Gut Microbiota Homeostasis Research Articles

The Wu-Shi-Cha formula protects against ulcerative colitis by orchestrating immunity and microbiota homeostasis

Ethnopharmacological relevanceUlcerative colitis (UC) has become a healthy burden worldwide due to its insidious onset and repetitive relapse, with a rather complex etiology, including inappropriate immune response, dysbiosis, genetic susceptibility, and unhealthy diets. The Wu-Shi-Cha (WSC) formula is a widely utilized drug to protect against gastrointestinal disorders. Aim of the studyThe study aspired to dissect the pertinent mechanisms of the WSC to treat UC. Materials and methodsNetwork pharmacology and weighted gene co-expression network analysis (WGCNA) were performed to predict the targets of WSC in the context of UC and colorectal cancer. Dextran sodium sulfate (DSS) was used to construct murine models of experimental colitis, and the WSC was given to colitis mice for 14 days. Feces and colon samples were subjected to 16S rRNA gene sequencing combined with liquid chromatography-mass spectrometry (LC-MS) and biochemical experiments, respectively. ResultsNetwork pharmacology analysis predicted that the WSC formula could orchestrate inflammation, infection, and tumorigenesis, and WGCNA based on The Cancer Genome Atlas (TCGA) database showed a potent anti-neoplastic effect of the WSC therapy for colorectal cancer. The WSC therapy rescued bursts of pro-inflammatory cytokines and colonic epithelial collapse in DSS-induced colitis mice. Moreover, the high dose of WSC treatment facilitated the alternative activation of peritoneal macrophages (Mφs) and these Mφs were conducive to the survival of intestinal stem cells (ISCs), and the disturbed homeostasis of gut microbiota was re-established after WSC treatment, as evidenced by the decreased colonization of pathological taxa in the fecal samples. ConclusionThe WSC formula suppresses inflammation and re-establishes the homeostasis of gut microbiota, thereby ameliorating colitis progression.

Bone marrow mesenchymal stem cells alleviate stress-induced hyperalgesia via restoring gut microbiota and inhibiting neuroinflammation in the spinal cord by targeting the AMPK/NF-κB signaling pathway

AimSpinal neuroinflammation contributes to the mechanism of stress-induced hyperalgesia (SIH). Recent research has demonstrated that bone marrow mesenchymal stem cells (BMSCs) alleviate chronic pain. However, what remains unidentified is whether BMSCs could improve hyperalgesia induced by chronic restraint stress (CRS). In another dimension, our previous study proved that gut microbiota played an important role in CRS-induced hyperalgesia in mice. Yet, whether BMSCs treatments change gut microbiota composition in CRS mice remains unexplored. Main methodsMechanical allodynia and thermal hyperalgesia were used to assess pain behavior. Composition of fecal samples were verified by 16S rRNA analysis. Western blot was used to investigate the expression of adenosine monophosphate-activated protein kinase (AMPK)/ nuclear factor kappa B (NF-κB) signaling pathway, pro-inflammatory cytokines [interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), IL-6], and the markers of microglia and astrocytes. The morphology of glia cells was evaluated by immunofluorescence staining. Key findingsCRS down-regulated phosphorylated AMPK (p-AMPK), up-regulated phosphorylated NF-κB p65 (p-NF-κB p65), activated microglia and astrocytes and promoted the secretion of IL-1β, TNF-α and IL-6 in the spinal cord. BMSCs alleviated CRS-induced hyperalgesia by inhibiting the activation of microglia and astrocytes and by reducing neuroinflammation via improving the disrupted AMPK/NF-κB pathway. Furthermore, BMSCs also raised the relative abundance of Muribaculaceae and Lachnospiraceae in CRS mice feces, which was significantly related to its effect of relieving hyperalgesia. SignificanceOur results support that BMSCs could alleviate CRS-induced hyperalgesia by reducing AMPK/NF-κB-dependent neuroinflammation in the spinal cord and restoring the homeostasis of gut microbiota.

Effects of maternal supplementation of fish oil during late gestation and lactation on growth performance, fecal microbiota structure and post-weaning diarrhoea of offspring piglets.

