Induce Gut Dysbiosis Research Articles

Gut dysbiosis mediates the association between antibiotic exposure and chronic disease

Antibiotics are safe, effective drugs and continue to save millions of lives and prevent long-term illness worldwide. A large body of epidemiological, interventional and experimental evidence shows that exposure to antibiotics has long-term negative effects on human health. We reviewed the literature data on the links between antibiotic exposure, gut dysbiosis, and chronic disease (notably with regard to the “developmental origins of health and disease” (“DOHaD”) approach). Molecular biology studies show that the systemic administration of antibiotic to infants has a rapid onset but also often a long-lasting impact on the microbial composition of the gut. Along with other environmental factors (e.g., an unhealthy “Western” diet and sedentary behavior), antibiotics induce gut dysbiosis, which can be defined as the disruption of a previously stable, functionally complete microbiota. Gut dysbiosis many harmful long-term effects on health. Associations between early-life exposure to antibiotics have been reported for chronic diseases, including inflammatory bowel disease, celiac disease, some cancers, metabolic diseases (obesity and type 2 diabetes), allergic diseases, autoimmune disorders, atherosclerosis, arthritis, and neurodevelopmental, neurodegenerative and other neurological diseases. In mechanistic terms, gut dysbiosis influences chronic disease through direct effects on mucosal immune and inflammatory pathways, plus a wide array of direct or indirect effects of short-chain fatty acids, the enteric nervous system, peristaltic motility, the production of hormones and neurotransmitters, and the loss of intestinal barrier integrity (notably with leakage of the pro-inflammatory endotoxin lipopolysaccharide into the circulation). To mitigate dysbiosis, the administration of probiotics in patients with chronic disease is often (but not always) associated with positive effects on clinical markers (e.g., disease scores) and biomarkers of inflammation and immune activation. Meta-analyses are complicated by differences in probiotic composition, dose level, and treatment duration, and large, randomized, controlled clinical trials are lacking in many disease areas. In view of the critical importance of deciding whether or not to prescribe antibiotics (especially to children), we suggest that the DOHaD concept can be logically extended to “gastrointestinal origins of health and disease” (“GOHaD”) or even “microbiotic origins of health and disease” (“MOHaD”).

How Gut Microbiome Perturbation Caused by Antibiotic Pre-Treatments Affected the Conjugative Transfer of Antimicrobial Resistance Genes

The global spread of antimicrobial resistance genes (ARGs) poses a significant threat to public health. While antibiotics effectively treat bacterial infections, they can also induce gut dysbiosis, the severity of which varies depending on the specific antibiotic treatment used. However, it remains unclear how gut dysbiosis affects the mobility and dynamics of ARGs. To address this, mice were pre-treated with streptomycin, ampicillin, or sulfamethazine, and then orally inoculated with Salmonella enterica serovar Typhimurium and S. Heidelberg carrying a multi-drug resistance IncA/C plasmid. The streptomycin pre-treatment caused severe microbiome perturbation, promoting the high-density colonization of S. Heidelberg and S. Typhimurium, and enabling an IncA/C transfer from S. Heidelberg to S. Typhimurium and a commensal Escherichia coli. The ampicillin pre-treatment induced moderate microbiome perturbation, supporting only S. Heidelberg colonization and the IncA/C transfer to commensal E. coli. The sulfamethazine pre-treatment led to mild microbiome perturbation, favoring neither Salmonella spp. colonization nor a conjugative plasmid transfer. The degree of gut dysbiosis also influenced the enrichment or depletion of the ARGs associated with mobile plasmids or core commensal bacteria, respectively. These findings underscore the significance of pre-existing gut dysbiosis induced by various antibiotic treatments on ARG dissemination and may inform prudent antibiotic use practices.

