating gut-microbiome.

Pretreatment with an antibiotics cocktail enhances the protective effect of probiotics by regulating SCFA metabolism and Th1/Th2/Th17 cell immune responses

BackgroundProbiotics are a potentially effective therapy for inflammatory bowel disease (IBD); IBD is linked to impaired gut microbiota and intestinal immunity. However, the utilization of an antibiotic cocktail (Abx) prior to the probiotic intervention remains controversial. This study aims to identify the effect of Abx pretreatment from dextran sulfate sodium (DSS)-induced colitis and to evaluate whether Abx pretreatment has an enhanced effect on the protection of Clostridium butyricum Miyairi588 (CBM) from colitis.ResultsThe inflammation, dysbiosis, and dysfunction of gut microbiota as well as T cell response were both enhanced by Abx pretreatment. Additionally, CBM significantly alleviated the DSS-induced colitis and impaired gut epithelial barrier, and Abx pretreatment could enhance these protective effects. Furthermore, CBM increased the benefit bacteria abundance and short-chain fatty acids (SCFAs) level with Abx pretreatment. CBM intervention after Abx pretreatment regulated the imbalance of cytokines and transcription factors, which corresponded to lower infiltration of Th1 and Th17 cells, and increased Th2 cells.ConclusionsAbx pretreatment reinforced the function of CBM in ameliorating inflammation and barrier damage by increasing beneficial taxa, eliminating pathogens, and inducing a protective Th2 cell response. This study reveals a link between Abx pretreatment, microbiota, and immune response changes in colitis, which provides a reference for the further application of Abx pretreatment before microbiota-based intervention.

Gut microbiota compositional profile in patients with posner-schlossman syndrome

The cause of Posner-Schlossman syndrome (PSS) remains unknown and its frequent recurrence may eventually lead to irreversible damage of the optic nerve. The influence of immune factors in the pathophysiology of PSS is gaining more and more interest. Increasing evidence suggests that gut dysbiosis plays vital roles in a variety of neurodegenerative and immune-related diseases. However, alterations of the gut microbiota in PSS patients have not been well defined yet. In this study, 16S rRNA sequencing was used to explore the difference of gut microbiota between PSS patients and healthy controls, and the correlation between the microbiota profile and clinical features was also analyzed. Our data demonstrated a significant increase of Prevotella and Prevotellaceae, and a significant reduction of Bacteroides and Bacteroidaceae in PSS patients, and KEGG analysis showed dysfunction of gut microbiota between PSS patients and healthy controls. Interestingly, further analysis showed that the alteration of gut microbiota was correlated with the PSS attack frequency of PSS. This study demonstrated the gut microbiota compositional profile of PSS patients and speculated the risk microbiota of PSS, which is expected to provide new insights for the diagnosis and treatment of PSS.

Revisiting the Role of Valeric Acid in Manipulating Ulcerative Colitis.

Ulcerative colitis (UC) is characterized by a complicated interaction between mucosal inflammation, epithelial dysfunction, abnormal activation of innate immune responses, and gut microbiota dysbiosis. Though valeric acid (VA), one type of short-chain fatty acids (SCFAs), has been identified in other inflammatory disorders and cancer development, the pathological role of VA and underlying mechanism of VA in UC remain under further investigation. Studies of human clinical specimens and experimental colitis models were conducted to confirm the pathological manifestations of the level of SCFAs from human fecal samples and murine colonic homogenates. Valeric acid-intervened murine colitis and a macrophage adoptive transfer were applied to identify the underlying mechanisms. In line with gut microbiota dysfunction in UC, alteration of SCFAs from gut microbes were identified in human UC patients and dextran sodium sulfate -induced murine colitis models. Notably, VA was consistently negatively related to the disease severity of UC, the population of monocytes, and the level of interluekin-6. Moreover, VA treatment showed direct suppressive effects on lipopolysaccharides (LPS)-activated human peripheral blood mononuclear cells and murine macrophages in the dependent manner of upregulation of GPR41 and GPR43. Therapeutically, replenishment of VA or adoptive transfer with VA-modulated macrophages showed resistance to dextran sodium sulfate-driven murine colitis though modulating the production of inflammatory cytokine interleukin-6. In summary, the research uncovered the pathological role of VA in modulating the activation of macrophages in UC and suggested that VA might be a potential effective agent for UC patients.

