Chronic lead poisoning-induced budgerigar liver damage, gut microbiota dysbiosis, and metabolic disorder.

Birds are sensitive to heavy metal pollution, and lead (Pb) contamination can negatively affect their liver and gut. Therefore, we used budgerigars to examine liver and gut toxicosis caused by Pb exposure in bird, and the possible toxic mechanisms. The findings showed Pb exposure increased liver weight and decreased body weight. Moreover, histopathological and immunofluorescence assay results demonstrated obvious liver damage and cell apoptosis increased in Pb- treated budgerigars. Quantitative polymerase chain reaction (qPCR) results also showed Pb caused an increase in apoptosis by inhibiting the PPAR-γ/PI3K/Akt pathway. The gut microbe analyses indicated Firmicutes, Proteobacteria, and Bacteroidetes were dominant microbial phyla, and Network analysis results shown Arthrobacter, Bradyrhizobium and Alloprevotella as the hubs of Modules I, II, and III, respectively. Phenylpropanoids and polyketides, Organoheterocyclic compounds, Organic oxygen compounds, and Organic nitrogen compounds were dominant metabolite superclasses. Tauroursodeoxycholic acid, taurochenodeoxycholic acid (sodium salt), and 2-[2-(5-bromo-2-pyridyl)diaz-1-enyl]-5-(diethylamino)phenol were significantly enriched in the Pb-treated group. It showed that 41 Kyoto Encyclopedia of Genes and Genomes (KEGG) orthologues and 183 pathways differed between the Pb-treated and control budgerigars using microbial and metabolomic data. Moreover, orthogonal partial least-squares discrimination analysis (OPLS-DA) based on microbial and metabolite indicated distinct clusters in the Pb-treated and control groups. Additionally, the correlation analysis results indicated that a positive correlation for the Pb-treated and control groups between gut microbiota and metabolomic data, respectively. Furthermore, the microenvironment of the gut and liver were found to affect each other, and this study demonstrated heavy metal especially Pb may pose serious health risks to birds through the "gut-liver axis" too.

Gut microbiota mediates the protective effects of ß-hydroxybutyrate against cisplatin-induced acute kidney injury.

The gut microbiota has been reported to be perturbed by chemotherapeutic agents and to modulate side effects. However, the critical role of ß-hydroxybutyrate (BHB) in the regulation of the gut microbiota and the pathogenesis of chemotherapeutic agents related nephrotoxicity remains unknown. We conducted a comparative analysis of the composition and function of gut microbiota in healthy, cisplatin-challenged, BHB-treated, and high-fat diet-treated mice using 16 S rDNA gene sequencing. To understand the crucial involvement of intestinal flora in BHB's regulation of cisplatin -induced nephrotoxicity, we administered antibiotics to deplete the gut microbiota and performed fecal microbiota transplantation (FMT) before cisplatin administration. 16 S rDNA gene sequencing analysis demonstrated that both endogenous and exogenous BHB restored gut microbiota dysbiosis and cisplatin-induced intestinal barrier disruption in mice. Additionally, our findings suggested that the LPS/TLR4/NF-κB pathway was responsible for triggering renal inflammation in the gut-kidney axis. Furthermore, the ablation of the gut microbiota ablation using antibiotics eliminated the renoprotective effects of BHB against cisplatin-induced acute kidney injury. FMT also confirmed that administration of BHB-treated gut microbiota provided protection against cisplatin-induced nephrotoxicity. This study elucidated the mechanism by which BHB affects the gut microbiota mediation of cisplatin-induced nephrotoxicity by inhibiting the inflammatory response, which may help develop novel therapeutic approaches that target the composition of the microbiota.

Exposure to Microcystin-LR Promotes Colorectal Cancer Progression by Altering Gut Microbiota and Associated Metabolites in APCmin/+ Mice.

