Intestinal Microbiota Dysbiosis Research Articles

The gut microbial metabolite indole-3-aldehyde alleviates impaired intestinal development by promoting intestinal stem cell expansion in weaned piglets

BackgroundWeaning stress-induced diarrhea is widely recognized as being associated with gut microbiota dysbiosis. However, it has been challenging to clarify which specific intestinal microbiota and their metabolites play a crucial role in the antidiarrhea process of weaned piglets.ResultsIn this study, we first observed that piglets with diarrhea exhibited a lower average daily gain and higher diarrhea score, and elevated levels of lipopolysaccharide (LPS) and D-lactate (D-LA) compared to healthy piglets. Subsequently, we analyzed the differences in intestinal microbial composition and metabolite levels between healthy and diarrheal weaned piglets. Diarrheal piglets demonstrated intestinal microbiota dysbiosis, characterized primarily by a higher Firmicutes to Bacteroidota ratio, a deficiency of Lactobacillus amylovorus and Lactobacillus reuteri, and an increased abundance of Bacteroides sp.HF-5287 and Bacteroides thetaiotaomicron. Functional profiling of the gut microbiota based on Kyoto Encyclopedia of Genes and Genomes (KEGG) data was performed, and the results showed that tryptophan metabolism was the most significantly inhibited pathway in piglets with diarrhea. Most tryptophan metabolites were detected at lower concentrations in diarrheal piglets than in healthy piglets. Furthermore, we explored the effects of dietary indole-3-aldehyde (IAld), a key tryptophan metabolite, on intestinal development and gut barrier function in weaned piglets. Supplementation with 100 mg/kg IAld in the diet increased the small intestine index and improved intestinal barrier function by promoting intestinal stem cell (ISC) expansion in piglets. The promotion of ISC expansion by IAld was also confirmed in porcine intestinal organoids.ConclusionsThese findings revealed that intestinal microbial tryptophan metabolite IAld alleviates impaired intestinal development by promoting ISC expansion in weaned piglets.

Angiotensin-(1-7) improves intestinal microbiota disturbances and modulates fecal metabolic aberrations in acute pancreatitis.

Acute pancreatitis (AP) is a serious health problem that dysregulates intestinal microbiota. Angiotensin (Ang)-(1-7) plays a protective role in the intestinal barrier in AP, but its effect on intestinal microbiota remains clear. To investigate the impact of Ang-(1-7) on AP-induced intestinal microbiota disorder and metabolites. We collected blood and fecal samples from 31 AP patients within 48 h after admission to the hospital, including 11 with mild AP (MAP), 14 with moderately severe AP (MSAP), six with severe AP (SAP). Mice were divided into four groups: control, AP, AP + Ang-(1-7) via tail vein injection, and AP + Ang-(1-7) via oral administration. The samples of mice were collected 12 h after AP. Pancreatic and intestinal histopathology scores were analyzed using the Schmidt and Chiu scores. Fecal microbiota and metabolites analysis was performed via 16S rDNA sequencing and nontargeted metabolomics analysis, respectively. In patients, the abundance of beneficial bacteria (Negativicutes) decreased and pathogenic bacteria (Clostridium bolteae and Ruminococcus gnavus) increased in SAP compared with MAP. Ang-(1-7) levels were associated with changes in the microbiota. There were differences in the intestinal microbiota between control and AP mice. Ang-(1-7) attenuated intestinal microbiota dysbiosis in AP mice, reflecting in the increase in beneficial bacteria (Odoribacter and Butyricimonas) than AP, as well as pancreatic and intestinal injuries. Oral administration of Ang-(1-7) reversing AP-induced decreases in metabolisms: secondary bile acids, emodin, and naringenin. Ang-(1-7) may improve intestinal microbiota dysbiosis and modulate fecal metabolites in AP, thereby reducing the damage of AP.

Delving the depths of 'terra incognita' in the human intestine - the small intestinal microbiota.