A-239 Cxcl10 induced gut dysbiosis exacerbates acute lung injury and secondary infection in influenza by inhibiting il22

Abstract Background Secondary infections are the most cause of severe pulmonary injury and death in influenza. CXCL10, known as interferon γ-induced protein 10(IP-10), is highly upregulated in response to IFN-γstimulation during influenza. Previous studies show that CXCL10 contributes to bacteria co-infections and worse finales in influenza. However, the underlying mechanisms by which CXCL10 facilitate secondary infections remains unclear. Emerging evidences show that influenza virus infections disturb the composition and function of gut microbiota, which in turn influences the infection process. Herein, we aimed to explore whether CXCL10 could affect the progress of influenza infection and secondary infection in a gut microbiota dependent manner. Methods CXCL10 knockout mice were used to determine the role of CXCL10 in staphylococcus aureus co-infection after influenza A virus (IAV) infection. Lung tissues from CXCL10 knockout mice were collected for Transcriptomics sequencing. Feces from mice and clinicals including IAV patients and healthy individuals were collected for Metagenomic sequencing. Paired serum samples were collected for Metabolomic sequencing. QRT-PCR was performed to determine the expression of inflammatory factors in lung tissues from CXCL10 knockout mice. Elisa assays were used to measure the serum expression levels of CXCL10 and IL22. Flow cytometry was applied to detect the proportion of IL22+ cells. Fecal microbiota transplantation (FMT) was applied to confirm that CXCL10 plays an adverse role in acute lung injury and staphylococcus aureus co-infection after IAV infection by disrupting intestinal microbiome homeostasis. Results CXCL10 aggravated acute lung injury and promoted staphylococcus aureus coinfection after IAV infection. Transcriptomics sequencing results suggests improved cell membrane integrity and regeneration of epithelial cells after IAV infection in CXCL10 knockout mice with an upregulation of integrity proteins. CXCL10 knockout significantly increased the expression levels of IL22 without influencing virus duplication. rh-IL22 protects lung epithelial cell from staphylococcus aureus co-infection in influenza and increased the expression of tight junction proteins. The gut microbiome shows different structures between wild type mice and knockout mice, as well as clinical samples according to serum CXCL10 expression levels. We found some genera were markedly increased in knockout mice and patients with low serum CXCL10 expression levels including Lactobacillus, Lachnospiraceae, Oscillibacter, Odoribacter, Eubacterium. FMT from patients with low serum CXCL10 levels and healthy individuals ameliorating lung pathological damage. Conclusions This study interpreted that CXCL10 exacerbates acute lung injury and secondary infection in influenza by inducing gut dysbiosis, suggesting that balancing the gut flora could be assistant treatments to protect from acute lung injury and secondary infections in influenza. And IL22 may be a potential mediating factor between gut-lung axis to improve epithelial integrity.

An Update on Blastocystis: Possible Mechanisms of Blastocystis-Mediated Colorectal Cancer.

Blastocystis is an anaerobic parasite that colonizes the intestinal tract of humans and animals. When it was first discovered, Blastocystis was considered to be a normal flora with beneficial effects on human health, such as maintaining gut hemostasis and improving intestinal barrier integrity. Later, with increasing research on Blastocystis, reports showed that Blastocystis sp. is associated with gastrointestinal disorders, colorectal cancer (CRC), and neurological disorders. The association between Blastocystis sp. and CRC has been confirmed in several countries. Blastocystis sp. can mediate CRC via similar mechanisms to CRC-associated bacteria, including infection-mediated inflammation, increased oxidative stress, induced gut dysbiosis, and damage to intestinal integrity, leading to a leaky gut. IL-8 is the main inflammatory cytokine released from epithelial cells and can promote CRC development. The causal association of Blastocystis sp. with other diseases needs further investigation. In this review, we have provided an update on Blastocystis sp. and summarized the debate about the beneficial and harmful effects of this parasite. We have also highlighted the possible mechanisms of Blastocystis-mediated CRC.

An Enteric Bacterial Infection Triggers Neuroinflammation and Neurobehavioral Impairment in 3xTg-AD Transgenic Mice.