Microcystins (MCs), toxins generated by cyanobacteria, feature microcystin-LR (MC-LR) as one of the most prevalent and toxic variants in aquatic environments. MC-LR not only causes environmental problems but also presents a substantial risk to human health. This study aimed to investigate the impact of MC-LR on APCmin/+ mice, considered as an ideal animal model for intestinal tumors. We administered 40 µg/kg MC-LR to mice by gavage for 8 weeks, followed by histopathological examination, microbial diversity and metabolomics analysis. The mice exposed to MC-LR exhibited a significant promotion in colorectal cancer progression and impaired intestinal barrier function in the APCmin/+ mice compared with the control. Gut microbial dysbiosis was observed in the MC-LR-exposed mice, manifesting a notable alteration in the structure of the gut microbiota. This included the enrichment of Marvinbryantia, Gordonibacter and Family_XIII_AD3011_group and reductions in Faecalibaculum and Lachnoclostridium. Metabolomics analysis revealed increased bile acid (BA) metabolites in the intestinal contents of the mice exposed to MC-LR, particularly taurocholic acid (TCA), alpha-muricholic acid (α-MCA), 3-dehydrocholic acid (3-DHCA), 7-ketodeoxycholic acid (7-KDCA) and 12-ketodeoxycholic acid (12-KDCA). Moreover, we found that Marvinbryantia and Family_XIII_AD3011_group showed the strongest positive correlation with taurocholic acid (TCA) in the mice exposed to MC-LR. These findings provide new insights into the roles and mechanisms of MC-LR in susceptible populations, providing a basis for guiding values of MC-LR in drinking water.

L-Glutamine Substantially Improves 5-Fluorouracil-Induced Intestinal Mucositis by Modulating Gut Microbiota and Maintaining the Integrity of the Gut Barrier in Mice.

SCOPE: This study investigates the potential of glutamine to mitigate intestinal mucositis and dysbiosis caused by the chemotherapeutic agent 5-fluorouracil (5-FU). METHODS AND RESULTS: Over twelve days, Institute of Cancer Research (ICR) mice are given low (0.5 mg kg-1) or high (2 mg kg-1) doses of L-Glutamine daily, with 5-FU (50 mg kg-1) administered between days six and nine. Mice receiving only 5-FU exhibited weight loss, diarrhea, abnormal cell growth, and colonic inflammation, correlated with decreased mucin proteins, increased endotoxins, reduced fecal short-chain fatty acids, and altered gut microbiota. Glutamine supplementation counteracted these effects by inhibiting the Toll-like receptor 4/nuclear factor kappa B (TLR4/NF-κB) pathway, modulating nuclear factor erythroid 2-related factor 2/heme oxygenase 1 (Nrf2/HO-1) oxidative stress proteins, and increasing mammalian target of rapamycin (mTOR) levels, thereby enhancing microbial diversity and protecting intestinal mucosa. CONCLUSIONS: These findings underscore glutamine's potential in preventing 5-FU-induced mucositis by modulating gut microbiota and inflammation pathways.

Long-term Bisphenol S exposure induced gut microbiota dysbiosis, obesity, hepatic lipid accumulation, intestinal lesions and dyslipidemia in mice.

Bisphenol S (BPS) is a commonly detected chemical raw material in water, which poses significant threats to both the ecological environment and human health. Despite being recognized as a typical endocrine disruptor and a substitute for Bisphenol A, the toxicological effects of BPS remain nonnegligible. In order to comprehensively understand the health impacts of BPS, a long-term (154 days) exposure experiment was conducted on mice, during which the physiological indicators of the liver, intestine, and blood were observed. The findings revealed that exposure to BPS resulted in dysbiosis of the gut microbiota, obesity, hepatic lipid accumulation, intestinal lesions, and dyslipidemia. Furthermore, there exists a significant correlation between gut microbiota and indicators of host health. Consequently, the identification of specific gut microbiota can be considered as potential biomarkers for the evaluation of risk associated with BPS. This study will effectively address the deficiency in toxicological data pertaining to BPS. The novel BPS data obtained from this research can serve as a valuable reference for professionals in the field.

The role of morphine- and fentanyl-induced impairment of intestinal epithelial antibacterial activity in dysbiosis and its impact on the microbiota-gut-brain axis.