The small intestinal microbiota has a crucial role in gastrointestinal health, affecting digestion, immune function, bile acid homeostasis and nutrient metabolism. The challenges of accessibility at this site mean that our knowledge of the small intestinal microbiota is less developed than of the colonic or faecal microbiota. Here, we summarize the features and fluctuations of the microbiota along the small intestinal tract, focusing on humans, and discuss physicochemical factors and assessment methods, including the technical challenges of investigating the low microbial biomass of the proximal small bowel. We highlight the essential protective mechanisms of the small intestine, including motility, the paracellular barrier and mucus, and secretory immunity, to show their roles in limiting excessive exposure of host tissues to microbial metabolites. We address current knowledge gaps, particularly the variability among individuals, the effects of dysbiosis of the small intestinal microbiota on health and how different taxa in small intestinal microbiota could compensate for each other functionally.

GYY4137, as a slow-releasing H2S donor, ameliorates sodium deoxycholate-induced chronic intestinal barrier injury and gut microbiota dysbiosis.

Numerous studies have revealed that a long-term high-fat diet can raise intestinal deoxycholate acid concentration, which can harm intestinal mucosal barrier function in several ways. This study aims to verify the protective effect of GYY4137, as a slow-releasing H2S donor, on microbiome disturbance and the chronic injury of the intestinal mucosal barrier function caused by sodium deoxycholate. Caco-2 monolayer and mouse models were treated with a relatively high concentration of sodium deoxycholate (1.0mM and 0.2%, respectively) for longer periods (32h and 12 weeks, respectively) to understand the effects of GYY4137 on sodium deoxycholate-induced chronic intestinal barrier dysfunction and its fundamental mechanisms. A relatively long period of sodium deoxycholate treatment can remarkably increase the intestinal barrier permeability, alter the distribution and expression of tight junction proteins and generate the production of pro-inflammatory cytokines (TNF-α and IL-1β) in the Caco-2 monolayers and mouse models. Moreover, it can activate the MLCK-P-MLC2 pathway in the Caco-2 monolayers, which was further confirmed using RNA sequencing. The body weight, intestinal barrier histological score, and TUNEL index of sodium deoxycholate-treated mice worsened. In addition, an induced microbiome imbalance was observed in these mice. The above variations can be reversed with the administration of GYY4137. This study demonstrates that GYY4137 ameliorates sodium deoxycholate-induced chronic intestinal barrier injury by restricting the MLCK-P-MLC2 pathway while elevating the expression level of tight junction proteins, anti-apoptosis and maintaining the microbiome's homeostasis.

Giardia spp.-induced microbiota dysbiosis disrupts intestinal mucin glycosylation

ABSTRACT Infection with the protozoan parasite Giardia duodenalis (syn. intestinalis, lamblia) has been associated with intestinal mucus disruptions and microbiota dysbiosis. The mechanisms remain incompletely understood. Mucus consists primarily of densely glycosylated mucin glycoproteins. Mucin O-glycans influence mucus barrier properties and mucin–microbe interactions and are frequently altered during disease. In this study, we observed time-dependent and regiospecific alterations to intestinal mucin glycosylation patterns and the expression of mucin-associated glycosyltransferase genes during Giardia infection. Glycosylation alterations were observed in Giardia-infected mice in the upper small intestine, the site of parasite colonization, and in the distal colon, where active trophozoites were absent. Alterations occurred as early as day 2 post-infection and persisted in mice after parasite clearance. We also observed small intestinal goblet cell hyperplasia and thinning of the distal colon mucus barrier during early infection, and microbiota alterations and altered production of cecal SCFAs. Giardia-induced alterations to mucin glycosylation were at least in part dependent on microbiota dysbiosis, as transplantation of a dysbiotic mucosal microbiota collected from Giardia-infected mice recapitulated some alterations. This study describes a novel mechanism by which Giardia alters intestinal mucin glycosylation, and implicates the small intestinal microbiota in regulation of mucin glycosylation patterns throughout the gastrointestinal tract.