Klebsiella pneumoniae is infamous for hospital-acquired infections and sepsis, which have also been linked to Alzheimer disease (AD)-related neuroinflammatory and neurodegenerative impairment. However, its causative and mechanistic role in AD pathology remains unstudied. A preclinical model of K. pneumoniae enteric infection and colonization is developed in an AD model (3xTg-AD mice) to investigate whether and how K. pneumoniae pathogenesis exacerbates neuropathogenesis via the gut-blood-brain axis. K. pneumoniae, particularly under antibiotic-induced dysbiosis, was able to translocate from the gut to the bloodstream by penetrating the gut epithelial barrier. Subsequently, K. pneumoniae infiltrated the brain by breaching the blood-brain barrier. Significant neuroinflammatory phenotype was observed in mice with K. pneumoniae brain infection. K. pneumoniae-infected mice also exhibited impaired neurobehavioral function and elevated total tau levels in the brain. Metagenomic analyses revealed an inverse correlation of K. pneumoniae with gut biome diversity and commensal bacteria, highlighting how antibiotic-induced dysbiosis triggers an enteroseptic "pathobiome" signature implicated in gut-brain perturbations. The findings demonstrate how infectious agents following hospital-acquired infections and consequent antibiotic regimen may induce gut dysbiosis and pathobiome and increase the risk of sepsis, thereby increasing the predisposition to neuroinflammatory and neurobehavioral impairments via breaching the gut-blood-brain barrier.

Changes in short-chain fatty acids affect brain development in mice with early life antibiotic-induced dysbacteriosis.

Early enteral nutrition and the gut microbiota profoundly influence neonatal brain development, with short-chain fatty acids (SCFAs) from the microbiota playing a pivotal role. Understanding the relationship between dysbiosis, SCFAs, and brain development is crucial. In this study, we investigated the impact of antibiotics on the concentration of SCFAs in neonatal feces. Additionally, we developed a model of gut dysbiosis in neonatal mice to examine the potential relationship between this imbalance, SCFAs production, and brain function development. We measured the SCFAs content in the feces of two groups of neonates, categorized based on whether antibiotics were used, and conducted the Neonatal Behavioral Neurological Assessment (NBNA) test on all neonates. Then we evaluated fecal SCFAs levels in neonates and neonatal mice post-antibiotic treatment using liquid chromatography-mass spectrometry (LC-MS) analysis. Morris water maze (MWM) tests assessed behavioral performance, and western blot analysis examined brain tissue-related proteins-neuron-specific enolase (NSE), ionized calcium binding adaptor molecule-1 (IBA1), and myelin basic proteins (MBP). The use of antibiotics did not affect the NBNA scores of the two groups of neonates, but it did reduce the SCFAs content in their feces. Antibiotic administration induced gut dysbiosis in mice, resulting in decreased IBA1 and MBP expression. Interventions to restore gut microbiota ameliorated these effects. Mice with dysbiosis displayed cognitive deficits in the MWM test. SCFAs levels decreased during dysbiosis, and increased upon microbiota recovery. Neonatal dysbiosis affects the microbiota-gut-brain axis, impairing cognitive function and nervous system development. Reduced SCFAs may contribute significantly to these alterations.

Alleviating effects of guar gum on high-fat diet-induced liver injury in common carp (Cyprinus carpio)

This research aimed to determine the effect of dietary guar gum inclusion in high-lipid diets on the liver health of common carp (Cyprinus carpio). Four high-fat diets (10 % crude lipid) containing 0 % (HF), 0.3 % (HFG0.3), 1 % (HFG1), and 3 % (HFG3) of guar gum and a normal-lipid diet (5 % crude lipid; Control) were formulated. The tested diets were evenly and randomly distributed to fifteen tanks, with each tank containing thirty fish (4.53 ± 0.05 g). Fish were fed until apparent satiation for eight weeks. Compared to HF, diets HFG0.3, HFG1, and HFG3 significantly improved feed efficiency, with the HFG0.3 diet enhancing weight gain rate and specific growth rate. The results indicated that HF induced gut dysbiosis, hepatic lipid accumulation, oxidative stress, inflammation, and disturbance in hepatic lipid and cholesterol metabolism. Compared to the HF diet, diets HFG0.3, HFG1, and HFG3 substantially decreased hepatic lipid accumulation and malonaldehyde content, increased catalase activity and the expression of AMP-activated protein kinase (AMPKα2), peroxisomal proliferator-activated receptor alpha (PPARα), cholesterol 7alpha-hydroxylase, and decreased the expression of interleukin-1β (IL-1β). Moreover, the HFG0.3 and HFG1 diets dramatically increased nuclear factor erythroid 2-related factor 2 and liver X receptor expression and decreased protein carbonyl contents and expression of IL-8, nuclear factor kappa B (NF-κB p65), and tumor necrosis factor α. Furthermore, the HFG1 diet significantly increased carnitine palmitoyltransferase 1 and peroxisomal proliferator-activated receptor gamma coactivator 1 expression and reduced expression levels of fibroblast growth factor 19, farnesoid X receptor, and sterol regulatory element-binding protein type 1. The linear discriminant analysis effect size (LEfSe) analysis showed that HFG 0.3 and HFG1 substantially increased the enrichment of beneficial microbiota (e.g., lactic acid bacteria, Cetobacterium, and Fusobacterial) and decreased the enrichment of harmful microbiota (e.g., Proteobacteria, Acinetobacter, and Pseudomonas) compared to HF. These results suggested that guar gum can mitigate high-fat diet-induced liver damage in fish.

