Alterations In Intestinal Microbiota Research Articles

Mesenchymal stem cells: a novel therapeutic approach for feline inflammatory bowel disease

BackgroundInflammatory bowel disease (IBD) poses a significant and growing global health challenge, affecting both humans and domestic cats. Research on feline IBD has not kept pace with its widespread prevalence in human populations. This study aimed to develop a model of feline IBD by incorporating dextran sulfate sodium (DSS) to evaluate the therapeutic potential of MSCs and to elucidate the mechanisms that enhance their action.MethodsWe conducted a comprehensive clinical assessment, including magnetic resonance imaging (MRI), endoscopy, and histopathological examination. Additionally, alterations in intestinal microbiota were characterized by 16 S rDNA sequencing, and the influence of MSCs on IBD-related gene expression was investigated through transcriptome analysis.ResultsAccording to our findings, MSC treatment significantly mitigated DSS-induced clinical manifestations, reduced inflammatory cell infiltration, decreased the production of inflammatory mediators, and promoted mucosal repair. Regarding the intestinal microbiota, MSC intervention effectively corrected the DSS-induced dysbiosis, increasing the presence of beneficial bacteria and suppressing the proliferation of harmful bacteria. Transcriptome analysis revealed the ability of MSCs to modulate various inflammatory and immune-related signaling pathways, including cytokine-cytokine receptor interactions, TLR signaling pathways, and NF-κB pathways.ConclusionThe collective findings indicate that MSCs exert multifaceted therapeutic effects on IBD, including the regulation of intestinal microbiota balance, suppression of inflammatory responses, enhancement of intestinal barrier repair, and modulation of immune responses. These insights provide a solid scientific foundation for employing MSCs as an innovative therapeutic strategy for IBD and pave the way for future clinical explorations.

Lactobacillus rhamnosus modulates murine neonatal gut microbiota and inflammation caused by pathogenic Escherichia coli

BackgroundPathogenic Escherichia coli strains produce neonatal septicemia after colonizing the neonatal gut. While the probiotic Lactobacillus rhamnosus GG (LGG) effectively reduces neonatal sepsis, LGG’s effects on the neonatal intestinal microbiota alterations and inflammation triggered by E. coli are incompletely understood. We hypothesized that LGG significantly modulates the specific neonatal gut microbial populations changes and the inflammatory response elicited by the enteral introduction of septicemia-producing E. coli. To test this hypothesis, newborn rats were pretreated orally with LGG or placebo prior to infection with the neonatal E. coli septicemia clinical isolate SCB34. Amplicon 16S rRNA gene sequencing was performed on intestinal samples. Intestinal injury and expression of inflammatory mediators and apoptosis were determined.ResultsAlpha diversity of gut microbiota was greater in SCB34-infected pups in comparison to sham-infected pups, these changes were not modified by LGG pretreatment. Beta diversity analyses also showed differences between SCB34-infected vs. uninfected pups. LGG pretreatment before SCB34 infection did not result in significant beta diversity changes compared to placebo. Moreover, individual genera and species abundance analyses by linear discriminant analysis effect size (LEfSe) showed significant changes in Gram-negative, Gram-positive, and anaerobic populations resulting from LGG pretreatment and SCB34 infection. LGG significantly suppressed the expression of inflammatory cytokines but did not attenuate SCB34-induced apoptosis or histologic injury.ConclusionsLGG modulates clinically significant microbiota features and inflammation triggered by pathogenic E. coli intestinal infection shortly after birth. This new knowledge can potentially be harnessed to design novel interventions against gut-derived neonatal sepsis.

Convergence of Neuroinflammation, Microbiota, and Parkinson's Disease: Therapeutic Insights and Prospects.

Parkinson's disease (PD) is a complex neurodegenerative disorder. Recent evidence reveals connections between neuroinflammatory processes and intestinal microbiota alterations in the progression of this pathology. This comprehensive review explores the intricate relationships between them, highlighting their combined impact on PD. Neuroinflammation, characterized by immune activation in the central nervous system, is increasingly acknowledged as a critical factor in the development of PD. Concurrently, alterations in the gut microbiota composition have been linked to PD, suggesting a potential modulatory role in disease progression. Thus, bidirectional communication along the gut-brain axis has become pivotal in comprehending the pathogenesis of PD. Furthermore, we explore emerging therapeutic strategies that target these interconnected pathways, providing insights into potential avenues for PD treatment. The elucidation of these intricate relationships establishes a promising foundation for innovative therapeutic strategies aimed at altering disease progression and improving the quality of life for individuals affected by PD.