Abnormal enterohepatic circulation of bile acids caused by fructooligosaccharide supplementation along with a high-fat diet.

Fructooligosaccharide (FOS) is a widely used prebiotic and health food ingredient, but few reports have focused on its risk to specific populations. Recently, it has been shown that the intake of inulin, whose main component is FOS, can lead to cholestasis and induce hepatocellular carcinoma in mice fed a high-fat diet (HFD); however, the molecular mechanism behind this is not clear. This study found that FOS supplementation induced abnormal enterohepatic circulation of bile acids in HFD-fed mice, which showed a significant increase in bile acid levels in the blood and liver, especially the secondary bile acids with high cytotoxicity, such as deoxycholic acid. The abundance of Clostridium, Bacteroides, and other bacteria in the gut microbiota also increased significantly. The analysis of the signaling pathway involved in regulating the enterohepatic circulation of bile acids showed that the weakening of the feedback inhibition of FXR-FGF15 and FXR-SHP signalling pathways possibly induced the enhancement of CYP7A1 activity and bile acid reabsorption in the blood and liver and led to an increase in bile acid synthesis and accumulation in the liver, increasing the risk of cholestasis. This study showed the risk of health damage caused by FOS supplementation in HFD-fed mice, which is caused by gut microbiota dysfunction and abnormal enterohepatic circulation of bile acids. Therefore, the application of FOS should be standardized to avoid the health risks of unreasonable FOS use in specific populations.

Effects of Lacticaseibacillus paracasei SNB-derived postbiotic components on intestinal barrier dysfunction and composition of gut microbiota

The bacterial surface components are considered as effector molecules and show the potential to support intestinal health, but the detailed mechanism of how the gut microbiota changes after the intervention of surface molecules is still unknown. In the present study, capsular polysaccharide (B-CPS) and surface layer protein (B-SLP) were extracted from Lacticaseibacillus paracasei S-NB. The protective effect of direct administration of B-CPS (100 μg/mL) and B-SLP (100 μg/mL) on intestinal epithelial barrier dysfunction was verified based on the LPS-induced Caco-2 cell model. Additionally, the B-CPS and B-SLP could be utilized as carbon source and nitrogen source for the growth of several Lactobacillus strains, respectively. The postbiotic potential of B-CPS and B-SLP was further evaluated by in vitro fermentation with fecal cultures. The B-CPS and a combination of B-CPS and B-SLP regulated the composition of gut microbiota by increasing the relative abundances of Bacteroides, Bifidobacterium, Phascolarctobacterium, Parabacteroides, Subdoligranulum and Collinsella and decreasing the abundance of pathogenic bacteria like Escherichia-Shigella, Blautia, Citrobacter and Fusobacterium. Meanwhile, the total short-chain fatty acid production markedly increased after fermentation with either B-CPS individually or in combination with B-SLP. These results provided an important basis for the application of B-CPS and B-SLP as postbiotics to improve human intestinal health.

Barley Vinegar Relieves Loperamide-Induced Constipation in Mice via the Modulation of the Gut Microbiota and Serum Metabolism

This study investigated the effect of barley vinegar on constipation by regulating the structure of intestinal microbiota and the level of short-chain fatty acids (SCFAs). BALB/c mice with loperamide-induced constipation were treated with barley vinegar in the intervention. After treatment, constipation-related factors were identified. The effect of barley vinegar on the composition of the intestinal microbiota was evaluated by means of 16S rDNA gene sequencing, and the content of SCFAs in enteral feces was determined via the GC-MS method. Treating constipated mice with barley vinegar accelerated gastrointestinal peristalsis, inhibited the inflammatory response, protected the intestinal barrier, upregulated the production of beneficial intestinal bacteria, and downregulated the production of harmful intestinal bacteria. These therapeutic effects are attributed to reversed gut microbiota dysfunction, which favors the production of intestinal metabolites such as SCFAs. The purgative function of highland barley vinegar may improve the intestinal environment by regulating the balance of intestinal flora and the concentration of SCFAs. In addition, LC-MS metabolomics was used to analyze the effect of barley vinegar on intestinal metabolites in mice with constipation. The results show that the treatment of barley vinegar inhibited the decrease in aspartate, L-threonine, L-serine, L-proline, 3,4-dihydroxymandelic acid, epinephrine, glyceric acid, and 3,4-dihydroxymandelic acid content in intestinal metabolites caused by constipation. 4-2 hydroxy benzene acetic acid and fumaric acid content increased. KEGG pathway analysis showed that digestive system, amino acid and lipid metabolism pathways were important pathways for highland barley vinegar relieving constipation. This study proves that highland barley vinegar mainly regulates lipid metabolism, the digestive system and amino acid metabolism to maintain a steady state, prevent intestinal injury, and improve constipation. In short, this study demonstrates that highland barley vinegar can alleviate constipation in mice and repair colitis damage.