Ginger essential oil prevents NASH progression by blocking the NLRP3 inflammasome and remodeling the gut microbiota-LPS-TLR4 pathway in mice

BackgroundDiet and gut microbiota contribute to non-alcoholic steatohepatitis (NASH) progression. High-fat diets (HFDs) change gut microbiota compositions, induce gut dysbiosis, and intestinal barrier leakage, which facilitates portal influx of pathogen-associated molecular patterns including lipopolysaccharides (LPS) to the liver and triggers inflammation in NASH. Current therapeutic drugs for NASH have adverse side effects; however, several foods and herbs that exhibit hepatoprotection could be an alternative method to prevent NASH.MethodsWe investigated ginger essential oil (GEO) against palm oil-containing HFDs in LPS-injected murine NASH model.ResultsGEO reduced plasma alanine aminotransferase levels and hepatic pro-inflammatory cytokine levels; and increased antioxidant catalase, glutathione reductase, and glutathione levels to prevent NASH. GEO alleviated hepatic inflammation through mediated NLR family pyrin domain-containing 3 (NLRP3) inflammasome and LPS/Toll-like receptor four (TLR4) signaling pathways. GEO further increased beneficial bacterial abundance and reduced NASH-associated bacterial abundance.ConclusionThis study demonstrated that GEO prevents NASH progression which is probably associated with the alterations of gut microbiota and inhibition of the LPS/TLR4/NF-κB pathway. Hence, GEO may offer a promising application as a dietary supplement for the prevention of NASH.

Soybean oil-based HFD induces gut dysbiosis that leads to steatosis, hepatic inflammation and insulin resistance in mice.

High-fat diets (HFDs) shape the gut microbiome and promote obesity, inflammation, and liver steatosis. Fish and soybean are part of a healthy diet; however, the impact of these fats, in the absence of sucrose, on gut microbial dysbiosis and its association with liver steatosis remains unclear. Here, we investigated the effect of sucrose-free soybean oil-and fish oil-based high fat diets (HFDs) (SF-Soy-HFD and SF-Fish-HFD, respectively) on gut dysbiosis, obesity, steatosis, hepatic inflammation, and insulin resistance. C57BL/6 mice were fed these HFDs for 24 weeks. Both diets had comparable effects on liver and total body weights. But 16S-rRNA sequencing of the gut content revealed induction of gut dysbiosis at different taxonomic levels. The microbial communities were clearly separated, showing differential dysbiosis between the two HFDs. Compared with the SF-Fish-HFD control group, the SF-Soy-HFD group had an increased abundance of Bacteroidetes, Firmicutes, and Deferribacteres, but a lower abundance of Verrucomicrobia. The Clostridia/Bacteroidia (C/B) ratio was higher in the SF-Soy-HFD group (3.11) than in the SF-Fish-HFD group (2.5). Conversely, the Verrucomicrobiacae/S24_7 (also known as Muribaculaceae family) ratio was lower in the SF-Soy-HFD group (0.02) than that in the SF-Fish-HFD group (0.75). The SF-Soy-HFD group had a positive association with S24_7, Clostridiales, Allobaculum, Coriobacteriaceae, Adlercreutzia, Christensenellaceae, Lactococcus, and Oscillospira, but was related to a lower abundance of Akkermansia, which maintains gut barrier integrity. The gut microbiota in the SF-Soy-HFD group had predicted associations with host genes related to fatty liver and inflammatory pathways. Mice fed the SF-Soy-HFD developed liver steatosis and showed increased transcript levels of genes associated with de novo lipogenesis (Acaca, Fasn, Scd1, Elovl6) and cholesterol synthesis (Hmgcr) pathways compared to those in the SF-Fish-HFD-group. No differences were observed in the expression of fat uptake genes (Cd36 and Fabp1). The expression of the fat efflux gene (Mttp) was reduced in the SF-Soy-HFD group. Moreover, hepatic inflammation markers (Tnfa and Il1b) were notably expressed in SF-Soy-HFD-fed mice. In conclusion, SF-Soy-HFD feeding induced gut dysbiosis in mice, leading to steatosis, hepatic inflammation, and impaired glucose homeostasis.