Role of Inflammation and Motility Disorders in the Development, Course and Consequences of Functional Gastrointestinal and Biliary Tract Diseases (Literature Review and Expert Panel Resolution)

Aim: to present the results of the Expert Panel with a discussion of modern concepts of the pathogenesis of functional gastrointestinal diseases and the possibilities of multitarget therapy with trimebutine. Key points. Low-grade inflammation can be considered as a morphological substrate of functional diseases with an increase in activated mastocytes and eosinophils, T-helpers 2 and T-helpers 17 in the gastrointestinal mucosa. In the development in the content of visceral hypersensitivity, the functional connection between mastocytes and TRPV1-positive sensory endings of the vagus nerve is of great importance. Proinflammatory cytokines and matrix metalloproteinases can enter the systemic circulation, provoking the development of systemic manifestations. Increased levels of proinflammatory cytokines are supported by altered intestinal permeability and microbiota. Functional diseases are believed to modify the symptoms and course of concomitant organic diseases of the gastrointestinal tract (for example, functional diseases of the biliary tract may contribute to the development of cholelithiasis, pancreatitis). The peripheral μ-, κ- and δ-receptor agonist trimebutine (Trimedat®) regulates the production of enterohormones, modulates motility throughout the gastrointestinal tract and normalizes visceral sensitivity. The effectiveness of trimebutine in the treatment of functional disorders has been shown in various studies. Trimebutine helps reduce the production of proinflammatory cytokines, including interleukin-6. Conclusion. In the treatment of functional diseases of the gastrointestinal tract, trimebutine can be considered as a multitarget agent, since the drug helps to normalize motility, reduces the degree of visceral hypersensitivity, exhibits anti-inflammatory and neuroregenerative effects, and can also increase the effectiveness of treatment of concomitant diseases.

Dietary Clostridium butyricum metabolites mitigated the disturbances in growth, immune response and gut health status of Ctenopharyngodon idella subjected to high cottonseed and rapeseed meal diet

Cottonseed meal and rapeseed meal exhibit a potential for fishmeal substitute in grass carp feed, while their excessive use contribute to growth decline and weakening immunity of aquatic animals. Clostridium butyricum metabolites (CBM) was recognized as a functional additive due to its antioxidant properties and maintenance of intestinal microbiota balance. CBM was added to a high of cottonseed and rapeseed meal diet to determine its effects on growth, immunity, and intestinal microbiota alterations of grass carp (Ctenopharyngodon idella) over 56 days. Eight hundred grass carp (mean weight, around 50 g) were randomized to five treatments and fed with the basic diet (CON), CBM0 diet (28 % cottonseed and 27 % rapeseed meal), and CBM diets (CBM0.5, CBM1, and CBM2, namely CBM0 diet supplemented with 500, 1000, and 2000 mg kg−1 CBM). The results indicated that compared to CBM0, The ingestion of 1000 mg kg−1 CBM diet by grass carp significantly promoted growth as measured by intestinal lipase activity, villus height, and muscle thickness. Moreover, accompanied by a decrease in intestine MDA content, and enhance antioxidant capacity by activating Keap1/Nrf2 signaling pathway to increase enzyme activities (SOD, CAT and T-AOC) and corresponding gene expression (mnsod, cat, gsto and gpx1) in the intestine of grass crap fed CBM1 diet. The dietary CBM1 diet increased serum levels of C3 and IgM, increased ACP activity and expression of the corresponding anti-inflammatory factors (tgf-β1 and il-15), and suppressed the expression of pro-inflammatory factors (tnf-α and il-12β), resulting in enhanced immunity. The dietary CBM1 diet up-regulates gene expression of tight junction proteins (zo-1, occludin, occludin7a and occludin-c), coupled with the decreases in DAO and D-lactate contents, implying that the decreased mucosal permeability could be observed in the gut. The dietary CBM1 diet largely altered the intestinal microbial community, especially reducing the relative abundance of intestinal pathogenic bacteria (Streptococcus and Actinomyces). And it significantly increased the content of short-chain fatty acids (acetic acid, butyric acid, isobutyric acid, propionic acid and isovaleric acid). Taken above, dietary CBM supplementation improved growth in grass carp and attenuated the intestinal oxidative stress, inflammation and microflora dysbacteriosis caused by high proportions of cottonseed and rapeseed meal diets.