Investigation of Gut Microbiota Disorders in Sepsis and Sepsis Complicated with Acute Gastrointestinal Injury Based on 16S rRNA Genes Illumina Sequencing.

Sepsis is a life-threatening organ dysfunction caused by the host's dysfunctional response to infection, which can cause acute gastrointestinal injury (AGI). The gut microbiota is dynamic and plays a role in the immune and metabolic. The aim of this study was to investigate the composition and function of gut microbiota in patients with sepsis, as well as the gut microbiome that may be involved in the occurrence of AGI. A total of 23 stool samples from healthy control individuals and 41 stool samples from sepsis patients were collected. Patients with sepsis were followed up for one week to observe whether AGI has occurred. Finally, 41 patients included 21 sepsis complicated with AGI (referred to as Com-AGI) and 20 sepsis without complicated with AGI (referred to as No-AGI). The gut microbiota was analyzed by 16S rRNA gene sequencing, followed by composition analysis, difference analysis, correlation analysis, functional prediction analysis. The diversity and evenness of gut microbiota were decreased in patients with sepsis. Compared with No-AGI, the gut microbiota of Com-AGI has higher community diversity, richness, and phylogenetic diversity. Escherichia-Shigella, Blautia and Enterococcus may be important indicators of sepsis. The correlation analysis showed that aspartate aminotransferase (AST) and Barnesiella have the most significant positive correlation. Moreover, Clostridium_innocuum_group, Christensenellaceae_R-7_group and Eubacterium were all significantly correlated with LAC and DAO. Clostridium_innocuum_group, Barnesiella, Christensenellaceae_R-7_group and Eubacterium may play important roles in the occurrence of AGI in sepsis. PICRUSt analysis revealed multiple functional pathways involved in the relationship between gut microbiota and sepsis, including starch degradation V, glycogen degradation I (bacterial), Lipoic acid metabolism and Valine, leucine and isoleucine biosynthesis. BugBase analysis showed that the gut microbiota with Aerobic phenotype may play an important role in sepsis. Dysfunction of gut microbiota was associated with sepsis and AGI in patients with sepsis.

Gut microbiota adaptation to low and high carbohydrate-to-protein ratio diets in grass carp (Ctenopharyngodon idella)

This study attempted to explore the adaptability of gut microbiota in grass carp to diets with different carbohydrate-to-protein ratios in order to better understand the immunological and metabolic changes in the organism. Three different ratios of carbohydrate and protein diets (12.5%-carbohydrate 46.3%-protein (LCHP), 27.5%-carbohydrate 33.7%-protein (MCMP), and 42.5%-carbohydrate 16.9%-protein (HCLP)) were satiety-fed to grass carp. After feeding, the growth performance, gut microbial community composition and function were analyzed. Growth performance results showed that LCHP group exhibited the significantly lower specific growth ratio than MCMP group, and HCLP group displayed the significantly higher feed coefficient and lower survival rate. The community composition results showed that the abundance of the beneficial genus Cetobacterium was the highest in MCMP group, and the abundance of the harmful genera Ruminiclostridium_9 and Phreatobacter was the highest in the LCHP and HCLP groups, respectively. Furthermore, the ratio of Firmicutes to Bacteroidetes considered as an indicator of gut microbiota dysfunction, was significantly higher in the LCHP and HCLP groups than that in the MCMP group. The community functional analysis showed that the abundance levels of cofactors and vitamin metabolism were significantly lower and the abundance levels of neurodegenerative diseases were significantly higher in the LCHP and HCLP groups than those in the MCMP group. The abundance levels of energy metabolism and a range of biomolecules metabolism were significantly decreased in the HCLP group. These results suggested that high-carbohydrate diets have a greater negative impact on the gut microbiota than high-protein diets. The gut microbiota results echoed the growth performance parameters, reflecting that gut microbiota may play an important role in the influence of different carbohydrate-to-protein ratios diets on host. Bacterial genera such as Ruminiclostridium_9 and Phreatobacter may play key roles in the effects of high-protein and high-carbohydrate diets on host health and metabolism, respectively.