Brain-Gut and Microbiota-Gut-Brain Communication in Type-2 Diabetes Linked Alzheimer's Disease.

The gastrointestinal (GI) tract, home to the largest microbial population in the human body, plays a crucial role in overall health through various mechanisms. Recent advancements in research have revealed the potential implications of gut-brain and vice-versa communication mediated by gut-microbiota and their microbial products in various diseases including type-2 diabetes and Alzheimer's disease (AD). AD is the most common type of dementia where most of cases are sporadic with no clearly identified cause. However, multiple factors are implicated in the progression of sporadic AD which can be classified as non-modifiable (e.g., genetic) and modifiable (e.g. Type-2 diabetes, diet etc.). Present review focusses on key players particularly the modifiable factors such as Type-2 diabetes (T2D) and diet and their implications in microbiota-gut-brain (MGB) and brain-gut (BG) communication and cognitive functions of healthy brain and their dysfunction in Alzheimer's Disease. Special emphasis has been given on elucidation of the mechanistic aspects of the impact of diet on gut-microbiota and the implications of some of the gut-microbial products in T2D and AD pathology. For example, mechanistically, HFD induces gut dysbiosis with driven metabolites that in turn cause loss of integrity of intestinal barrier with concomitant colonic and systemic chronic low-grade inflammation, associated with obesity and T2D. HFD-induced obesity and T2D parallel neuroinflammation, deposition of Amyloid β (Aβ), and ultimately cognitive impairment. The review also provides a new perspective of the impact of diet on brain-gut and microbiota-gut-brain communication in terms of transcription factors as a commonly spoken language that may facilitates the interaction between gut and brain of obese diabetic patients who are at a higher risk of developing cognitive impairment and AD. Other commonality such as tyrosine kinase expression and functions maintaining intestinal integrity on one hand and the phagocytic clarence by migratory microglial functions in brain are also discussed. Lastly, the characterization of the key players future research that might shed lights on novel potential pharmacological target to impede AD progression are also discussed.

Association of breast milk-derived arachidonic acid-induced infant gut dysbiosis with the onset of atopic dermatitis

ObjectiveThe specific breast milk-derived metabolites that mediate host–microbiota interactions and contribute to the onset of atopic dermatitis (AD) remain unknown and require further investigation.DesignWe enrolled 250 mother–infant pairs and collected...

Disproportionately higher cardiovascular disease risk and incidence with high fructose corn syrup sweetened beverage intake among black young adults–the CARDIA study