Homeostasis of gut microbiota is a critical contributor to growth and health in weaned piglets. Fish oil is widely reported to benefit health of mammals including preventing intestinal dysfunction, yet its protective effect during suckling-to-weaning transition in piglets remains undetermined. Low (30 g/d) and high (60 g/d) doses of n-3-rich fish oil were supplemented in sows from late gestation to lactation. Serum indicators and gut microbiota were determined to evaluate the effects of maternal fish oil on growth performance, immunity and diarrhea of piglets. DHA and EPA in the colostrum as well as serum of suckling and 1-week post-wean piglets were significantly and linearly increased by maternal supplementation of fish oil (P < 0.05). IGF1 and T3 in nursing and weaned piglets were significantly elevated by maternal fish oil (P < 0.05), and the increase of IGF1 was concerning the dosage of fish oil. Colostrum IgG, plasma IgG, IgM in suckling piglets, IgG, IgM and IgA in weaned piglets were significantly increase as maternal replenishment of fish oil increased (P < 0.05). Additionally, cortisol was significantly reduced in weaned pigs (P < 0.05), regardless of dosage. 16S rRNA sequencing revealed that α-diversity of fecal microbiota in nursery piglets, and fecal Lactobacillus genus, positively correlated with post-weaning IgA, was significantly increased by high dosage. Collectively, maternal fish oil during late pregnancy and lactation significantly promoted growth, enhanced immunity, and reduced post-weaning diarrhea in piglets, therefore facilitated suckling-to-weaning transition in piglets, which may be partially due to the altered gut microbial community.

Gut microbiota and fecal metabolic signatures in rat models of disuse-induced osteoporosis.

Assessing the correlation between gut microbiota (GM) and bone homeostasis has increasingly attracted research interest. Meanwhile, GM dysbiosis has been found to be associated with abnormal bone metabolism. However, the function of GM in disuse-induced osteoporosis (DIO) remains poorly understood. In our research, we evaluated the characteristics of GM and fecal metabolomics to explore their potential correlations with DIO pathogenesis. DIO rat models and controls (CON) underwent micro-CT, histological analyses, and three-point bending tests; subsequently, bone microstructures and strength were observed. ELISAs were applied for the measurement of the biochemical markers of bone turnover while GM abundance was observed using 16S rDNA sequencing. Metabolomic analyses were used to analyze alterations fecal metabolites. The potential correlations between GM, metabolites, and bone loss were then assessed. In the DIO group, the abundance of GM was significantly altered compared to that in the CON group. Moreover, DIO significantly altered fecal metabolites. More specifically, an abnormally active pathway associated with bile acid metabolism, as well as differential bacterial genera related to bone/tissue volume (BV/TV), were identified. Lithocholic acid, which is the main secondary bile acid produced by intestinal bacteria, was then found to have a relationship with multiple differential bacterial genera. Alterations in the intestinal flora and metabolites in feces, therefore, may be responsible for DIO-induced bone loss. The results indicated that changes in the abundance of GM abundance and fecal metabolites were correlated with DIO-induced bone loss, which might provide new insights into the DIO pathogenesis. The detailed regulatory role of GM and metabolites in DIO-induced bone loss needs to be explored further.

Longitudinal Study of the Effects of Flammulina velutipes Stipe Wastes on the Cecal Microbiota of Laying Hens.

Because antibiotics have been phased out of use in poultry feed, measures to improve intestinal health have been sought. Dietary fiber may be beneficial to intestinal health by modulating gut microbial composition, but the exact changes it induces remain unclear. In this study, we evaluated the effect of Flammulina velutipes stipe wastes (FVW) on the cecal microbiotas of laying chickens at ages spanning birth to 490 days. Using clonal sequencing and 16S rRNA high-throughput sequencing, we showed that FVW improved the microbial diversity when they under fluctuated. The evolvement of the microbiota enhanced the physiological development of laying hens. Supplementation of FVW enriched the relative abundance of Sutterella, Ruminiclostridium, Synergistes, Anaerostipes, and Rikenellaceae, strengthened the positive connection between Firmicutes and Bacteroidetes, and increased the concentration of short-chain fatty acids (SCFAs) in early life. FVW maintains gut microbiota homeostasis by regulating Th1, Th2, and Th17 balance and secretory IgA (S-IgA) level. In conclusion, we showed that FVW induces microbial changes that are potentially beneficial for intestinal immunity. IMPORTANCE Dietary fiber is popularly used in poultry farming to improve host health and metabolism. Microbial composition is known to be influenced by dietary fiber use, although the exact FVW-induced changes remain unclear. This study provided a first comparison of the effects of FVW and the most commonly used antibiotic growth promoter (flavomycin) on the cecal microbiotas of laying hens from birth to 490 days of age. We found that supplementation with FVW altered cecal microbial composition, thereby affecting the correlation network between members of the microbiota, and subsequently affecting the intestinal immune homeostasis.