Recent evidence suggests that chronic exposure to opioid analgesics such as morphine disrupts the intestinal epithelial layer and causes intestinal dysbiosis. Depleting gut bacteria can preclude the development of tolerance to opioid-induced antinociception, suggesting an important role of the gut-brain axis in mediating opioid effects. The mechanism underlying opioid-induced dysbiosis, however, remains unclear. Host-produced antimicrobial peptides (AMPs) are critical for the integrity of the intestinal epithelial barrier as they prevent the pathogenesis of the enteric microbiota. Here, we report that chronic morphine or fentanyl exposure reduces the antimicrobial activity in the ileum, resulting in changes in the composition of bacteria. Fecal samples from morphine-treated mice had increased levels of Akkermansia muciniphila with a shift in the abundance ratio of Firmicutes and Bacteroidetes. Fecal microbial transplant (FMT) from morphine-naïve mice or oral supplementation with butyrate restored (a) the antimicrobial activity, (b) the expression of the antimicrobial peptide, Reg3γ, (c) prevented the increase in intestinal permeability and (d) prevented the development of antinociceptive tolerance in morphine-dependent mice. Improved epithelial barrier function with FMT or butyrate prevented the enrichment of the mucin-degrading A. muciniphila in morphine-dependent mice. These data implicate impairment of the antimicrobial activity of the intestinal epithelium as a mechanism by which opioids disrupt the microbiota-gut-brain axis.

Efficacy and safety of chemoimmunotherapy in advanced non-small cell lung cancer patients with antibiotics-induced dysbiosis: a propensity-matched real-world analysis.

PURPOSE: The gut microbiota is hypothesized as a prognostic biomarker for cancer immunotherapy. Antibiotic-induced dysbiosis negatively affects the clinical outcomes of immunotherapy. However, the effect of dysbiosis on the efficacy and safety of Chemoimmunotherapy (chemo-IOs), the frontline standard of care, in advanced non-small cell lung cancer (NSCLC) remains unknown. We aimed to compare the efficacy and safety of chemo-IOs in patients exposed to antibiotics before treatment with those of patients who were not exposed. METHODS: We retrospectively reviewed patients with advanced NSCLC treated with first-line chemo-IOs between 2018 and 2020 at the National Cancer Center Hospital. The patients were divided into two groups: those exposed to antibiotics within 30 days before induction therapy (ABx group) and those did not antibiotics (Non-ABx group). Propensity score matching was used to control for potential confounding factors. Clinical outcomes including progression-free survival (PFS), overall survival (OS), and immune-related adverse events (irAEs) were compared. RESULTS: Of 201 eligible patients, 21 were in the ABx group, and 42 were in the non-ABx group after propensity score matching. No differences in PFS or OS emerged between the two groups (ABx group vs. Non-ABx group) (PFS:7.0 months vs. 6.4 months, hazard ratio [HR] 0.89; 95% confidence interval [CI], 0.49-1.63, OS:20.4 months vs. 20.1 months, HR 0.87; 95% CI 0.44-1.71). The frequency of irAEs before propensity score matching was similar across any-grade irAEs (39.4% vs. 42.9%) or grade 3 or higher irAEs (9.1% vs. 11.3%). CONCLUSION: Antibiotic-induced dysbiosis may not affect the efficacy of chemo-IOs in patients with advanced NSCLC.

Role of mucositis in predicting gut microbiota composition in people with cancer.

PURPOSE OF REVIEW: Disruption of the precious ecosystem of micro-organisms that reside in the gut - the gut microbiota - is rapidly emerging as a key driver of the adverse side effects/toxicities caused by numerous anti-cancer agents. Although the contribution of the gut microbiota to these toxicities is understood with ever increasing precision, the cause of microbial disruption (dysbiosis) remains poorly understood. Here, we discuss current evidence on the cause(s) of dysbiosis after cancer therapy, positioning breakdown of the intestinal mucosa (mucositis) as a central cause. RECENT FINDINGS: Dysbiosis in people with cancer has historically been attributed to extensive antibiotic use. However, evidence now suggests that certain antibiotics have minimal impacts on the microbiota. Indeed, recent evidence shows that the type of cancer therapy predicts microbiota composition independently of antibiotics. Given most anti-cancer drugs have modest effects on microbes directly, this suggests that their impact on the gut microenvironment, in particular the mucosa, which is highly vulnerable to cytotoxicity, is a likely cause of dysbiosis. Here, we outline evidence that support this hypothesis, and discuss the associated clinical implications/opportunities. SUMMARY: The concept that mucositis dictates microbiota compositions provides two important implications for clinical practice. Firstly, it reiterates the importance of prioritising the development of novel mucoprotectants that preserve mucosal integrity, and indirectly support microbial stability. Secondly, it provides an opportunity to identify dysbiotic events and associated consequences using readily accessible, minimally invasive biomarkers of mucositis such as plasma citrulline.