Modulatory Effects of Isolated Lactobacillus paracasei from Malaysian Water Kefir Grains on the Intestinal Barrier and Gut Microbiota in Diabetic Mice.

Type 2 diabetes (T2DM) is one of the four major types of non-communicable diseases that have become a global health concern. Water kefir is a product of a brown sugar solution fermented with kefir grains which comprises around 30 microbial species in its grains. Water kefir possesses a wide range of health benefits, including anti-hyperlipidemic effects, and reduces hypertension and blood glucose levels in animal models. Reportedly, consuming water kefir containing probiotics may enhance the intestinal barrier and positively influence the composition of the intestinal microflora. The present study aimed to evaluate the regulatory effects of Lactobacillus paracasei isolated from Malaysian water kefir grains (MWKG) on the alterations of intestinal barrier and gut microbiota in diabetic mice via histopathological analysis of the distal colon and 16S rRNA gene sequencing on fecal microbiome. Results indicated that the administration of isolated Lactobacillus paracasei from MWKG to diabetic mice ameliorated the dominant probiotic phyla in the gut microbiota. Results showed that lower dose (LD) and high dose (HD) treatments of the isolated Lactobacillus paracasei could significantly reduce inflammatory cell infiltration in the distal colon of diabetic mice. The treatments revealed a significant decrease in the relative abundance of Firmicutes in the gut, 0.27 ± 0.06% for LD and 0.34 ± 0.04% for HD, compared to untreated (UN) diabetic mice, 0.40 ± 0.02%. These results suggest that L. paracasei isolated from MWKG could serve as a potential dietary supplement against intestinal inflammation and modify gut microbiota composition in patients with T2DM.

Sex-dependent effects of a high fat diet on metabolic disorders, intestinal barrier function and gut microbiota in mouse

Obesity is often associated with sex-dependent metabolic complications, in which altered intestinal barrier function and gut microbiota contribute. We aimed to characterize in mice the sex-dependent effects of a high fat diet on these parameters. Male and female C57BL/6 mice received a standard (SD) or high fat diet (HFD; 60% kcal from fat) during 14 weeks (W14). Body composition, glucose tolerance, insulin sensitivity, intestinal permeability, colonic expression of 44 genes encoding factors involved in inflammatory response and gut barrier function, cecal microbiota, plasma adipokines and white adipose tissue response have been assessed. Both male and female HFD mice exhibited an increase of body weight and fat mass gain and glucose intolerance compared to SD mice. However, only male HFD mice tended to develop insulin resistance associated to increased Tnfα and Ccl2 mRNA expression in perigonadal adipose tissue. By contrast, only female HFD mice showed significant intestinal hyperpermeability that was associated with more markedly altered colonic inflammatory response. Cecal microbiota richness was markedly reduced in both sexes (Observed species) with sex-dependent modifications at the phyla or family level, e.g. decreased relative abundance of Bacillota and Lachnospiraceae in females, increased of Bacteroidaceae in males. Interestingly, some of these microbiota alterations were correlated with peripheral metabolic and inflammatory markers. In conclusions, male and female mice exhibit different responses to a high fat diet with specific changes of gut microbiota, intestinal barrier function, colonic and white adipose tissue inflammation, metabolic markers and body weight gain. The underlying mechanisms should be deciphered in further investigations.

Psidium guajava Seed Oil Reduces the Severity of Colitis Induced by Dextran Sulfate Sodium by Modulating the Intestinal Microbiota and Restoring the Intestinal Barrier.