Chronic lead exposure exacerbates hepatic glucolipid metabolism disorder and gut microbiota dysbiosis in high-fat-diet mice.

Lead (Pb) and obesity are co-occurring risk factors for metabolic disorders. However, there is still a lack of study on the combined effects of both stressors on metabolism. C57BL/6J mice were exposed to 200mg/L Pb or/and HFD for 24 weeks and were used to investigate the effects and underlying mechanisms of chronic Pb exposure on obese mice. The results showed that Pb significantly increased body weight, visceral obesity, fasting blood glucose levels, and insulin resistance, and aggravated liver damage, hepatic lipid accumulation and steatosis in HFD-fed mice. Further analysis showed that Pb significantly inhibited insulin signaling pathway PI3K/AKT and fatty acid β-oxidation, and accelerated fatty acid synthesis. Moreover, Pb exacerbated HFD-induced disruption of gut microbiota homeostasis, manifested by increased proportions of pathogenic genera such as Desulfovibrio, Alistipes and Helicobacter, and decreased proportions of beneficial microbes Akkermansia and Barnesiella, which were negatively associated with obesity. These results indicated that Pb exposure exacerbated the disruption of liver glucolipid metabolism in HFD mice possibly by disrupting gut microbiota.

The Effect of Quadruple Therapy with Polaprezinc or Bismuth on Gut Microbiota after Helicobacter pylori Eradication: A Randomized Controlled Trial.

Background: Quadruple therapy with polaprezinc provided an alternative to Helicobacter pylori eradication; however, the effect on gut microbiota remains uncertain. This study aims to identify whether polaprezinc-containing quadruple therapy causes adverse microbiota effects among asymptomatic adults, compared with bismuth therapy. Methods: This was a randomized control trial. One hundred asymptomatic H. pylori-infected adults were randomly (1:1) assigned to two treatment groups (polaprezinc-containing therapy, PQT; or bismuth-containing therapy, BQT). Fecal samples were collected from subjects before and 4−8 weeks after therapy. Samples were sequenced for the V4 regions of the 16S rRNA gene. Results: The relative abundance of the three dominant bacterial phyla (Bacteroidota, Firmicutes, and Proteobacteria) accounted for more than 95% of each treatment group. The alpha diversity between eradications that succeeded and those that failed had no significant difference (p > 0.05). After successful eradication, the alpha diversity in the BQT group decreased in comparison with the baseline (p < 0.05). Subjects who were successfully eradicated by BQT showed considerably lower alpha diversity indices than those of the PQT at follow-up (p < 0.05). The abundance of Parasutterella in subjects who were successfully eradicated by PQT was four times greater than that of BQT (q < 0.05). Conclusion: A 14-day PQT may be superior to BQT in maintaining short-term gut microbiota homeostasis after H. pylori treatment. Our findings preliminarily provide evidence of the short-term impacts of the gut microbiota after PQT treatment of H. pylori infection.

Non-Digestible Oligosaccharides: A Novel Treatment for Respiratory Infections?

Emerging antimicrobial resistance in respiratory infections requires novel intervention strategies. Non-digestible oligosaccharides (NDOs) are a diverse group of carbohydrates with broad protective effects. In addition to promoting the colonization of beneficial gut microbiota and maintaining the intestinal homeostasis, NDOs act as decoy receptors, effectively blocking the attachment of pathogens on host cells. NDOs also function as a bacteriostatic agent, inhibiting the growth of specific pathogenic bacteria. Based on this fact, NDOs potentiate the actions of antimicrobial drugs. Therefore, there is an increasing interest in characterizing the anti-infective properties of NDOs. This focused review provides insights into the mechanisms by which representative NDOs may suppress respiratory infections by targeting pathogens and host cells. We summarized the most interesting mechanisms of NDOs, including maintenance of gut microbiota homeostasis, interference with TLR-mediated signaling, anti-oxidative effects and bacterial toxin neutralization, bacteriostatic and bactericidal effects, and anti-adhesion or anti-invasive properties. A detailed understanding of anti-infective mechanisms of NDOs against respiratory pathogens may contribute to the development of add-on therapy or alternatives to antimicrobials.