Inulin mitigated antibiotic-induced intestinal microbiota dysbiosis - a comparison of different supplementation stages.

Antibiotics are unavoidable to be prescribed to subjects due to different reasons, and they decrease the relative abundance of beneficial microbes. Inulin, a fructan type of polysaccharide carbohydrate, on the contrary, could promote the growth of beneficial microbes. In this study, we investigated the effect of inulin on antibiotic-induced intestinal microbiota dysbiosis and compared their overall impact at different supplementation stages, i.e., post-antibiotic, at the time of antibiotic administration or prior to antibiotic treatment, in the C57BL/6 mice model. Although supplementation of inulin after antibiotic treatment could aid in the reconstruction of the intestinal microbial community its overall impact was limited and no remarkable differences were identified as compared to the spontaneous restoration. On the contrary, the effect of simultaneous and pre-supplementation was more remarkable. Simultaneous inulin supplementation significantly mitigated the antibiotic-induced dysbiosis based on alterations as evaluated using weighted and unweighted UniFrac distance between baseline and after treatment. Moreover, comparing the effect of simultaneous supplementation, pre-supplemented inulin further mitigated the antibiotic-induced dysbiosis, especially on the relative abundance of dominant microbes. Collectively, the current study found that the use of inulin could alleviate antibiotic-induced microbiota dysbiosis, and the best supplementation stage (overall effect as evaluated by beta diversity distance changes) was before the antibiotic treatment, then simultaneous supplementation and supplementation after the antibiotic treatment.

Baicalin restore intestinal damage after early-life antibiotic therapy: the role of the MAPK signaling pathway.

Antibiotic related intestinal injury in early life affects subsequent health and susceptibility. Here, we employed weaned piglets as a model to investigate the protective effects of baicalin against early-life antibiotic exposure-induced microbial dysbiosis. Piglets exposed to lincomycin showed a marked reduction in body weight (p < 0.05) and deterioration of jejunum intestinal morphology, alongside an increase in antibiotic-resistant bacteria such as Staphylococcus, Dolosicoccus, Escherichia-Shigella, and Raoultella. In contrast, baicalin treatment resulted in body weights, intestinal morphology, and microbial profiles that closely resembled those of the control group (p > 0.05), with a significant increase in norank_f_Muribaculaceae and Prevotellaceae_NK3B31_group colonization compared with lincomycin group (p < 0.05). Further analysis through fecal microbial transplantation into mice revealed that lincomycin exposure led to significant alterations in intestinal morphology and microbial composition, notably increasing harmful microbes and decreasing beneficial ones such as norank_Muribaculaceae and Akkermansia (p < 0.05). This shift was associated with an increase in harmful metabolites and disruption of the calcium signaling pathway gene expression. Conversely, baicalin supplementation not only counteracted these effects but also enhanced beneficial metabolites and regulated genes within the MAPK signaling pathway (MAP3K11, MAP4K2, MAPK7, MAPK13) and calcium channel proteins (ORA13, CACNA1S, CACNA1F and CACNG8), suggesting a mechanism through which baicalin mitigates antibiotic-induced intestinal and microbial disturbances. These findings highlight baicalin's potential as a plant extract-based intervention for preventing antibiotic-related intestinal injury and offer new targets for therapeutic strategies.

In situ profiling reveals spatially metabolic injury in the initiation of polystyrene nanoplastic-derived intestinal epithelial injury in mice.