Tryptophan metabolite norharman secreted by cultivated Lactobacillus attenuates acute pancreatitis as an antagonist of histone deacetylases

BackgroundPatients with acute pancreatitis (AP) exhibit specific phenotypes of gut microbiota associated with severity. Gut microbiota and host interact primarily through metabolites; regrettably, little is known about their roles in AP biological networks. This study examines how enterobacterial metabolites modulate the innate immune system in AP aggravation.MethodsIn AP, alterations in gut microbiota were detected via microbiomics, and the Lactobacillus metabolites of tryptophan were identified by liquid chromatography-tandem mass spectrometry (LC–MS/MS). By culturing Lactobacillus with tryptophan, differential metabolites were detected by LC–MS/MS. Lipopolysaccharide (LPS)-stimulated RAW264.7 cells and mice with cerulein plus LPS-induced AP were used to evaluate the biological effect of norharman on M1 macrophages activation in AP development. Further, RNA sequencing and lipid metabolomics were used for screening the therapeutic targets and pathways of norharman. Confocal microscopy assay was used to detect the structure of lipid rafts. Molecular docking was applied to predict the interaction between norharman and HDACs. Luciferase reporter assays and chromatin immunoprecipitation (ChIP) were used to explore the direct mechanism of norharman promoting Rftn1 expression. In addition, myeloid-specific Rftn1 knockout mice were used to verify the role of Rftn1 and the reversed effect of norharman.ResultsAP induced the dysfunction of gut microbiota and their metabolites, resulting in the suppression of Lactobacillus-mediated tryptophan metabolism pathway. The Lactobacillus metabolites of tryptophan, norharman, inhibited the release of inflammatory factor in vitro and in vivo, as a result of its optimal inhibitory action on M1 macrophages. Moreover, norharman blocked multiple inflammatory responses in AP exacerbation due to its ability to maintain the integrity of lipid rafts and restore the dysfunction of lipid metabolism. The mechanism of norharman’s activity involved inhibiting the enzyme activity of histone deacetylase (HDACs) to increase histone H3 at lysine 9/14 (H3K9/14) acetylation, which increased the transcription level of Rftn1 (Raftlin 1) to inhibit M1 macrophages’ activation.ConclusionsThe enterobacterial metabolite norharman can decrease HDACs activity to increase H3K9/14 acetylation of Rftn1, which inhibits M1 macrophage activation and restores the balance of lipid metabolism to relieve multiple inflammatory responses. Therefore, norharman may be a promising prodrug to block AP aggravation.Graphical

D-Psicose intake exacerbates dextran sulfate sodium-induced colitis in mice through alteration in the gut microbiota and dysfunction of mucosal barrier

D-Psicose, as a low-calorie rare sugar, has attracted a lot of attention in recent years for alternating to sucrose. The anti-obesity effect of D-psicose has been extensively confirmed in previous studies, however, the impact of D-psicose on colitis remains vague. Here, we firstly evaluated the effect of the D-psicose prophylactic intervention on dextran sulfate sodium-induced colitis in C57BL/6 mice. The pathological symptoms, inflammatory cytokines levels, gut microbiota composition, short chain fatty acids (SCFAs) production and colonic barrier integrity were comprehensively evaluated. The results confirmed that D-psicose intervention aggravated colitis, characterized by the exacerbation of colon shortening, increase of colonic inflammatory infiltration, and marked exaltation of disease activity indices and IL-6, IL-1β and TNF-α levels. Further, the dysfunction of gut microbiota was identified in the psicose group. The abundance of pro-inflammatory bacteria Lachnospiraceae_NK4A136_group was significantly up-regulated while the abundance of probiotics Akkermansia and Lactobacillus were significantly down-regulated in the psicose group compared to the model group. Moreover, the production of SCFAs was suppressed in the psicose group, accompanied by a decrease in the level of mucin 2 (Muc-2). Collectively, the underlying mechanism of the exacerbation of colitis by D-psicose intervention might be attributed to microbiota dysfunction accompanied by the reduction of SCFAs, which leads to the damage of the mucosal barrier and the intensification of inflammatory invasion.