Unveiling the impact of dietary components on tropomyosin-induced anaphylaxis: Analysis from the perspective of intestinal barrier

There exists a strong correlation between diets and the increased incidence of food allergy. However, the precise mechanism underlying the impact of dietary fat, sucrose, or inulin on tropomyosin (TM)-induced anaphylaxis remains unclear. Therefore, the murine model of TM-induced food allergy fed with a high-fat, high-sucrose, high-dietary-fiber, or control diet was used to explore the mechanism. The high-sucrose diet was found to result in glucose and lipid metabolism disorders, as well as heightened allergic reactions characterized by decreased specific IgG2a levels and increased levels of specific IgE, specific IgG1, IL-4, peritoneal albumin, histamine, and mast cell degranulation. The aggravating impact of a high-fat diet on allergic reactions was weaker than that of a high-sucrose diet. It was attributed to the destruction of the intestinal mucus layer, the decreased expression of zona occludens 1 and occludin, and the increased release of IL-25 and IL-33. Meanwhile, a high sucrose intake led to dysbiosis of intestinal microbiota, and increased the abundance of Roseburia and norank_f_Oscillospiraceae, contributing to a further impairment of intestinal barrier function. Additionally, inulin intake significantly reduced the level of specific IgG1 and peritoneal albumin due to its protective effect on the intestinal barrier. To sum up, a better understanding of the relationship between diet and immune responses will be crucial for developing effective strategies for managing TM-induced food allergy.

Ternary inulin hydrogel with long-term intestinal retention for simultaneously reversing IBD and its fibrotic complication.

Excessive accumulation of reactive oxygen and nitrogen species (RONS) and dysbiosis of intestinal microbiota are pivotal symptoms for inflammatory bowel disease (IBD) and its associated complications, such as intestinal fibrosis. This research introduces a probiotic inulin hydrogel loaded with polypyrrole (PPy) nanozymes and antifibrotic drug pirfenidone (PFD) (PPy/PFD@Inulin gel) designed for the concurrent amelioration of IBD and its fibrotic complication. Upon oral administration, the inulin gel matrix could extend the gastrointestinal residence time of PPy nanozymes and PFD, facilitating the efficient reduction of pro-inflammatory cytokine levels and enhancement of the intestinal epithelial barrier repair as well as the suppression of intestinal fibrosis through sustained RONS scavenging, modulation of gut microbiota and attenuation of the TGF-β/Smad signaling pathway to inhibit fibroblast proliferation. Notably, the PPy/PFD@Inulin gel demonstrated significant prophylactic and therapeutic efficacy in acute and chronic colitis as well as intestinal fibrosis induced by dextran sodium sulfate (DSS) in mouse models. Thus, the engineered ternary PPy/PFD@Inulin gel offered a pioneered paradigm for simultaneous reversal of IBD and its associated complications, such as intestinal fibrosis, in a single therapeutic regimen.

Role of Gut Microbiome in the Pathogenesis and Progression of Acute Pancreatitis

Introduction and purpose Acute pancreatitis (AP) is one of the most common abdominal conditions leading to hospital admissions worldwide. It is characterized by an inflammatory reaction triggered by the premature activation of trypsinogen and other enzymes, resulting in pancreatic autodigestion. While most cases of AP are mild and self-limiting, approximately 15-20% of patients develop severe AP with organ failure, which is associated with a mortality rate of up to 30%. In recent years, the impact of intestinal microbiome dysregulation on various diseases has been increasingly debated. This study aims to summarize the current knowledge regarding the role of intestinal microbiota dysbiosis in the pathogenesis and progression of acute pancreatitis. Material and methods This review is based on materials collected from the PubMed database. We conducted a search using the following keywords: "acute pancreatitis," "microbiome," and "dysbiosis," focusing on articles published between 2018 and 2024. Results Studies have demonstrated a relationship between gut dysbiosis and various disorders, including digestive, metabolic, and even cancer-related conditions. It is well-established that the pancreas is closely connected to the intestines, and its exocrine function can influence the composition of the gut microbiome. This interaction is often referred to as the “gut–pancreas axis.” Conclusion The interaction between the pancreas and intestinal microbiota is believed to play a role in the pathophysiology of acute pancreatitis. Further research into this relationship could lead to the development of new diagnostic and therapeutic strategies.