Despite increasing concerns regarding the harmful effects of plastic-induced gut injury, mechanisms underlying the initiation of plastic-derived intestinal toxicity remain unelucidated. Here, mice were subjected to long-term exposure to polystyrene nanoplastics (PS-NPs) of varying sizes (80, 200, and 1000 nm) at doses relevant to human dietary exposure. PS-NPs exposure did not induce a significant inflammatory response, histopathological damage, or intestinal epithelial dysfunction in mice at a dosage of 0.5 mg/kg/day for 28 days. However, PS-NPs were detected in the mouse intestine, coupled with observed microstructural changes in enterocytes, including mild villous lodging, mitochondrial membrane rupture, and endoplasmic reticulum (ER) dysfunction, suggesting that intestinal-accumulating PS-NPs resulted in the onset of intestinal epithelial injury in mice. Mechanistically, intragastric PS-NPs induced gut microbiota dysbiosis and specific bacteria alterations, accompanied by abnormal metabolic fingerprinting in the plasma. Furthermore, integrated data from mass spectrometry imaging-based spatial metabolomics and metallomics revealed that PS-NPs exposure led to gut dysbiosis-associated host metabolic reprogramming and initiated intestinal injury. These findings provide novel insights into the critical gut microbial-host metabolic remodeling events vital to nanoplastic-derived-initiated intestinal injury.

Exposure to environmental toxicants is associated with gut microbiome dysbiosis, insulin resistance and obesity.

Environmental toxicants (ETs) are associated with adverse health outcomes. Here we hypothesized that exposures to ETs are linked with obesity and insulin resistance partly through a dysbiotic gut microbiota and changes in the serum levels of secondary bile acids (BAs). Serum BAs, per- and polyfluoroalkyl substances (PFAS) and additional twenty-seven ETs were measured by mass spectrometry in 264 Danes (121 men and 143 women, aged 56.6 ± 7.3 years, BMI 29.7 ± 6.0 kg/m2) using a combination of targeted and suspect screening approaches. Bacterial species were identified based on whole-genome shotgun sequencing (WGS) of DNA extracted from stool samples. Personalized genome-scale metabolic models (GEMs) of gut microbial communities were developed to elucidate regulation of BA pathways. Subsequently, we compared findings from the human study with metabolic implications of exposure to perfluorooctanoic acid (PFOA) in PPARα-humanized mice. Serum levels of twelve ETs were associated with obesity and insulin resistance. High chemical exposure was associated with increased abundance of several bacterial species (spp.) of genus (Anaerotruncus, Alistipes, Bacteroides, Bifidobacterium, Clostridium, Dorea, Eubacterium, Escherichia, Prevotella, Ruminococcus, Roseburia, Subdoligranulum, and Veillonella), particularly in men. Conversely, females in the higher exposure group, showed a decrease abundance of Prevotella copri. High concentrations of ETs were correlated with increased levels of secondary BAs including lithocholic acid (LCA), and decreased levels of ursodeoxycholic acid (UDCA). In silico causal inference analyses suggested that microbiome-derived secondary BAs may act as mediators between ETs and obesity or insulin resistance. Furthermore, these findings were substantiated by the outcome of the murine exposure study. Our combined epidemiological and mechanistic studies suggest that multiple ETs may play a role in the etiology of obesity and insulin resistance. These effects may arise from disruptions in the microbial biosynthesis of secondary BAs.

Lycium barbarum polysaccharide mitigated methamphetamine addiction and altered methamphetamine-induced gut microbiota dysbiosis.

Methamphetamine (MA) is a highly addictive mental stimulant, and MA abuse remains a significant public health problem worldwide, while effective treatment options are limited. Lycium barbarum polysaccharide (LBP), a major effective component extracted from Lycium barbarum, has potential health-promoting effects on the nervous system; however, its role in MA dependence remains unclear. In this study, the conditioned place preference (CPP) of MA addiction in adult male mice was established to detect changes in gut microbiota profiles after LBP treatment through 16S rRNA gene sequencing. Our results found that LBP administration could alleviate MA-induced CPP and hyperactivity. Interestingly, LBP improved MA-induced gut microbiota dysbiosis by increasing some beneficial autochthonous genus abundances, such as Allobaculum, Gordonibacter, and Ileibacterium. MA exposure induced the co-occurrence network of intestinal microbiota to become weaker and more unstable when compared with the control group, while LBP changed the above effects when compared with the MA group. Bacterial gene function prediction showed that amphetamine addiction, cocaine addiction, and short-chain fatty acid metabolism were enriched. These findings reveal that LBP might regulate MA-induced gut microbiota and behavior changes, which showed potential therapeutic applicability in treating MA addiction by regulating the gut microbiota.