Shaoyao-Gancao-Tang regulates the T-helper-type 1/T-helper-type 2 ratio in the lung and gut and alters gut microbiota in rats with ovalbumin-induced asthma.

Shaoyao-Gancao Tang (SGT) is a traditional Chinese medicine formulation. It has been used to treat kinds of pain and to alleviate asthma in clinic. However, the mechanism of action is not known. To investigate the anti-asthma effect of SGT involving modulation of the T-helper type 1 (Th1) Th1/Th2 ratio in the gut-lung axis and alteration of the gut microbiota (GM) in rats with ovalbumin (OVA)-induced asthma. The main constituents of SGT were analyzed by high-performance liquid chromatography (HPLC). A model of asthma was established in rats by OVA-induced allergen challenge. Rats suffering from asthma (RSAs) were treated with SGT (2.5, 5.0 and 10.0 g/kg), dexamethasone (1 mg/kg) or physiologic saline for 4 weeks. The level of immunoglobulin (Ig)E in bronchoalveolar lavage fluid (BALF) and serum was determined by enzyme-linked immunosorbent assay. Histology of lung and colon tissues was investigated using staining (hematoxylin and eosin and periodic acid-Schiff). The Th1/Th2 ratio and levels of cytokines (interferon (IFN)-γ and interleukin (IL)-4) in the lung and colon were detected by immunohistochemistry. The GM in fresh feces was analyzed by 16 S rRNA gene sequencing. Twelve main constituents (gallic acid, albiflorin, paeoniflorin, liquiritin apioside, liquiritin, benzoic acid, isoliquiritin apioside, isoliquiritin, liquiritigenin, glycyrrhizic acid, isoliquiritigenin and glycyrrhetinic acid) of SGT were simultaneously determined by HPLC. SGT treatment (5.0 and 10.0 g/kg) was found to reduce the IgE level (a vital marker of hyper-responsiveness) in BALF and serum, improve typical morphological changes (inflammatory-cell infiltration and goblet cell metaplasia) in the lung and colon, alleviate airway remodeling (including bronchiostenosis and basement membrane-thickening) in the lung, significantly decrease the IL-4 level and increase the IFN-γ level in the lung and colon, which led to restoration of the IFN-γ/IL-4 ratio. The dysbiosis and dysfunction of GM in RSAs were modulated by SGT. The abundance of bacteria of the genera Ethanoligenens and Harryflintia was increased in RSAs and was decreased upon SGT treatment. The abundance of Family_XIII_AD3011_group was decreased in RSAs and increased upon SGT treatment. Moreover, SGT therapy increased the abundance of bacteria of the genera Ruminococcaceae_UCG-005 and Candidatus_Sacchrimonas, and decreased that of Ruminococcus_2 and Alistipes. SGT ameliorated rats with OVA-induced asthma via regulation of the Th1/Th2 ratio in the lung and gut, and modulated the GM.

Magnesium lithospermate B ameliorates diabetic nephropathy by suppressing the uremic toxin formation mediated by gut microbiota