BackgroundThe black/white heart disease mortality disparity began increasing in the early 1980’s, coincident with the switch from sucrose to high-fructose-corn-syrup/(HFCS) in the US food supply. There has been more fructose in HFCS than generally-recognized-as-safe/GRAS, which has contributed to unprecedented excess-free-fructose/(unpaired-fructose) in foods/beverages. Average- per-capita excess-free-fructose, from HFCS, began exceeding dosages/(5-10 g) that trigger fructose-malabsorption in the early 1980’s. Fructose malabsorption contributes to gut-dysbiosis and gut-in-situ-fructosylation of dietary peptides/incretins/(GLP-1/GIP) which forms atherosclerotic advanced-glycation-end-products. Both dysregulate gut endocrine function and are risk factors for cardiovascular disease/(CVD). Limited research shows that African Americans have higher fructose malabsorption prevalence than others. CVD risk begins early in life.MethodsCoronary-Artery-Risk-Development-in-Adults/(CARDIA) study data beginning in 1985–86 with 2186 Black and 2277 White participants, aged 18–30 y, were used to test the hypothesis that HFCS sweetened beverage intake increases CVD risk/incidence, more among Black than White young adults, and at lower intakes; while orange juice-a low excess-free-fructose juice with comparable total sugars and total fructose, but a 1:1 fructose-to-glucose-ratio, i.e., low excess-free-fructose, does not. Cox proportional hazards models were used to calculate hazard ratios.ResultsHFCS sweetened beverage intake was associated with higher CVD risk (HR = 1.7) than smoking (HR = 1.6). CVD risk was higher at lower HFCS sweetened beverage intake among Black than White participants. Intake, as low as 3 times/wk, was associated with twice the CVD risk vs. less frequent/never, among Black participants only (HR 2.1, 95% CI 1.2–3.7; P = 0.013). Probability of an ordered relationship approached significance. Among Black participants, CVD incidence jumped 62% from 59.8/1000, among ≤ 2-times/wk, to 96.9/1000 among 3–6 times/wk consumers. Among White participants, CVD incidence increased from 37.6/1000, among ≤ 1.5-times/wk, to 41.1/1000, among 2 times/wk–once/d – a 9% increase. Hypertension was highest among Black daily HFCS sweetened beverage consumers.ConclusionThe ubiquitous presence of HFCS over-the-past-40 years, at higher fructose-to-glucose ratios than generally-recognized-as-safe, may have contributed to CVD racial disparities, due to higher fructose-malabsorption prevalence among Black individuals, unpaired/excess-free-fructose induced gut dysbiosis and gut fructosylation of dietary peptides/incretins (GLP-1/GIP). These disturbances contribute to atherosclerotic plaque; promote incretin insufficiency/dysregulation/altered satiety/dysglycemia; decrease protective microbiota metabolites; and increase hypertension, CVD morbidity and mortality.

Effects of fucoidan and synbiotics supplementation during bismuth quadruple therapy of Helicobacter pylori infection on gut microbial homeostasis: an open-label, randomized clinical trial.

The eradication regimen for Helicobacter pylori (H. pylori) infection can induce gut dysbiosis. In this open-label, prospective, and randomized clinical trial, we aimed to assess the effects of fucoidan supplementation on the eradication rate and gut microbial homeostasis in the context of quadruple therapy, as well as to investigate the combined effects of fucoidan and synbiotics supplementations. Eighty patients with H. pylori infection were enrolled and randomly assigned to one of four treatment groups: the QT (a 2-week quadruple therapy alone), QF (quadruple therapy plus a 6-week fucoidan supplementation), QS (quadruple therapy plus a 6-week synbiotics supplementation), and QFS (quadruple therapy with a 6-week fucoidan and synbiotics supplementation), with 20 patients in each group. The QT regimen included rabeprazole, minocycline, amoxicillin, and bismuth potassium citrate. The synbiotics supplementation contained three strains of Bifidobacterium, three strains of Lactobacillus, along with three types of dietary fiber. All of the patients underwent 13C-urea breath test (13C-UBT) at baseline and at the end of the 6th week after the initiation of the interventions. Fresh fecal samples were collected at baseline and at the end of the 6th week for gut microbiota analysis via 16S rRNA gene sequencing. The eradication rates among the four groups showed no significant difference. In the QT group, a significant reduction in α-diversity of gut microbiota diversity and a substantial shift in microbial composition were observed, particularly an increase in Escherichia-Shigella and a decrease in the abundance of genera from the Lachnospiraceae and Ruminococcaceae families. The Simpson index was significantly higher in the QF group than in the QT group. Neither the QS nor QFS groups exhibited significant changes in α-diversity or β-diversity. The QFS group was the only one that did not show a significant increase in the relative abundance of Escherichia-Shigella, and the relative abundance of Klebsiella significantly decreased in this group. The current study provided supporting evidence for the positive role of fucoidan and synbiotics supplementation in the gut microbiota. The combined use of fucoidan and synbioticss might be a promising adjuvant regimen to mitigate gut dysbiosis during H. pylori eradication therapy.