Current Landscape and Evolving Therapies for Primary Biliary Cholangitis

Primary Biliary Cholangitis (PBC) is a chronic autoimmune liver disorder characterized by progressive cholestatic that, if untreated, can progress to liver fibrosis, cirrhosis and liver decompensation requiring liver transplant. Although the pathogenesis of the disease is multifactorial, there is a consensus that individuals with a genetic predisposition develop the disease in the presence of specific environmental triggers. A dysbiosis of intestinal microbiota is increasingly considered among the potential pathogenic factors. Cholangiocytes, the epithelial cells lining the bile ducts, are the main target of a dysregulated immune response, and cholangiocytes senescence has been recognized as a driving mechanism, leading to impaired bile duct function, in disease progression. Bile acids are also recognized as playing an important role, both in disease development and therapy. Thus, while bile acid-based therapies, specifically ursodeoxycholic acid and obeticholic acid, have been the cornerstone of therapy in PBC, novel therapeutic approaches have been developed in recent years. In this review, we will examine published and ongoing clinical trials in PBC, including the recently approved peroxisome-proliferator-activated receptor (PPAR) agonist, elafibranor and seladelpar. These novel second-line therapies are expected to improve therapy in PBC and the development of personalized approaches.

Vitamin B12 ameliorates gut epithelial injury via modulating the HIF-1 pathway and gut microbiota

Inflammatory bowel diseases (IBDs) are immune chronic diseases characterized by recurrent episodes, resulting in continuous intestinal barrier damage and intestinal microbiota dysbiosis. Safe strategies aimed at stabilizing and reducing IBDs recurrence have been vigorously pursued. Here, we constructed a recurrent intestinal injury Drosophila model and found that vitamin B12 (VB12), an essential co-factor for organism physiological functions, could effectively protect the intestine and reduce dextran sulfate sodium-induced intestinal barrier disruption. VB12 also alleviated microbial dysbiosis in the Drosophila model and inhibited the growth of gram-negative bacteria. We demonstrated that VB12 could mitigate intestinal damage by activating the hypoxia-inducible factor-1 signaling pathway in injured conditions, which was achieved by regulating the intestinal oxidation. In addition, we also validated the protective effect of VB12 in a murine acute colitis model. In summary, we offer new insights and implications for the potential supportive role of VB12 in the management of recurrent IBDs flare-ups.

Diagnosis and management of Clostridioides difficile in inflammatory bowel disease.

Patients with IBD have an increased risk for Clostridioides difficile infection (CDI), which can lead to worse IBD outcomes. The diagnosis of CDI in IBD patients is complicated by higher C. difficile colonization rates and shared clinical symptoms of intestinal inflammation. Traditional risk factors for CDI, such as antibiotic exposure, may be lacking in IBD patients due to underlying intestinal microbiota dysbiosis. While CDI disproportionately affects people with IBD, patients with IBD are typically excluded from CDI clinical trials creating a knowledge gap in the diagnosis and management of these two diseases. This narrative review aims to provide a comprehensive overview of the diagnosis, treatment, and prevention of CDI in IBD patients. Distinguishing CDI from C. difficile colonization in the setting of an IBD exacerbation is important to avoid treatment delays. When CDI is diagnosed, extended courses of anti-C. difficile antibiotics may lead to better CDI outcomes. Regardless of a diagnosis of CDI, the presence of C. difficile in an IBD patient should prompt a disease assessment of the underlying IBD. Microbiota-based therapies and bezlotoxumab appear to be effective in preventing CDI recurrence in IBD patients. Patients with IBD should be considered high risk for CDI recurrence and evaluated for a preventative strategy when diagnosed with CDI. Ultimately, the co-management of CDI in an IBD patient requires a nuanced, patient-specific approach to distinguish CDI from C. difficile colonization, prevent CDI recurrence, and manage the underlying IBD.