NLRP3 and Gut Microbiota Homeostasis: Progress in Research.

The inflammasome is a platform for inflammatory signaling, and the NLRP3 inflammasome recognizes stimuli in vitro and in vivo, and releases inflammatory cytokines that trigger inflammation and pyroptosis. In the gut, the NLRP3 inflammasome is a key sensor for protecting the body from damage and exogenous pathogens. It plays a fundamental role in maintaining the stability of the gut's immune system. We focus on the role of NLRP3 as a key node in maintaining the homeostasis of gut microbiota which has not been fully highlighted in the past; gut microbiota and innate immunity, as well as the NLRP3 inflammasome, are discussed in this article.

Feeding Rainbow Trout with Different Types of Non-Starch Polysaccharides: Impacts on Serum Metabolome and Gut Microbiota.

A 70-day feeding trial investigated the effects of dietary inclusion of different types of non-starch polysaccharides (NSPs) on gut microbiota and serum metabolome of rainbow trout. Four practical feeds (42% crude protein, 17% crude lipid) were prepared with 8% insoluble NSP (INSP, cellulose), 16.8% soluble NSP (SNSP, composed of 1.12% β-glucan, 1.28% mannan, 4.8% arabinoxylan, and 9.6% pectin), 24.8% NSPs (8% INSP + 16.8% SNSP), or no NSPs inclusion, respectively. Dietary NSPs inclusion had no significant influence on the Shannon, Simpson, ACE, and Chao1 indices of gut microbiota but induced a significant increase in the abundance of Pseudomonas aeruginosa and Photobacterium kishitanii, and a decrease in Firmicutes and Alistipes finegoldii. Besides, dietary SNSP upregulated the carnitine synthesis metabolic pathway. Our data suggest that dietary NSPs are detrimental to gut microbiota homeostasis and the health of rainbow trout, and dietary SNSP exhibit a stronger ability to interfere with physiological metabolism of rainbow trout than INSP. Therefore, the physiological effects of dietary NSPs, especially SNSP, should be carefully considered when designing the commercial feed formulations of rainbow trout.

Salvia miltiorrhiza extract may exert an anti-obesity effect in rats with high-fat diet-induced obesity by modulating gut microbiome and lipid metabolism

Studies have shown that a high-fat diet (HFD) can alter gut microbiota (GM) homeostasis and participate in lipid metabolism disorders associated with obesity. Therefore, regulating the construction of GM with the balance of lipid metabolism has become essential for treating obesity. Salvia miltiorrhiza extract (Sal), a common traditional Chinese medicine, has been proven effective against atherosclerosis, hyperlipidemia, obesity, and other dyslipidemia-related diseases. To investigate the anti-obesity effects of Sal in rats with HFD-induced obesity, and explore the underlying mechanism by focusing on GM and lipid metabolism. Obesity was induced in rats with an HFD for 7 wk, and Sal (0.675 g/1.35 g/2.70 g/kg/d) was administered to treat obese rats for 8 wk. The therapeutic effect was evaluated by body weight, body fat index, waistline, and serum lipid level. Lipid factors (cAMP, PKA, and HSL) in liver and fat homogenates were analyzed by ELISA. The effect of Sal on GM and lipid metabolism was assessed by 16S rRNA-based microbiota analysis and untargeted lipidomic analysis (LC-MS/MS), respectively. Sal treatment markedly reduced weight, body fat index, serum triglycerides (TG), total cholesterol (TC), low-density lipoprotein, glucose, free fatty acid, hepatic lipid accumulation, and adipocyte vacuolation, and increased serum high-density lipoprotein (HDL-C) in rats with HFD-induced obesity. These effects were associated with increased concentrations of lipid factors such as cAMP, PKA, and HSL in the liver and adipose tissues, enhanced gut integrity, and improved lipid metabolism. GM analysis revealed that Sal could reverse HFD-induced dysbacteriosis by promoting the abundance of Actinobacteriota and Proteobacteria, and decreasing the growth of Firmicutes and Desulfobacterita. Furthermore, LC-MS/MS analysis indicated that Sal decreased TGs (TG18:2/18:2/20:4, TG16:0/18:2/22:6), DGs (DG14:0/22:6, DG22:6/22:6), CL (18:2/ 18:1/18:1/20:0), and increased ceramides (Cers; Cer d16:0/21:0, Cer d16:1/24:1), (O-acyl)-ω-hydroxy fatty acids (OAHFAs; OAHFA18:0/14:0) in the feces of rats. Spearman's correlation analysis further indicated that TGs, DGs, and CL were negatively related to the abundance of Facklamia and Dubosiella, and positively correlated with Blautia and Quinella, while OAHFAs and Cers were the opposite. Sal has an anti-obesity effect by regulating the GM and lipid metabolism.