Bisphenol S exposure induces intestinal inflammation via altering gut microbiome

Bisphenol S (BPS), a substitute for bisphenol A, is widely used in the manufacture of food packaging materials, raising concern over its toxicity. However, evidence is still lacking on whether gut microbiota involved in BPS induced intestinal inflammation in mammals, as well as its underlying mechanism. Using mouse BPS exposure model, we found intestinal inflammation characterized by shortened colon length, crypt distortion, macrophage accumulation and increased apoptosis. As for gut microbiota, 16s rRNA gene amplicon sequencing showed BPS exposure induced gut dysbiosis, including increased pro-inflammatory microbes such as Ileibacterium, and decreased anti-inflammatory genera such as Lactobacillus, Blautia and Romboutsia. Besides, LC-MS/MS-based untargeted metabolomic analysis indicated BPS impaired both bacteria and host metabolism. Additionally, transcriptome analysis of the intestine revealed abnormal gene expression in intestinal mucosal barrier and inflammation. More importantly, treating mice with antibiotics significantly attenuated BPS-induced gut inflammation via the regulation of both bacterial and host metabolites, indicating the role of gut microbiota. Collectively, BPS exposure induces intestinal inflammation via altering gut microbiota in mouse. This study provides the possibility of madecassic acid, an anti-inflammatory metabolite, to prevent BPS-induced intestinal inflammation and also new insights in understanding host-microbiota interaction in BPS toxicity.

Gut Dysbiosis Shaped by Cocoa Butter-Based Sucrose-Free HFD Leads to Steatohepatitis, and Insulin Resistance in Mice.

High-fat diets cause gut dysbiosis and promote triglyceride accumulation, obesity, gut permeability changes, inflammation, and insulin resistance. Both cocoa butter and fish oil are considered to be a part of healthy diets. However, their differential effects on gut microbiome perturbations in mice fed high concentrations of these fats, in the absence of sucrose, remains to be elucidated. The aim of the study was to test whether the sucrose-free cocoa butter-based high-fat diet (C-HFD) feeding in mice leads to gut dysbiosis that associates with a pathologic phenotype marked by hepatic steatosis, low-grade inflammation, perturbed glucose homeostasis, and insulin resistance, compared with control mice fed the fish oil based high-fat diet (F-HFD). C57BL/6 mice (5-6 mice/group) were fed two types of high fat diets (C-HFD and F-HFD) for 24 weeks. No significant difference was found in the liver weight or total body weight between the two groups. The 16S rRNA sequencing of gut bacterial samples displayed gut dysbiosis in C-HFD group, with differentially-altered microbial diversity or relative abundances. Bacteroidetes, Firmicutes, and Proteobacteria were highly abundant in C-HFD group, while the Verrucomicrobia, Saccharibacteria (TM7), Actinobacteria, and Tenericutes were more abundant in F-HFD group. Other taxa in C-HFD group included the Bacteroides, Odoribacter, Sutterella, Firmicutes bacterium (AF12), Anaeroplasma, Roseburia, and Parabacteroides distasonis. An increased Firmicutes/Bacteroidetes (F/B) ratio in C-HFD group, compared with F-HFD group, indicated the gut dysbiosis. These gut bacterial changes in C-HFD group had predicted associations with fatty liver disease and with lipogenic, inflammatory, glucose metabolic, and insulin signaling pathways. Consistent with its microbiome shift, the C-HFD group showed hepatic inflammation and steatosis, high fasting blood glucose, insulin resistance, increased hepatic de novo lipogenesis (Acetyl CoA carboxylases 1 (Acaca), Fatty acid synthase (Fasn), Stearoyl-CoA desaturase-1 (Scd1), Elongation of long-chain fatty acids family member 6 (Elovl6), Peroxisome proliferator-activated receptor-gamma (Pparg) and cholesterol synthesis (β-(hydroxy β-methylglutaryl-CoA reductase (Hmgcr). Non-significant differences were observed regarding fatty acid uptake (Cluster of differentiation 36 (CD36), Fatty acid binding protein-1 (Fabp1) and efflux (ATP-binding cassette G1 (Abcg1), Microsomal TG transfer protein (Mttp) in C-HFD group, compared with F-HFD group. The C-HFD group also displayed increased gene expression of inflammatory markers including Tumor necrosis factor alpha (Tnfa), C-C motif chemokine ligand 2 (Ccl2), and Interleukin-12 (Il12), as well as a tendency for liver fibrosis. These findings suggest that the sucrose-free C-HFD feeding in mice induces gut dysbiosis which associates with liver inflammation, steatosis, glucose intolerance and insulin resistance.