Effects of fecal microbiota transplantation on clinical outcomes and fecal microbiota of foals with diarrhea.

Diarrhea in foals can be associated with disruption of the intestinal microbiota (dysbiosis). Effective management of intestinal dysbiosis in foals has not been demonstrated. Fecal microbiota transplantation (FMT) in foals with diarrhea influences the intestinal microbiota and improves clinical and clinicopathological outcomes. Twenty-five foals <6 months of age with diarrhea and systemic inflammatory response syndrome at 3 veterinary hospitals. A prospective randomized placebo-controlled cohort study. Foals in the FMT group (n = 19) or control group (n = 9) received FMT or electrolyte solution once daily for 3 days. Fecal samples were obtained on Day 0 (D0), D1, D2, D3, and D7. Within group and between group data analyses were performed for clinical, clinicopathological, and microbiota variables. Treatment had no effect on survival (FMT 79%; control 100%, P = .3) or resolution of diarrhea (FMT 68%; control 55%, P = .4). On D3, the white blood cell count of the FMT group was lower than the control group (D3 FMT group median 6.4 g/L [5-8.3 g/L]; D3 control group median 14.3 g/L [6.7-18.9 g/L] P = .04). Heart rate reduced over time in the FMT group (D0 median 80 bpm [60-150 bpm]; D2 median 70 bpm [52-110 bpm] [P = .005]; and D3 median 64, [54-102 bpm] [P < .001]). Phylum Verrucomicrobiota, genus Akkermansia, and family Prevotellaceae were enriched in the FMT group on D1 (linear discriminate analysis > 4). In foals with diarrhea, FMT appears safe and can be associated with some clinical and microbiota changes suggestive of beneficial effect.

Conversation between host and gut microbiota unveils a “silver bullet” therapeutic option for chemotherapy

Chemotherapy is associated with the induction of intestinal microbiota dysbiosis and gastrointestinal injuries. In this Cell Host & Microbe issue, Anderson etal. demonstrate that chemotherapy-induced epithelial cell apoptosis drives microbiota imbalance and transcriptional rewiring, which in turn delays intestinal recovery.

Synthesis of Ganoderic Acids Loaded Zein-Chitosan Nanoparticles and Evaluation of Their Hepatoprotective Effect on Mice Given Excessive Alcohol.

Ganoderma lucidum, used in East Asia for its health benefits, contains ganoderic acids (GA) which have various pharmacological activities but are limited by poor water solubility and low oral bioaccessibility. This study synthesized and characterized ganoderic acids loaded zein-chitosan nanoparticles (GA-NPs), and investigated its advantages in alleviating alcoholic liver injury (ALI) in mice model. The GA-NPs demonstrated high encapsulation efficiency (92.68%), small particle size (177.20 nm), and a +29.53 mV zeta potential. The experimental results of alcohol-induced liver injury mouse model showed that GA-NPs significantly improved liver metabolic function, reduced alcohol-induced liver oxidative stress in liver by decreasing lactate dehydrogenase activity and malondialdehyde level, while increasing the activities of liver antioxidant enzymes and alcohol dehydrogenase. Moreover, GA-NPs were favorable to ameliorate intestinal microbiota dysbiosis in mice exposed to alcohol by increasing the proportion of probiotics such as Romboutsia, Faecalibaculum, Bifidobacterium and Turicibacter, etc., which were highly correlated with the improvement of liver function. Furthermore, GA-NPs modulated the mRNA expression related to ethanol metabolism, oxidative stress and lipid metabolism. Conclusively, this study revealed that GA-NPs have stronger hepatoprotective effects than non-encapsulated ganoderic acids on alleviating ALI by regulating intestinal microbiota and liver metabolism.