Diabetic nephropathy (DN) is a major cause of renal failure and urgently necessitates new therapeutic strategies. Magnesium lithospermate B (MLB) showed a good protective effect on kidney injure by oral administration, despite its extremely low bioavailability. The current study aimed to investigate its gut microbiota-targeted mechanism to explain the paradoxical properties of pharmacodynamics and pharmacokinetics. Here we show that MLB alleviated DN by recovering the dysfunction of gut microbiota and their associated metabolites in colon content, such as short-chain fatty acids and amino acids. Moreover, MLB significantly decreased uremic toxin levels in plasma, especially the p-cresyl sulfate. We further discovered that MLB could affect the metabolism of p-cresyl sulfate by suppressing the formation of its intestinal precursors, i.e. the microbiota-mediated conversion from 4-hydroxyphenylacetate to p-cresol. In addition, the inhibition effects of MLB were confirmed. MLB and its metabolite danshensu exhibited inhibitory effects on p-cresol formation mediated by three strains belonging to the genus Clostridium, Bifidobacterium, and Fusobacterium, respectively. Meanwhile, MLB decreased the levels of p-cresyl sulfate in plasma and p-cresol in feces caused by rectal administration of tyrosine in mice. To summarize, the results indicated that MLB ameliorated DN through modulating gut microbiota-associated p-cresyl sulfate metabolism. Together, this study provides new insights on the microbiota-targeted mechanism of MLB in intervening DN and a new strategy in lowering plasma uremic toxins by blocking the formation of their precursors in intestine.

Soluble dietary fiber from Prunus persica dregs alleviates gut microbiota dysfunction through lead excretion.

Lead (Pb) can pollute the environment and food through air, water and other means, resulting in human exposure to lead pollution, and there is no threshold level of lead toxicity, even small doses of lead will have a range of harmful effects in humans. This study demonstrates for the first time that dietary addition of soluble dietary fiber (SDF) from Prunus persica dregs reduces lead bioaccumulation in mice, and eliminates lead through feces. Compared with lead-exposed mice, SDF supplementation effectively prevented lead-induced changes in colon tissue, and increased expression of tight junction proteins (ZO-1 and occludin). We analyzed the effects of SDF on gut microbiota and metabolites by a combination of 16S rRNA high-throughput sequencing and untargeted metabolomics. The results showed that SDF altered lead-induced perturbations in the layout and structure of the gut microbiota, including increased Desulfovibrio and Alistipes abundance and decreased Bacteroidetes abundance. Meanwhile, we also provide evidence that SDF supplementation alters the levels of amino acids, bile acids, and lipids in the gut, and that these metabolites are closely associated with microbiota with good lead binding capacity. Therefore, we speculate that SDF has the potential to provide a protective effect against intestinal damage by promoting lead excretion.

Gut microbiota from sigma-1 receptor knockout mice induces depression-like behaviors and modulates the cAMP/CREB/BDNF signaling pathway.

Depression is a common mental disorder that affects approximately 350 million people worldwide. Much remains unknown about the molecular mechanisms underlying this complex disorder. Sigma-1 receptor (Sig-1R) is expressed at high levels in the central nervous system. Increasing evidence has demonstrated a close association between the Sig-1R and depression. Recently, research has suggested that the gut microbiota may play a crucial role in the development of depression. Male Sig-1R knockout (Sig-1R KO) and wild-type (WT) mice were used for this study. All transgenic mice were of a pure C57BL/6J background. Mice received a daily gavage of vancomycin (100 mg/kg), neomycin sulfate (200 mg/kg), metronidazole (200 mg/kg), and ampicillin (200 mg/kg) for one week to deplete gut microbiota. Fecal microbiota transplantation (FMT) was conducted to assess the effects of gut microbiota. Depression-like behaviors was evaluated by tail suspension test (TST), forced swimming test (FST) and sucrose preference test (SPT). Gut microbiota was analyzed by 16s rRNA and hippocampal transcriptome changes were assessed by RNA-seq. We found that Sig-1R knockout induced depression-like behaviors in mice, including a significant reduction in immobility time and an increase in latency to immobility in the FST and TST, which was reversed upon clearance of gut microbiota with antibiotic treatment. Sig-1R knockout significantly altered the composition of the gut microbiota. At the genus level, the abundance of Alistipes, Alloprevotella, and Lleibacterium decreased significantly. Gut microbiota dysfunction and depression-like phenotypes in Sig-1R knockout mice could be reproduced through FMT experiments. Additionally, hippocampal RNA sequencing identified multiple KEGG pathways that are associated with depression. We also discovered that the cAMP/CREB/BDNF signaling pathway is inhibited in the Sig-1R KO group along with lower expression of neurotrophic factors including CTNF, TGF-α and NGF. Fecal bacteria transplantation from Sig-1R KO mice also inhibited cAMP/CREB/BDNF signaling pathway. In our study, we found that the gut-brain axis may be a potential mechanism through which Sig-1R regulates depression-like behaviors. Our study provides new insights into the mechanisms by which Sig-1R regulates depression and further supports the concept of the gut-brain axis.