Prenatal PFAS exposure, gut microbiota dysbiosis, and neurobehavioral development in childhood.

Studies on the role of the gut microbiota in the associations between per- and polyfluoroalkyl substance (PFAS) exposure and adverse neurodevelopment are limited. Umbilical cord serum and faeces samples were collected from children, and the Strengths and Difficulties Questionnaire (SDQ) was conducted. Generalized linear models, linear mixed-effects models, multivariate analysis by linear models and microbiome regression-based kernel association tests were used to evaluate the associations among PFAS exposure, the gut microbiota, and neurobehavioural development. Perfluorohexane sulfonic acid (PFHxS) exposure was associated with increased scores for conduct problems and externalizing problems, as well as altered gut microbiota alpha and beta diversity. PFHxS concentrations were associated with higher relative abundances of Enterococcus spp. but lower relative abundances of several short-chain fatty acid-producing genera (e.g., Ruminococcus gauvreauii group spp.). PFHxS exposure was also associated with increased oxidative phosphorylation. Alpha and beta diversity were found significantly associated with conduct problems and externalizing problems. Ruminococcus gauvreauii group spp. abundance was positively correlated with prosocial behavior scores. Increased alpha diversity played a mediating role in the associations of PFHxS exposure with conduct problems. Our results suggest that the gut microbiota might play an important role in PFAS neurotoxicity, which may have implications for PFAS control.

Polystyrene microplastics promote intestinal colonization of Aeromonas veronii through inducing intestinal microbiota dysbiosis.

The premise that pathogen colonized microplastics (MPs) can promote the spread of pathogens has been widely recognized, however, their role in the colonization of pathogens in a host intestine has not been fully elucidated. Here, we investigated the effect of polystyrene MPs (PS-MPs) on the colonization levels of Aeromonas veronii, a typical aquatic pathogen, in the loach (Misgurnus anguillicaudatus) intestine. Multiple types of MPs were observed to promote the intestinal colonization of A. veronii, among which PS-MPs exhibited the most significant stimulating effect (67.18% increase in A. veronii colonization). PS-MPs inflicted serious damage to the intestinal tracts of loaches and induced intestinal microbiota dysbiosis. The abundance of certain intestinal bacteria with resistance against A. veronii colonization decreased, with Lactococcus sp. showing the strongest colonization resistance (73.64% decline in A. veronii colonization). Fecal microbiota transplantation was performed, which revealed that PS-MPs induced intestinal microbiota dysbiosis was responsible for the increased colonization of A. veronii in the intestine. It was determined that PS-MPs reshaped the intestinal microbiota community to attenuate the colonization resistance against A. veronii colonization, resulting in an elevated intestinal colonization levels of A. veronii.

Bisphenol A exposure affects specific gut taxa and drives microbiota dynamics in childhood obesity.