Neurotoxicity and intestinal microbiota dysbiosis induced by per- and polyfluoroalkyl substances in crucian carp (Carassius auratus)

Per- and polyfluoroalkyl substances (PFAS) have been called "forever chemicals" due to their inherent chemical stability. Their potential toxic effects on aquatic animals and health risk assessments have not been fully elucidated. In this study, we investigated the toxic effects of PFASs at environmentally relevant concentrations (200 ng/L) on crucian carp (Carassius auratus). The results showed that PFAS reduced the comfort behaviour of crucian carp and was associated with reduced levels of acetylcholinesterase and dopamine in the brain. PFAS exposure also decreased the activities of total superoxide dismutase, catalase and glutathione peroxidase, while increasing the levels of malondialdehyde. PFAS caused over-expression of the pro-inflammatory cytokines TNF-α, IFN-γ and stress-related genes Caspase-3, HSP-70 in the fish brain. Pathological staining showed that PFAS caused multifocal demyelination and perineural vacuolization in brain, intestinal tissue also showed reduced villus length and focal damage. PFASs altered the composition of the gut microbiota of crucian carp, significantly increasing the abundance of potentially pathogenic bacteria and the potential pathogenicity of the microbiota. It is suggested that PFASs may cause varying degrees of tissue damage by destabilising the gut microbiota. These results provide insights for assessing the toxicity of PFAS contaminants at aquatic environmental concentrations.

Epicatechin and β-glucan from whole highland barley grain ameliorates hyperlipidemia associated with attenuating intestinal barrier dysfunction and modulating gut microbiota in high-fat-diet-fed mice

Hyperlipidemia is associated with intestinal barrier dysfunction and gut microbiota dysbiosis. Here, we aimed at investigating whether epicatechin (EC) and β-glucan (BG) from whole highland barley grain alleviated hyperlipidemia associated with ameliorating intestinal barrier dysfunction and modulating gut microbiota dysbiosis in high-fat-diet-induced mice. It was observed that EC and BG significantly improved serum lipid disorders and up-regulated expression of PPARα protein and genes. Supplementation of EC and BG attenuated intestinal barrier dysfunction via promoting goblet cells proliferation and tight junctions. Supplementation of EC and BG prevented high fat diet-induced gut microbiota dysbiosis via modulating the relative abundance of Ruminococcaceae, Lactobacillus, Desulfovibrio, Lactococcus, Allobaculum and Akkermansia, and the improving of short chain fatty acid contents. Notably, combination of EC and BG showed synergistic effect on activating PPARα expression, improving colonic physical barrier dysfunction and the relative abundance of Lactobacillus and Desulfovibrio, which may help explain the effect of whole grain highland barley on alleviating hyperlipidemia.

Prefeeding of berberine alleviates waterborne copper-induced hepatic oxidative stress, lipid deposition, and intestinal microbiota dysbiosis in yellow catfish (Pelteobagrus fulvidraco)