New Insights into the Gut Microbiota in Neurodegenerative Diseases from the Perspective of Redox Homeostasis.

An imbalance between oxidants and antioxidants in the body can lead to oxidative stress, which is one of the major causes of neurodegenerative diseases. The gut microbiota contains trillions of beneficial bacteria that play an important role in maintaining redox homeostasis. In the last decade, the microbiota-gut-brain axis has emerged as a new field that has revolutionized the study of the pathology, diagnosis, and treatment of neurodegenerative diseases. Indeed, a growing number of studies have found that communication between the brain and the gut microbiota can be accomplished through the endocrine, immune, and nervous systems. Importantly, dysregulation of the gut microbiota has been strongly associated with the development of oxidative stress-mediated neurodegenerative diseases. Therefore, a deeper understanding of the relationship between the gut microbiota and redox homeostasis will help explain the pathogenesis of neurodegenerative diseases from a new perspective and provide a theoretical basis for proposing new therapeutic strategies for neurodegenerative diseases. In this review, we will describe the role of oxidative stress and the gut microbiota in neurodegenerative diseases and the underlying mechanisms by which the gut microbiota affects redox homeostasis in the brain, leading to neurodegenerative diseases. In addition, we will discuss the potential applications of maintaining redox homeostasis by modulating the gut microbiota to treat neurodegenerative diseases, which could open the door for new therapeutic approaches to combat neurodegenerative diseases.

Lactobacillus johnsonii alleviates colitis by TLR1/2-STAT3 mediated CD206+ macrophagesIL-10 activation

ABSTRACT Imbalance of gut microbiota homeostasis is related to the occurrence of ulcerative colitis (UC), and probiotics are thought to modulate immune microenvironment and repair barrier function. Here, in order to reveal the interaction between UC and gut microbiota, we screened a new probiotic strain by 16S rRNA sequencing from Dextran Sulfate Sodium (DSS)-induced colitis mice, and explored the mechanism and clinical relevance. Lactobacillus johnsonii (L. johnsonii), as a potential anti-inflammatory bacterium was decreased colonization in colitis mice. Gavage L. johnsonii could alleviate colitis by specifically increasing the proportion of intestinal macrophages and the secretion of Il-10 with macrophages depleted model and in Il10−/− mice. We identified this subset of immune cells activated by L. johnsonii as CD206+ macrophagesIL−10. Mechanistically, L. johnsonii supplementation enhanced the mobilization of CD206+ macrophagesIL−10 through the activation of STAT3 in vivo and in vitro. In addition, we revealed that TLR1/2 was essential for the activation of STAT3 and the recognition of L. johnsonii by macrophages. Clinically, there was positive correlation between the abundance of L. johnsonii and the expression level of MRC1, IL10 and TLR1/2 in UC tissues. L. johnsonii could activate native macrophages into CD206+ macrophages and release IL-10 through TLR1/2-STAT3 pathway to relieve experimental colitis. L. johnsonii may serve as an immunomodulator and anti-inflammatory therapeutic target for UC.