The oil derived from Psidium guajava seeds (TKSO) exhibits an abundance of diverse unsaturated fatty acids, notably oleic, linoleic, and α-linolenic acids, conferring substantial health advantages in addressing metabolic irregularities and human diseases. This research endeavor focused on elucidating the impacts of TKSO on colonic inflammatory responses and intestinal microbiota alterations in a murine model of colitis induced by dextran sulfate sodium (DSS), demonstrated that substantial supplementation with TKSO reduces the severity of colitis induced by DSS. Furthermore, TKSO effectively attenuated the abundance and expression of proinflammatory mediators while augmenting the expression of tight junction proteins in DSS-challenged mice. Beyond this, TKSO intervention modulated the intestinal microbial composition in DSS-induced colitis mice, specifically by enhancing the relative presence of Lactobacillus, Norank_f_Muribaculaceae, and Lachnospiraceae_NK4A136_group, while concurrently diminishing the abundance of Turicibacter. Additionally, an analysis of short-chain fatty acids (SCFAs) revealed noteworthy elevations in acetic, propionic, isobutyric, and butyric acids, and total SCFAs levels in TKSO-treated mice. In summary, these findings underscore the potential of TKSO to reduce the severity of colitis induced by DSS in mice through intricate modulation of the intestinal microbiota, metabolite profiles, and intestinal barrier repair, thereby presenting a promising avenue for the development of therapeutic strategies against intestinal inflammatory conditions.

Inulin Supplementation Alleviates Ochratoxin A-Induced Kidney Injury through Modulating Intestinal Microbiota.

Ochratoxin A (OTA) is a prevalent mycotoxin found in feed that causes significant kidney injury in animals. Further investigation was needed to devise strategies for treating OTA-induced kidney damage through the gut-kidney axis. Evidence indicates the crucial role of intestinal microbiota in kidney damage development. Inulin, a dietary fiber, protects kidneys by modulating intestinal microbiota and promoting short-chain fatty acid (SCFA) production. However, its precise mechanism in OTA-induced kidney damage remained unclear. In this study, chickens were orally administered OTA and inulin for 2 weeks to investigate inulin's effects on OTA-induced kidney damage and underlying mechanisms. The alteration of intestinal microbiota, SCFAs contents, and SCFA receptors was further analyzed. Results demonstrated that inulin supplementation influenced intestinal microbiota, increased SCFAs production, and mitigated OTA-induced kidney damage in chickens. The importance of microbiota in mediating inulin's renal protection was further confirmed by antibiotic and fecal microbiota transplantation experiments. Additionally, inulin exhibited antioxidant and anti-inflammatory properties, alleviating NLRP3 inflammasome activation and pyroptosis. In summary, inulin protected chickens from OTA-induced kidney damage, which might provide a potential strategy to mitigate the harmful effects of mycotoxins through prebiotics and safeguard renal health.

Intestinal microbiota homeostasis analysis in riboflavin-treated alcoholic liver disease

Alcoholic liver disease (ALD) is a disease with high incidence, limited therapies, and poor prognosis. The present study aims to investigate the effect of riboflavin on ALD and explore its potential therapeutic mechanisms. C57BL/6 mice were divided into the control, alcohol, and alcohol+ riboflavin groups. 16S rRNA-seq and RNA-seq analysis were utilized to analyze the polymorphism of intestinal microbiota and the transcriptome heterogeneity respectively. KEGG and GO enrichment analysis were performed. CIBERSORTx was applied to evaluate the immune cell infiltration level. Publicly available transcriptome data of ALD was enrolled and combined with the RNA-seq data to identify the immune subtypes of ALD. Pathological and histology analysis demonstrated that riboflavin reversed the progression of ALD. 16S rRNA-seq results showed that riboflavin could regulate alcohol-induced intestinal microbiota alteration. Intestinal microbiota polymorphism analysis indicated that VLIDP may contribute to the progression of ALD. Based on the VLIDP pathway, two subtypes were identified. Immune microenvironment analysis indicated that the upregulated inflammatory factors may be important regulators of ALD. In conclusion, intestinal microbiota homeostasis was associated with the protective effect of riboflavin against ALD, which was likely mediated by modulating inflammatory cell infiltration. Riboflavin emerges as a promising therapeutic candidate for the management of ALD.

Protective function of sclerosing cholangitis on IBD

ObjectiveThere is a strong clinical association between IBD and primary sclerosing cholangitis (PSC), a chronic disease of the liver characterised by biliary inflammation that leads to strictures and fibrosis. Approximately...