Copper (Cu) contamination is a common issue in aquaculture and normally leads to hepatic and intestinal damage in fish. Due to the effective lipid-lowering, antioxidative, and intestinal microbiota-maintaining properties of berberine (BBR), it has the potential to be a feed additive to diminish Cu toxicity in fish. This study aimed to determine whether berberine could alleviate hepatic and intestinal damage in yellow catfish (Pelteobagrus fulvidraco) caused by waterborne Cu2+ exposure. The fish with the same weight (2.65 ± 0.25 g) were assigned to four groups: a control group (Con) that received a control diet for nine weeks; a Cu group, a BBR100 group, and a BBR400 group that received the control diet, 100 mg/kg berberine, and 400 mg/kg berberine for eight weeks, respectively, and after that, they were exposed to 0.8 mg/L Cu2+ for an additional week. The BBR100 and BBR 400 groups had significantly higher weight gain than the Cu group, but significantly lower hepatic and serum total cholesterol and triglyceride levels, and berberine treatment significantly improved intestinal and hepatic histological damage (P < 0.05). Berberine treatment significantly increased intestinal complement 3 and complement 4 levels but distinctly regulated hepatic and intestinal antioxidant enzyme activities while significantly reducing malondialdehyde levels compared to those in the Cu group. In addition, pretreatment with berberine significantly increased the expression levels of intestinal farnesoid X receptor (fxr) and fibroblast growth factor 19, as well as hepatic fxr, and downregulated the expression of its downstream lipogenesis genes (srebp1c, fas, and pparγ). Based on 16S rDNA analysis, the abundances of some probiotic bacteria (e.g., Lactobacillus) were elevated, but the abundances of some pathogenic bacteria (e.g., Morganella) decreased in the BBR400 group. At KEGG level 3, the pathway related to “Pathogenic Escherichia coli infection” was significantly enriched in the Cu group but significantly lower enriched in the BBR100 group. These findings indicated that berberine alleviated waterborne copper-induced hepatic and intestinal damage mainly by activating the FXR pathway, reducing oxidative stress and lipid deposition, and maintaining intestinal microbiota homeostasis in yellow catfish.

TMAO is involved in kidney-yang deficiency syndrome diarrhea by mediating the “gut-kidney axis”

BackgroundTrimethylamine-N-oxide (TMAO) is a harmful metabolite dependent on the intestinal microbiota and excreted through the kidneys. According to numerous investigations, rich circulation concentrations of TMAO have been linked to kidney and gastrointestinal disorders. Through the “gut-kidney axis” mediated by TMAO, this research attempted to clarify the microbiological causes of kidney-yang deficiency syndrome diarrhea. MethodsAdenine and Folium Sennae were used to create a mouse model of kidney-yang deficiency syndrome diarrhea. 16S rRNA sequencing was used to identify the traits of the intestinal mucosal microbiota. ELISA was used to assess TMAO, transforming growth factor-β1 (TGF-β1), interleukin-1β (IL-1β), and NOD-like receptor thermal protein domain associated protein 3 (NLRP3). Kidney tissue fibrosis was evaluated using Masson's trichrome staining, and immunohistochemical labeling was used to investigate the protein expression of occludin and Zonula Occludens-1(ZO-1) in small intestine tissue. Microbial activity was determined by using fluorescein diacetate (FDA) hydrolysis spectrophotometry. ResultsTMAO showed a positive correlation with NLRP3, IL-1β and TGF-β1, all of which exhibited substantial increases (P < 0.05). Significant renal fibrosis and decreased ZO-1 and occludin expression in small intestine tissues were detected in the model group. The sequencing results revealed alterations in both α and β diversities of small intestinal mucosal microbiota. Elevated TMAO concentrations were potentially associated with increasing Firmicutes/Bacteroidota (F/B) ratios, Streptococcus, Pseudomonas and unclassified Clostridia UCG 014, but with decreasing Rothia and RB41 abundances. ConclusionThis study establishes a link between intestinal microbiota dysbiosis and elevated TMAO concentrations. TMAO can activate inflammatory responses and cytokines, contributing to kidney-yang deficiency syndrome diarrhea via the “gut-kidney axis”. Moreover, TMAO may coincide with disruptions in the intestinal barrier and renal fibrosis. Dysfunction of the “gut-kidney axis” further elevates TMAO levels, perpetuating a vicious cycle.

Bacillus coagulans restores pathogen-induced intestinal dysfunction via acetate-FFAR2-NF-κB-MLCK-MLC axis in Apostichopus japonicus.