Qingrequzhuo capsule alleviated methionine and choline deficient diet-induced nonalcoholic steatohepatitis in mice through regulating gut microbiota, enhancing gut tight junction and inhibiting the activation of TLR4/NF-κB signaling pathway.

Qingrequzhuo capsule (QRQZ), composed of Morus alba L., Coptis chinensis Franch., Anemarrhena asphodeloides Bunge, Alisma plantago-aquatica subsp. orientale (Sam.) Sam., Citrus × aurantium L., Carthamus tinctorius L., Rheum palmatum L., Smilax glabra Roxb., Dioscorea oppositifolia L., Cyathula officinalis K.C.Kuan, has been used to treat nonalcoholic steatohepatitis (NASH) in clinic. However, the mechanism of QRQZ on NASH remains unclear. Recent studies have found that the dysfunction of gut microbiota could impair the gut barrier and induce the activation of TLR4/NF-kB signaling pathway, and further contribute to the inflammatory response in NASH. Modulating the gut microbiota to reduce inflammation could prevent the progression of NASH. In this study, a mouse model of NASH was generated by methionine and choline deficient diet (MCD) and treated with QRQZ. First, we evaluated the therapeutic effects of QRQZ on liver injury and inflammation in the NASH mice. Second, the changes in the gut microbiota diversity and abundance in each group of mice were measured through 16S rRNA sequencing. Finally, the effects of QRQZ on gut mucosal permeability, endotoxemia, and liver TLR4/NF-kB signaling pathway levels were examined. Our results showed that QRQZ significantly reduced the lipid accumulation in liver and the liver injury in NASH mice. In addition, QRQZ treatment decreased the levels of inflammatory cytokines in liver. 16S rRNA sequencing showed that QRQZ affected the diversity of gut microbiota and a f f e c t e d t h e r e l a t i v e a b u n d a n c e s o f D u b o s i e l l a , Lachnospiraceae_NK4A136_group, and Blautiain NASH mice. Besides, QRQZ could increase the expression of tight junction proteins (zonula occludens-1 and occludin) in gut and decrease the lipopolysaccharide (LPS) level in serum. Western blot results also showed that QRQZ treatment decreased the protein expression ofTLR4, MyD88 and the phosphorylation of IkB and NF-kBp65 and qPCR results showed that QRQZ treatment down-regulated the gene expression of interleukin (IL)-1b, IL-6, and tumor necrosis factor (TNF)-a in liver. In conclusion, our study demonstrated that QRQZ could reduce the lipid accumulation and inflammatory response in NASH model mice. The mechanisms of QRQZ on NASH were associated with modulating gut microbiota, thereby inducing the tight junction of gut barrier, reducing the endotoxemia and inhibiting the activation of TLR4/NFkB signaling pathway in liver.

Improvement of myocardial injury and gut microbiota disturbance in type 2 diabetic mice by inulin with various degrees of polymerization

This study is to explore the effects of low-performance inulin (SI, DP < 10) and high-performance inulin (HI, DP > 10) on myocardial injury in type 2 diabetic mice fed a high-fat diet (HFD) and its underlying mechanism. Six weeks of supplementation of type 2 diabetic mice with HI significantly improved blood glucose, insulin, and triglyceride levels in comparison with SI (p < 0.05). HI had more advantageous effects in ameliorating myocardial injury by suppressing TNF-α, IL-1β, and CK-MB and promoting SDF-1β than SI. Compared to SI, HI more significantly reduced the abundance of Firmicutes from 60.5% to 36.3% in type 2 diabetic mice fed a HFD and increased the abundance of Muribaculum, Blautia and Ruminococcaceae UCG−011 at the genus level (p < 0.05). Metabolomics revealed that both SI and HI supplementation regulated tryptophan metabolism, bile acid metabolism, sphingolipid metabolism, and arachidonic acid metabolism, whereas HI supplementation increased prostaglandin h2 compared to SI. In summary, HI exhibited superior positive regulation of myocardial injury and gut microbiota dysfunction compared to SI.