Neoadjuvant Immunotherapy and Intestinal Microbiota: Unraveling their roles in Anastomotic Leakage and Fistula after Colorectal Cancer Surgery

This comprehensive review explores the multifaceted relationship between neoadjuvant immunotherapy, intestinal microbiota alterations, and anastomotic leakage risk in patients undergoing colectomy for colon neoplasia. With the advent of immunotherapy, remarkably immune checkpoint inhibitors, there has been a significant shift in the treatment paradigms for various cancers, including colon neoplasia. These treatments, while effective, have been associated with changes in the intestinal microbiome, which, in turn, may influence wound healing and the integrity of anastomotic sites. The review delves into the complex interactions between the immune system and the gut microbiota, examining how immunotherapy-induced dysbiosis could disrupt the delicate balance necessary for optimal anastomotic healing. It discusses the role of specific bacterial species in modulating the immune response to cancer and their impact on the efficacy of immunotherapeutic agents. Moreover, the review highlights the potential mechanisms through which the microbiota-immune system interaction could affect surgical outcomes, focusing on the development of anastomotic leaks. The implications of these findings for clinical practice are discussed, including the need for targeted strategies to modulate the gut microbiota in patients undergoing immunotherapy and colectomy. Through this discussion, the review aims to provide insights into improving patient outcomes by integrating microbiome management into colon neoplasia patients' treatment and perioperative care.

Intestinal epithelial Cldn-7 regulates intestinal inflammation by altering the gut microbiota

Background and aimTight junctions maintain gut homeostasis by forming a physical barrier that protects the gut from invasion by microbiota. Cldn-7 is an important component involved in this protection, but the relationship between Cldn-7, intestinal inflammation, and gut microbiota has not been clarified. Here, we hypothesize that Cldn-7 depletion affects intestinal inflammation by altering the gut microbiota. MethodsBased on the induced intestinal condition of Cldn-7 knockout mice (Cldn7fl/fl;villin-CreaERT2), we established the intestinal flora depletion model and colitis model by antibiotic drinking and feeding with dextran sodium sulfate (DSS). The environment of Cldn-7 gene deletion mice was changed by co-housing experiment. AB-PAS staining and Muc2 were used to detect the effect of co-housing and Cldn-7 deficiency on the mucus layer after flora depletion. qRT-PCR was used to detect the expression of intestinal inflammatory factors and AMPs in mice. Feces were collected and proportions of microbiota were analyzed by 16 S rRNA amplicon sequencing. ResultsMice in the co-housing experiment had altered intestinal microbiota, including diversity, composition, and functional prediction, compared to controls. Intestinal inflammation was restored to some extent following altered intestinal microbiota. The intestinal inflammation caused by Cldn-7 deficiency and susceptibility to DSS could be reduced after antibiotic administration compared to controls, in terms of phenotype, pathological changes, inflammatory factors, mucus barrier, and expression of AMPs. ConclusionsIn analyses of intestinal tissues, colitis induction, and gut microbiota in mice with intestinal disruption of Cldn-7, we found this protein to prevent intestinal inflammation by regulating the gut microbiota. Cldn-7might therefore be an important mediator of host–microbiome interactions. Our research has revealed that Cldn-7 plays an indispensable role in maintaining intestinal homeostasis by regulating the gut microbiota and impacting intestinal inflammation. These findings provide new insights into the pathogenesis of ulcerative colitis.

Butyrate promotes visceral hypersensitivity in IBS model via mast cell-derived DRG neuron lincRNA-01028-PKC-TRPV1 pathway.

Emerging evidence indicates that gut dysbiosis is involved in the pathogenesis of visceral hypersensitivity (VH). However, how gut microbiota contributes to the development of VH is unknown. Here, we sought to examine the signal transduction pathways from gut to dorsal root ganglion (DRG) responsible for this. Therefore, abdominal withdrawal reflex (AWR) scores, fecal output, fecal water content, and total gastrointestinal transit time (TGITT) were assessed in Con rats, VH rats, rats treated with NaB, and VH rats treated with VSL#3. Fecal microbiota and its metabolite (short-chain fatty acids, SCFAs), mast cell degranulation in colon, lincRNA-01028, miR-143, and protease kinase C (PKC) and TRPV1 expression in DRGs were further detected. VH rats showed an increased fecal water content, a shortened TGITT, an increased abundance of Clostridium sensu stricto 1 and increased butyrate in fecal samples, an increased mast cell degranulation, an increased expression of lincRNA-01028, PKC, and TRPV1, and a decreased expression of miR-143 in DRGs compared with control rats, which could be restored by the application of probiotic VSL#3. The above-mentioned detection in rats treated with butyrate was similar to that of VH rats. We further confirm whether butyrate sensitized DRG neurons by a lincRNA-01028, miR-143, and PKC-dependent mechanism via mast cell in vitro. In co-cultures, MCs treated with butyrate elicited a higher TRPV1 current, a higher expression of lincRNA-01028, PKC, and a lower expression of miR-143 in DRG neurons, which could be inhibited by a lincRNA-01028 inhibitor. These findings indicate that butyrate promotes visceral hypersensitivity via mast cell-derived DRG neuron lincRNA-01028-PKC-TRPV1 pathway.IMPORTANCEIrritable bowel syndrome (IBS), characterized by visceral hypersensitivity, is a common gastrointestinal dysfunction syndrome. Although the gut microbiota plays a role in the pathogenesis and treatment of irritable bowel syndrome (IBS), the possible underlying mechanisms are unclear. Therefore, it is of critical importance to determine the signal transduction pathways from gut to DRG responsible for this in vitro and in vivo assay. This study demonstrated that butyrate sensitized TRPV1 in DRG neurons via mast cells in vivo and in vitro by a lincRNA-01028, miR-143, and PKC-dependent mechanism. VH rats similarly showed an increased abundance of Clostridium sensu stricto 1, an increased fecal butyrate, an increased mast cell degranulation, and increased expression of TRPV1 compared with control rats, which could be restored by the application of VSL#3. In conclusion, butyrate produced by the altered intestinal microbiota is associated with increased VH.