Cumulative xenobiotic exposure has an environmental and human health impact which is currently assessed under the One Health approach. Bisphenol A (BPA) exposure and its potential link with childhood obesity that has parallelly increased during the last decades deserve special attention. It stands during prenatal or early life and could trigger comorbidities and non-communicable diseases along life. Accumulation in the nature of synthetic chemicals supports the "environmental obesogen" hypothesis, such as BPA. This estrogen-mimicking xenobiotic has shown endocrine disruptive and obesogenic effects accompanied by gut microbiota misbalance that is not yet well elucidated. This study aimed to investigate specific microbiota taxa isolated and selected by direct BPA exposure and reveal its role on the overall children microbiota community and dynamics, driving toward specific obesity dysbiosis. A total of 333 BPA-resistant isolated species obtained through culturing after several exposure conditions were evaluated for their role and interplay with the global microbial community. The selected BPA-cultured taxa biomarkers showed a significant impact on alpha diversity. Specifically, Clostridium and Romboutsia were positively associated promoting the richness of microbiota communities, while Intestinibacter, Escherichia-Shigella, Bifidobacterium, and Lactobacillus were negatively associated. Microbial community dynamics and networks analyses showed differences according to the study groups. The normal-weight children group exhibited a more enriched, structured, and connected taxa network compared to overweight and obese groups, which could represent a more resilient community to xenobiotic substances. In this sense, subnetwork analysis generated with the BPA-cultured genera showed a correlation between taxa connectivity and more diverse potential enzymatic BPA degradation capacities.IMPORTANCEOur findings indicate how gut microbiota taxa with the capacity to grow in BPA were differentially represented within differential body mass index children study groups and how these taxa affected the overall dynamics toward patterns of diversity generally recognized in dysbiosis. Community network and subnetwork analyses corroborated the better connectedness and stability profiles for normal-weight group compared to the overweight and obese groups.

Consumption of Apigenin Prevents Radiation-induced Gut Dysbiosis in Male C57BL/6J Mice Exposed to Silicon Ions.

The search for medical treatments to prevent radiation-induced damage to gastrointestinal tissue is crucial as such injuries can be fatal. This study aimed to investigate the effects of apigenin (AP) on the gut microbiome of irradiated mice, as it is a promising radiation countermeasure. Male C57BL/6J mice were divided into four groups, with six mice in each group. Two groups were given food with apigenin (20 mg/kg body weight or AP 20) before and after exposure to 0 or 50 cGy of silicon (28Si) ions, while another two groups of mice received regular diet without apigenin (0 mg/kg body weight or AP 0) before and after irradiation. The duodenum, the primary site for oral AP absorption, was collected from each mouse seven days after radiation exposure. Using 16S rRNA amplicon sequencing, we found significant differences in microbial diversity among groups. Firmicutes and Bacteroidetes were the major phyla for all groups, while actinobacterial and proteobacterial sequences represented only a small percentage. Mice not given dietary apigenin had a higher Firmicutes and Bacteroidetes (F/B) ratio and an imbalanced duodenal microbiota after exposure to radiation, while irradiated mice given apigenin had maintained homeostasis of the microbiota. Additionally, irradiated mice not given apigenin had decreased probiotic bacteria abundance and increased inflammation, while apigenin-supplemented mice had reduced inflammation and restored normal histological structure. In conclusion, our results demonstrate the potential of dietary apigenin as a countermeasure against radiation-induced gut injuries due to its anti-inflammatory activity, reduction of gut microbiota dysbiosis, and increase in probiotic bacteria (e.g., Lachnospiraceae, Muribaculaceae and Bifidobacteriaceae).

Development of a new antibiotic-induced dysbiosis model of the canine colonic microbiota.

As in humans, antibiotics are widely used in dogs to treat gastrointestinal infections, contributing to the global burden of antimicrobial resistance on both human and animal health. Close contact between pets and their owners can lead to horizontal transfer of gut microbes, including transmission of antibiotic resistance. Nevertheless, until now, the impact of antibiotics on the canine gut microbiota has been poorly described. The aim of this study was to adapt the canine mucosal artificial colon (CANIM-ARCOL) model, reproducing the main nutritional, physicochemical and microbial parameters found in the large intestine of the dog to simulate an antibiotic-induced perturbation. Following initial investigation of five antibiotic cocktails at in-field doses, a 5-day regimen of metronidazole/enrofloxacin (ME) was selected for further model development. Two CANIM-ARCOL bioreactors were inoculated with a faecal sample (n=2 donors) and run in parallel for 26 days under control or antibiotic conditions. ME reduced microbial diversity and induced major shifts in bacterial populations, leading to a state of dysbiosis characterized by an increase in the relative abundance of Streptococcaceae, Lactobacillaceae and Enterobacteriaceae, and a decrease in the relative abundance of Bacteroidaceae, Fusobacteriota and Clostridiaceae. Overall, mucus-associated microbiota were less impacted by antibiotics than luminal microbes. Microbial alterations were associated with drastic decreases in gas production and short-chain fatty acid concentrations. Finally, the model was well validated through in-vitro-in-vivo comparisons in a study in dogs. The CANIM-ARCOL model provides a relevant platform as an alternative to in-vivo assays for an in-depth understanding of antibiotic-microbiota interactions and further testing of restoration strategies at individual level.