Skin ulceration syndrome (SUS) is currently the main disease threatening Apostichopus japonicus aquaculture due to its higher mortality rate and infectivity, which is caused by Vibrio splendidus. Our previous studies have demonstrated that SUS is accompanied by intestinal microbiota (IM) dysbiosis, alteration of short-chain fatty acids (SCFAs) content and the damage to the intestinal barrier. However, the mediating effect of IM on intestine dysfunction is largely unknown. Herein, we conducted comprehensive intestinal microbiota transplantation (IMT) to explore the link between IM and SUS development. Furthermore, we isolated and identified a Bacillus coagulans strain with an ability to produce acetic acid from both healthy individual and SUS individual with IM from healthy donors. We found that dysbiotic IM and intestinal barrier function in SUS recipients A. japonicus could be restored by IM from healthy donors. The B. coagulans strain could restore IM community and intestinal barrier function. Consistently, acetate supply also restores intestinal homeostasis of SUS-diseased and V. splendidus-infected A. japonicus. Mechanically, acetate was found to specifically bind to its receptor-free fatty acid receptor 2 (FFAR2) to mediate IM structure community and intestinal barrier function. Knockdown of FFAR2 by transfection of specific FFAR2 siRNA could hamper acetate-mediated intestinal homeostasis in vivo. Furthermore, we confirmed that acetate/FFAR2 could inhibit V. splendidus-activated NF-κB-MLCK-MLC signaling pathway to restore intestinal epithelium integrity and upregulated the expression of ZO-1 and Occludin. Our findings provide the first evidence that B. coagulans restores pathogen-induced intestinal barrier dysfunction via acetate/FFAR2-NF-κB-MLCK-MLC axis, which provides new insights into the control and prevention of SUS outbreak from an ecological perspective.IMPORTANCESkin ulceration syndrome (SUS) as a main disease in Apostichopus japonicus aquaculture has severely restricted the developmental A. japonicus aquaculture industry. Intestinal microbiota (IM) has been studied extensively due to its immunomodulatory properties. Short-chain fatty acids (SCFAs) as an essential signal molecule for microbial regulation of host health also have attracted wide attention. Therefore, it is beneficial to explore the link between IM and SUS for prevention and control of SUS. In the study, the contribution of IM to SUS development has been examined. Additionally, our research further validated the restoration of SCFAs on intestinal barrier dysfunction caused by SUS via isolating SCFAs-producing bacteria. Notably, this restoration might be achieved by inhibition of NF-κB-MLCK-MLC signal pathway, which could be activated by V. splendidus. These findings may have important implications for exploration of the role of IM in SUS occurrence and provide insight into the SUS treatment.

Effect of Urolithin A on the Improvement of Circadian Rhythm Dysregulation in Intestinal Barrier Induced by Inflammation.

Circadian rhythm plays an important role in intestinal homeostasis and intestinal immune function. Circadian rhythm dysregulation was reported to induce intestinal microbiota dysbiosis, intestinal barrier disruption, and trigger intestinal inflammation. However, the relationship between intestinal microbiota metabolites and the circadian rhythm of the intestinal barrier was still unclear. Urolithin A (UA), a kind of intestinal microbial metabolite, was selected in this study. Results showed UA influenced on the expression rhythm of the clock genes BMAL1 and PER2 in intestinal epithelial cells. Furthermore, the study investigated the effects of UA on the expression rhythms of clock genes (BMAL1 and PER2) and tight junctions (OCLN, TJP1, and CLND1), all of which were dysregulated by inflammation. In addition, UA pre-treatment by oral administration to female C57BL/6 mice showed the improvement in the fecal IgA concentrations, tight junction expression (Clnd1 and Clnd4), and clock gene expression (Bmal1 and Per2) in a DSS-induced colitis model induced using DSS treatment. Finally, the Nrf2-SIRT1 signaling pathway was confirmed to be involved in UA's effect on the circadian rhythm of intestinal epithelial cells by antagonist treatment. This study also showed evidence that UA feeding showed an impact on the central clock, which are circadian rhythms in SCN. Therefore, this study highlighted the potential of UA in treating diseases like IBD with sleeping disorders by improving the dysregulated circadian rhythms in both the intestinal barrier and the SCN.