Yeast peptides alleviate lipopolysaccharide-induced intestinal barrier damage in rabbits involving Toll-like receptor signaling pathway modulation and gut microbiota regulation.

Yeast peptides have garnered attention as valuable nutritional modifiers due to their potential health benefits. However, the precise mechanisms underlying their effects remain elusive. This study aims to explore the potential of yeast peptides, when added to diets, to mitigate lipopolysaccharide (LPS)-induced intestinal damage and microbiota alterations in rabbits. A total of 160 35-day-old Hyla line rabbits (0.96 ± 0.06 kg) were randomly assigned to 4 groups. These groups constituted a 2 × 2 factorial arrangement: basal diet (CON), 100 mg/kg yeast peptide diet (YP), LPS challenge + basal diet (LPS), LPS challenge +100 mg/kg yeast peptide diet (L-YP). The experiment spanned 35 days, encompassing a 7-day pre-feeding period and a 28-day formal trial. The results indicated that yeast peptides mitigated the intestinal barrier damage induced by LPS, as evidenced by a significant reduction in serum Diamine oxidase and D-lactic acid levels in rabbits in the L-YP group compared to the LPS group (p < 0.05). Furthermore, in the jejunum, the L-YP group exhibited a significantly higher villus height compared to the LPS group (p < 0.05). In comparison to the LPS group, the L-YP rabbits significantly upregulated the expression of Claudin-1, Occludin-1 and ZO-1 in the jejunum (p < 0.05). Compared with the CON group, the YP group significantly reduced the levels of rabbit jejunal inflammatory cytokines (TNF-α, IL-1β and IL-6) and decreased the relative mRNA expression of jejunal signaling pathway-associated inflammatory factors such as TLR4, MyD88, NF-κB and IL-1β (p < 0.05). Additionally, notable changes in the hindgut also included the concentration of short-chain fatty acids (SCFA) of the YP group was significantly higher than that of the CON group (p < 0.05). 16S RNA sequencing revealed a substantial impact of yeast peptides on the composition of the cecal microbiota. Correlation analyses indicated potential associations of specific gut microbiota with jejunal inflammatory factors, tight junction proteins, and SCFA. In conclusion, yeast peptides have shown promise in mitigating LPS-induced intestinal barrier damage in rabbits through their anti-inflammatory effects, modulation of the gut microbiota, and maintenance of intestinal tight junctions.

Antibiotics affect the pharmacokinetics of n-butylphthalide in vivo by altering the intestinal microbiota.