Prescription opioids induced microbial dysbiosis worsens severity of chronic pancreatitis and drives pain hypersensitivity.

Opioids, such as morphine and oxycodone, are widely used for pain management associated with chronic pancreatitis (CP); however, their impact on the progression and pain sensitivity of CP has never been evaluated. This report investigates the impact of opioid use on the severity of CP, pain sensitivity, and the gut microbiome. C57BL/6 mice were divided into control, CP, CP with morphine/oxycodone, and either morphine or oxycodone alone groups. CP was induced by administration of caerulein (50ug/kg/h, i.p. hourly x7, twice a week for 10 weeks). The mouse-to-pancreas weight ratio, histology, and Sirius red staining were performed to measure CP severity. Tail flick and paw pressure assays were used to measure thermal and mechanical pain. DNA was extracted from the fecal samples and subjected to whole-genome shotgun sequencing. Germ-free mice were used to validate the role of gut microbiome in sensitizing acute pancreatic inflammation. Opioid treatment exacerbates CP by increasing pancreatic necrosis, fibrosis, and immune-cell infiltration. Opioid-treated CP mice exhibited enhanced pain hypersensitivity and showed distinct clustering of the gut microbiome compared to untreated CP mice, with severely compromised gut barrier integrity. Fecal microbiota transplantation (FMT) from opioid-treated CP mice into germ-free mice resulted in pancreatic inflammation in response to a suboptimal caerulein dose. Together, these analyses revealed that opioids worsen the severity of CP and induce significant alterations in pain sensitivity and the gut microbiome in a caerulein CP mouse model. Microbial dysbiosis plays an important role in sensitizing the host to pancreatic inflammation.

Gut microbiota contributes to bisphenol A-induced maternal intestinal and placental apoptosis, oxidative stress, and fetal growth restriction in pregnant ewe model by regulating gut-placental axis.

BACKGROUND: Bisphenol A (BPA) is an environmental contaminant with endocrine-disrupting properties that induce fetal growth restriction (FGR). Previous studies on pregnant ewes revealed that BPA exposure causes placental apoptosis and oxidative stress (OS) and decreases placental efficiency, consequently leading to FGR. Nonetheless, the response of gut microbiota to BPA exposure and its role in aggravating BPA-mediated apoptosis, autophagy, mitochondrial dysfunction, endoplasmic reticulum stress (ERS), and OS of the maternal placenta and intestine are unclear in an ovine model of gestation. RESULTS: Two pregnant ewe groups (n = 8/group) were given either a subcutaneous (sc) injection of corn oil (CON group) or BPA (5 mg/kg/day) dissolved in corn oil (BPA group) once daily, from day 40 to day 110 of gestation. The maternal colonic digesta and the ileum and placental tissue samples were collected to measure the biomarkers of autophagy, apoptosis, mitochondrial dysfunction, ERS, and OS. To investigate the link between gut microbiota and the BPA-induced FGR in pregnant ewes, gut microbiota transplantation (GMT) was conducted in two pregnant mice groups (n = 10/group) from day 0 to day 18 of gestation after removing their intestinal microbiota by antibiotics. The results indicated that BPA aggravates apoptosis, ERS and autophagy, mitochondrial function injury of the placenta and ileum, and gut microbiota dysbiosis in pregnant ewes. GMT indicated that BPA-induced ERS, autophagy, and apoptosis in the ileum and placenta are attributed to gut microbiota dysbiosis resulting from BPA exposure. CONCLUSIONS: Our findings indicate the underlying role of gut microbiota dysbiosis and gut-placental axis behind the BPA-mediated maternal intestinal and placental apoptosis, OS, and FGR. The findings further provide novel insights into modulating the balance of gut microbiota through medication or probiotics, functioning via the gut-placental axis, to alleviate gut-derived placental impairment or FGR. Video Abstract.