Translucent disease outbreak in Penaeus vannamei post-larva accompanies the imbalance of pond water and shrimp gut microbiota homeostasis

The health status of aquatic animals is closely related to environmental and gut microbiota. Imbalance in microbiota homeostasis may be an important cause of diseases outbreak in aquaculture. A new disease called "translucent post-larva disease" (TPD) or "bacterial vitrified syndrome" (BVS) has caused huge economic losses to Penaeus vannamei seed industry of China in recent years. However, no studies have been reported on the relationship between this disease and microbiota homeostasis in gut or environment. In the present study, we obtained a batch of shrimp post-larva (PL) showing translucent diseased features in clinically and histologically. We used high-throughput sequencing to analyze the differences of microbiota between healthy and diseased shrimp PL, and corresponding pond water. The results of alpha diversity analysis showed, the Shannon and Smithwilson indexes in diseased shrimp PL gut were significantly higher (P < 0.05). In addition, the occurrence of the disease increased similarity of microbiota characteristics between shrimp PL gut and pond water. Specifically, the microbiota clustering distance was shortened, and shared OUTs were increased between diseased shrimp PL gut and water. The abundance of Ralstonia in diseased shrimp PL gut was significantly decreased (P < 0.05), while Vibrio and Mycoplasmataceae were largely enrichment. The abundance of Vibrio in diseased shrimp PL gut reached to 50.04 %, and the dominant strain was identified as being the closest to V. owensii and V. hyugaensis. Functional prediction results showed that the abundances of genes closely related to bacterial growth, colonization, secretion and transport of virulence factors, such as carbohydrate metabolism, two-component system and membrane transport, were significantly increased in diseased shrimp PL gut (P < 0.05). This study provides a theoretical basis for a relationship between the occurrence of shrimp PL translucent disease and the imbalance of microbial homeostasis, and provides guidance for the disease prevention during shrimp farming.

Washed microbiota transplantation improves patients with metabolic syndrome in South China.

Metabolic syndrome (MS) is a growing public health problem worldwide. The clinical impact of fecal microbiota transplantation (FMT) from healthy donors in MS patients is unclear, especially in southern Chinese populations. This study aimed to investigate the effect of washed microbiota transplantation (WMT) in MS patients in southern China. The clinical data of patients with different indications receiving 1-3 courses of WMT were retrospectively collected. The changes of BMI, blood glucose, blood lipids, blood pressure and other indicators before and after WMT were compared, such as fasting blood glucose (FBG), glycated hemoglobin (HbA1c), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-c)), high-density lipoprotein cholesterol (HDL-c), non-high-density lipoprotein (non-HDL-c), systolic blood pressure (SBP), diastolic blood pressure (DBP), etc. At the same time, comprehensive efficacy evaluation and atherosclerotic cardiovascular disease (ASCVD) grade assessment were performed on MS patients. Finally, 16S rRNA gene amplicon sequencing was performed on fecal samples of MS patients before and after transplantation. A total of 237 patients were included, including 42 in the MS group and 195 in the non-MS group. For MS patients, WMT significantly improved the comprehensive efficacy of MS in short term 40.48% (p<0.001), medium term 36.00% (p=0.003), and long term 46.15% (p=0.020). Short-term significantly reduced FBG (p=0.023), TG (p=0.030), SBP (p=0.026) and BMI (p=0.031), and increased HDL-c (p=0.036). The medium term had a significant reduction in FBG (p=0.048), TC (p=0.022), LDL-c (p=0.043), non-HDL-c (p=0.024) and BMI (p=0.048). WMT had a significant short term (p=0.029) and medium term (p=0.011) ASCVD downgrading effect in the high-risk group of MS patients. WMT improved gut microbiota in MS patients. WMT had a significant improvement effect on MS patients and a significant downgrade effect on ASCVD risk in the high-risk group of patients with MS. WMT could restore gut microbiota homeostasis in MS patients. Therefore, the regulation of gut microbiota by WMT may provide a new clinical approach for the treatment of MS.

Hungatella hathewayi, an Efficient Glycosaminoglycan-Degrading Firmicutes from Human Gut and Its Chondroitin ABC Exolyase with High Activity and Broad Substrate Specificity.