N-butylphthalide (NBP) is a monomeric compound extracted from natural plant celery seeds, whether intestinal microbiota alteration can modify its pharmacokinetics is still unclear. The purpose of this study is to investigate the effect of intestinal microbiota alteration on the pharmacokinetics of NBP and its related mechanisms. After treatment with antibiotics and probiotics, plasma NBP concentrations in SD rats were determined by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The effect of intestinal microbiota changes on NBP pharmacokinetics was compared. Intestinal microbiota changes after NBP treatment were analyzed by 16S rRNA sequencing. Expressions of CYP3A1 mRNA and protein in the liver and small intestine tissues under different intestinal flora conditions were determined by qRT-PCR and Western Blot. KEGG analysis was used to analyze the effect of intestinal microbiota changes on metabolic pathways. Compared to the control group, the values of Cmax, AUC0-8, AUC0-∞, t1/2 in the antibiotic group increased by 56.1% (P<0.001), 56.4% (P<0.001), 53.2% (P<0.001), and 24.4% (P<0.05), respectively. In contrast, the CL and Tmax values decreased by 57.1% (P<0.001) and 28.6% (P<0.05), respectively. Treatment with antibiotics could reduce the richness and diversity of the intestinal microbiota. CYP3A1 mRNA and protein expressions in the small intestine of the antibiotic group were 61.2% and 66.1% of those of the control group, respectively. CYP3A1 mRNA and protein expressions in the liver were 44.6% and 63.9% of those in the control group, respectively. There was no significant change in the probiotic group. KEGG analysis showed that multiple metabolic pathways were significantly down-regulated in the antibiotic group. Among them, the pathways of drug metabolism, bile acid biosynthesis and decomposition, and fatty acid synthesis and decomposition were related to NBP biological metabolism. Antibiotic treatment could affect the intestinal microbiota, decrease CYP3A1 mRNA and protein expressions and increase NBP exposure in vivo by inhibiting pathways related to NBP metabolism.

Acute Administration of Calafate (Berberis microphylla) Extract Induces the Expression of Thermogenic Markers and Modulates Gut Microbiota in Mice Fed a High-Fat Chow Diet

Introduction: Obesity, characterized by excess adipose tissue, is a major public health problem worldwide. Brown adipose tissue (BAT) and beige adipose tissue participate in thermogenesis through uncoupling protein 1 (UCP1). Polyphenols including those from Calafate (a native polyphenol-rich Patagonian berry), are considered as potential anti-obesity compounds due to their pro-thermogenic characteristics. However, polyphenols are mainly metabolized by the gut microbiota (GM) that may influence their bioactivity and bioavailability. The aim of this study was to determine the impact of dietary administration with a Calafate polyphenol-rich extract on thermogenic activity of BAT and beige adipose tissue and GM composition. Methods: Eight-week-old C57BL6 mice (n = 30) were divided into 4 groups to receive for 24 weeks a control diet (C), a high-fat diet alone (HF), or high-fat diet supplemented with Calafate extract (HFC) or the same high-fat diet supplemented with Calafate extract but treated with antibiotics (HFCAB) from week 19–20. Administration with Calafate extract (50 mg/kg per day) was carried out for 3 weeks from week 21–23 in the HFC and HFCAB groups. After euthanasia, gene expression of thermogenic markers was analyzed in BAT and inguinal white adipose tissue (iWAT). Transmission electron microscopy was performed to assess mitochondrial morphology and cristae density in BAT. GM diversity and composition were characterized by deep sequencing with the MiSeq Illumina platform. Results: Calafate extract administration had no effect on weight gain in mice fed a high-fat diet. However, it prevented alterations in mitochondrial cristae induced by HFD and increased Dio2 expression in BAT and iWAT. The intervention also influenced the GM composition, preventing changes in specific bacterial taxa induced by the high-fat diet. However, the antibiotic treatment prevented in part these effects, suggesting the implications of GM. Conclusion: These results suggest that the acute administration of a Calafate extract modulates the expression of thermogenic markers, prevents alterations in mitochondrial cristae and intestinal microbiota in preclinical models. The study highlights the complex interaction between polyphenols, thermogenesis, and the GM, providing valuable insights into their potential roles in the treatment of obesity-related metabolic diseases.

Lowering mortality risk in CR-HvKP infection in intestinal immunohistological and microbiota restoration