The degradation of glycosaminoglycans (GAGs) by intestinal bacteria is critical for their colonization in the human gut and the health of the host. Both colonic Bacteroides and Firmicutes have been reported to degrade GAGs; however, the enzymatic details of the latter remain largely unknown. Our bioinformatic analyses of fecal Firmicutes revealed that their genomes, especially Hungatella hathewayi strains, are an abundant source of putative GAG-specific catabolic enzymes. Subsequently, we isolated a Firmicutes strain, H. hathewayi N2-326, that can catabolize various GAGs. While H. hathewayi N2-326 was as efficient in utilizing chondroitin sulfate A (CSA) and dermatan sulfate as Bacteroides thetaiotaomicron, a well-characterized GAG degrader, it outperformed B. thetaiotaomicron in assimilating hyaluronic acid. Unlike B. thetaiotaomicron, H. hathewayi N2-326 could not utilize heparin. The chondroitin lyase activity of H. hathewayi N2-326 was found to be present predominantly in the culture supernatant. Genome sequence analysis revealed three putative GAG lyases, but only the HH-chondroitin ABC lyase was upregulated in the presence of CSA. In addition, five CAZyme gene clusters containing GAG metabolism genes were significantly upregulated when grown on CSA. Further characterization of the recombinant HH-chondroitin ABC lyase revealed that it cleaves GAGs predominantly in an exo-mode to produce unsaturated disaccharides as the primary hydrolytic product while exhibiting a higher specific activity than reported chondroitin ABC lyases. HH-chondroitin ABC lyase represents the first characterized chondroitin lyase from intestinal Firmicutes and offers a viable commercial option for the production of chondroitin, dermatan, and hyaluronan oligosaccharides and also for potential medical applications. IMPORTANCE An increased understanding of GAG metabolism by intestinal bacteria is critical in identifying the driving factors for the composition, modulation, and homeostasis of the human gut microbiota. In addition, GAG-depolymerizing polysaccharide lyases are highly desired enzymes for the production of GAG oligosaccharides and as therapeutics. At present, the dissection of the enzymatic machinery for GAG degradation is highly skewed toward Bacteroides. In this study, we have isolated an efficient GAG-degrading Firmicutes bacterium from human feces and characterized the first chondroitin ABC lyase from a Firmicutes, which complements the fundamental knowledge of GAG utilization in the human colon. The genomic and transcriptomic analysis of the bacterium shows that Firmicutes might use a distinct approach to catabolize GAGs from that used by Bacteroides. The high specific activity of the characterized chondroitin ABC lyase aids future attempts to develop a commercial chondroitinase for industrial and medicinal applications.

Dietary pattern interfered with the impacts of pesticide exposure by regulating the bioavailability and gut microbiota

Dietary intake is an essential way for pesticides to enter the human body. The effects of dietary pattern on the risks of pesticides and what diet can reduce the damage are largely unknown. Here, it is found that Mediterranean diet and Vegetarian diet could alleviate insulin resistance and obesity induced by chlorpyrifos, while Western diet could aggravate that. Gut microbiota and chlorpyrifos bioavailability mediated by the diets were involved in these effects. Both the dietary pattern and chlorpyrifos could change the composition of gut microbiota. Chlorpyrifos caused gut dysbacteriosis which was an important reason for the induced metabolic syndrome. Mediterranean diet and Vegetarian diet could maintain gut microbiota homeostasis and increase intestinal bacteria producing short-chain fatty acids, repair the gut microbiota and intestinal barrier damaged by chlorpyrifos. High dietary fat intake increased the bioavailability of chlorpyrifos, which aggravated the gut dysbacteriosis and destruction of intestinal integrity. Thus, the amount of endotoxin entering the blood increased and caused low-grade inflammation, which was also an important pathway of metabolic syndrome. The results suggested that although it was almost impossible to avoid the exposure to pesticides in modern life, healthy diets could regulate beneficial gut microbiota and alleviate the risk of pesticide exposure.

Ursolic acid regulates gut microbiota and corrects the imbalance of Th17/Treg cells in T1DM rats.