Gut damage during carbapenem-resistant and hypervirulent Klebsiella pneumoniae (CR-HvKP) infection is associated with a death risk. Understanding the mechanisms by which CR-HvKP causes intestinal damage and gut microbiota alteration, and the impact on immunity, is crucial for developing therapeutic strategies. This study investigated if gastrointestinal tract damage and disruption of gut microbiota induced by CR-HvKP infection undermined host immunity and facilitated multi-organ invasion of CR-HvKP; whether the therapeutic value of the rifampicin (RIF) and zidovudine (ZDV) combination was attributed to their ability to repair damages and restore host immunity was determined. A sepsis model was utilized to assess the intestinal pathological changes. Metagenomic analysis was performed to characterize the alteration of gut microbiota. The effects of the RIF and ZDV on suppressing inflammatory responses and improving immune functions and gut microbiota were evaluated by immunopathological and transcriptomic analyses. Rapid colonic damage occurred upon activation of the inflammation signaling pathways during lethal infections. Gut inflammation compromised host innate immunity and led to a significant decrease in probiotics abundance, including Bifidobacterium and Lactobacillus. Treatment with combination drugs significantly attenuated the inflammatory response, up-regulated immune cell differentiation signaling pathways, and promoted the abundance of Bifidobacterium (33.40 %). Consistently, supplementation of Bifidobacterium alone delayed the death in sepsis model. Gut inflammation and disrupted microbiota are key disease features of CR-HvKP infection but can be reversed by the RIF and ZDV drug combination. The finding that these drugs can restore host immunity through multiple mechanisms is novel and deserves further investigation of their clinical application potential.

Atorvastatin improved ulcerative colitis in association with gut microbiota-derived tryptophan metabolism

AimsAtorvastatin is a commonly used cholesterol-lowering drug that possesses non-canonical anti-inflammatory properties. However, the precise mechanism underlying its anti-inflammatory effects remains unclear. Materials and methodsThe acute phase of ulcerative colitis (UC) was induced using a 5 % dextran sulfate sodium (DSS) solution for 7 consecutive days and administrated with atorvastatin (10 mg/kg) from day 3 to day 7. mRNA-seq, histological pathology, and inflammatory response were determined. Intestinal microbiota alteration, tryptophan, and its metabolites were analyzed through 16S rRNA sequencing and untargeted metabolomics. Key findingsAtorvastatin relieved the DSS-induced UC in mice, as evidenced by colon length, body weight, disease activity index score and pathological staining. Atorvastatin treatment reduced the level of pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α). Atorvastatin also relieved the intestinal microbiota disorder caused by UC and decreased the proliferation of pernicious microbiota such as Akkermansia and Bacteroides. Atorvastatin dramatically altered tryptophan metabolism and increased the fecal contents of tryptophan, indolelactic acid (ILA), and indole-3-acetic acid (IAA). Furthermore, atorvastatin enhanced the expression level of aryl hydrocarbon receptor (AhR) and interleukin-22 (IL-22) and further promoted the expression level of intestinal tight junction proteins, such as ZO-1 and occludin, in colitis mice. SignificanceThese findings indicated that atorvastatin could alleviate UC by regulating intestinal flora disorders, promoting microbial tryptophan metabolism, and repairing the intestinal barrier.

Gut microbiota from B-cell-specific TLR9-deficient NOD mice promote IL-10+ Breg cells and protect against T1D.

Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing β cells. Toll-like receptor 9 (TLR9) plays a role in autoimmune diseases, and B cell-specific TLR9 deficiency delays T1D development. Gut microbiota are implicated in T1D, although the relationship is complex. However, the impact of B cell-specific deficiency of TLR9 on intestinal microbiota and the impact of altered intestinal microbiota on the development of T1D are unclear. This study investigated how gut microbiota and the intestinal barrier contribute to T1D development in B cell-specific TLR9-deficient NOD mice. Additionally, this study explored the role of microbiota in immune regulation and T1D onset. The study assessed gut permeability, gene expression related to gut barrier integrity, and gut microbiota composition. Antibiotics depleted gut microbiota, and fecal samples were transferred to germ-free mice. The study also examined IL-10 production, Breg cell differentiation, and their impact on T1D development. B cell-specific TLR9-deficient NOD mice exhibited increased gut permeability and downregulated gut barrier-related gene expression. Antibiotics restored gut permeability, suggesting microbiota influence. Altered microbiota were enriched in Lachnospiraceae, known for mucin degradation. Transferring this microbiota to germ-free mice increased gut permeability and promoted IL-10-expressing Breg cells. Rag-/- mice transplanted with fecal samples from Tlr9 fl/fl Cd19-Cre+ mice showed delayed diabetes onset, indicating microbiota's impact. B cell-specific TLR9 deficiency alters gut microbiota, increasing gut permeability and promoting IL-10-expressing Breg cells, which delay T1D. This study uncovers a link between TLR9, gut microbiota, and immune regulation in T1D, with implications for microbiota-targeted T1D therapies.