Ursolic acid (UA), a natural pentacyclic triterpenoid obtained from fruit and several traditional Chinese medicinal plants, exhibits anti-inflammatory and hypoglycemic properties. However, its protective effects against type 1 diabetes mellitus (T1DM) have not been explored. In this study, streptozotocin-induced T1DM rat models were established and treated with UA for six weeks. T1DM rats treated with UA were used to observe the effects of UA on body weight and fasting blood glucose (FBG) levels. Pathological changes in the pancreas were observed using immunohistochemical staining. The gut microbiota distribution was measured using 16S rDNA high-throughput sequencing. The proportions of Th17 and Treg cells were examined using flow cytometry. Protein and mRNA expression of molecules involved in Th17/Treg cell differentiation were assessed by quantitative real-time PCR and western blotting. The correlation between gut microbiota and Th17/Treg cell differentiation in T1DM was analyzed using redundancy analysis (RDA) analysis. Compared with the model group, FBG levels declined, and the progressive destruction of pancreatic β cells was alleviated. The diversity and uniformity of gut microbiota in T1DM rats treated with UA increased significantly. Interestingly, the Th17/Treg cell differentiation imbalance was corrected and positively correlated with the expression of Foxp3 and IL-10, and negatively correlated with the expression of RORγt, IL-17A, and TNF-α. These findings suggest that UA can lower FBG levels in T1DM rats, delay the progressive destruction of pancreatic β-cells, and modulate gut microbiota homeostasis and immune function in streptozotocin-induced T1DM rats.

Chemopreventive role of probiotics against cancer: a comprehensive mechanistic review.

Probiotics use different mechanisms such as intestinal barrier improvement, bacterial translocation and maintaining gut microbiota homeostasis to treat cancer. Probiotics' ability to induce apoptosis against tumor cells makes them more effective to treat cancer. Moreover, probiotics stimulate immune function through an immunomodulation mechanism that induces an anti-tumor effect. There are different strains of probiotics, but the most important ones are lactic acid bacteria (LAB) having antagonistic and anti-mutagenic activities. Live and dead probiotics have anti-inflammatory, anti-proliferative, anti-oxidant and anti-metastatic properties which are useful to fight against different diseases, especially cancer. The main focus of this article is to review the anti-cancerous properties of probiotics and their role in the reduction of different types of cancer. However, further investigations are in progress to improve the efficiency of probiotics in cancer treatment.

H2S responsive PEGylated poly (lipoic acid) with ciprofloxacin for targeted therapy of Salmonella.

Targeted antibiotic delivery system would be an ideal solution for the treatment of enteropathogenic infections since it avoids the excessive usage of antibiotics clinically, which may lead to threat on public health and food safety. Salmonella spp. are Enteropathogens, but they are also robust H2S producers in the intestinal tracts of hosts. To this end, the PEGylated poly (α lipoic acid) (PEG-PALA) copolymer nanoparticles with hydrophilic exterior and hydrophobic interior were designated in this study to encapsulate the antibiotics and release them in response to H2S produced by Salmonella spp. The PEG-PALA nanoparticles demonstrated excellent stability in vitro and biocompatibility toward mammalian Caco-2 and 293T cells. The release of ciprofloxacin from PEG-PALA nanoparticle was only 25.44±0.57% and 26.98±1.93% (w/w) in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) solutions without H2S stimulation. However, the release amounts of ciprofloxacin were up to 73.68±1.63% (w/w) in the presence of 1mM Na2S as H2S source. In the mouse infection model, PEG-PALA nanoparticles encapsulated with ciprofloxacin (PEG-PALA@CIP) reduced the Salmonella colonization in the heart, liver, spleen, lung, cecum, and faeces, prolonged ciprofloxacin persistence in the intestine while reducing its absorption into the blood. More importantly, these nanoparticles reduced 3.4-fold of Enterobacteriaceae levels and increased 1.5-fold of the Lactobacillaceae levels compared with the drug administered in the free form. Moreover, these nanoparticles resulted in only minimal signs of intestinal tract inflammation. The H2S-responsive antibiotic delivery systems reported in this study demonstrating a variety of advantages including protected the drug from deactivation by gastric and intestinal fluids, maintained a high concentration in the intestinal tract and maximally kept the gut microbiota homeostasis. As such, this targeted antibiotic delivery systems are for the encapsulation of antibiotics to target specific enteropathogens.