Shaping the Microbial Landscape: Parasitoid-Driven Modifications of Bactrocera dorsalis Microbiota

Koinobiont endoparasitoids regulate the physiology of their hosts through altering host immuno-metabolic responses, processes which function in tandem to shape the composition of the microbiota of these hosts. Here, we employed 16S rRNA and ITS amplicon sequencing to investigate whether parasitization by the parasitoid wasps, Diachasmimorpha longicaudata (Ashmaed) (Hymenoptera: Braconidae) and Psyttalia cosyrae (Wilkinson) (Hymenoptera: Braconidae), induces gut dysbiosis and differentially alter the gut microbial (bacteria and fungi) communities of an important horticultural pest, Bactrocera dorsalis (Hendel) (Diptera: Tephritidae). We further investigated the composition of bacterial communities of adult D. longicaudata and P. cosyrae to ascertain whether the adult parasitoids and parasitized host larvae share microbial taxa through transmission. We demonstrated that parasitism by D. longicaudata induced significant gut perturbations, resulting in the colonization and increased relative abundance of pathogenic gut bacteria. Some pathogenic bacteria like Stenotrophomonas and Morganella were detected in both the guts of D. longicaudata-parasitized B. dorsalis larvae and adult D. longicaudata wasps, suggesting a horizontal transfer of microbes from the parasitoid to the host. The bacterial community of P. cosyrae adult wasps was dominated by Arsenophonus nasoniae, whereas that of D. longicaudata adults was dominated by Paucibater spp. and Pseudomonas spp. Parasitization by either parasitoid wasp was associated with an overall reduction in fungal diversity and evenness. These findings indicate that unlike P. cosyrae which is avirulent to B. dorsalis, parasitization by D. longicaudata induces shifts in the gut bacteriome of B. dorsalis larvae to a pathobiont-dominated community. This mechanism possibly enhances its virulence against the pest, further supporting its candidacy as an effective biocontrol agent of this frugivorous tephritid fruit fly pest.

#1270 Exploring the shift in gut microbiota due to renal ischemia/reperfusion injury in rats

Abstract Background and Aims Acute kidney injury (AKI) due to renal ischemia/reperfusion (I/R) is a major clinical problem in renal transplantation and partial nephrectomy, which is associated with morbidity and mortality and substantial healthcare expenditures, but there is no effective and specific treatment. Recently, the clinical impact of the interaction between gut bacteria and the kidney function has become increasingly clear. Experimental evidence has highlighted a bidirectional relationship between gut microbiota and kidney disease. Therefore, we investigated the possibility that I/R can ameliorate AKI by studying gut-renal interactions and gut microbiota in AKI. Method We induced varying degrees of renal I/R injury in adult male Wistar rats by clamping the left renal pelvis for 30 and 45 minutes, simulating mild and severe conditions, respectively. These samples were subjected to extensive histologic examination using standard techniques such as hematoxylin and eosin (HE), Sirius Red, and F4/80 staining. In addition, we performed a quantitative analysis of the mRNA expression levels of fibrotic and inflammatory markers in both kidney and colon tissues using real-time PCR. Gut microbiota genomic DNA was extracted from rat feces and microbial 16S ribosomal RNA (rRNA) gene sequencing was performed. Results Renal function deteriorated with increasing ischemia time and fibrosis progressed, as confirmed by Sirius Red staining and qPCR of fibrosis genes such as TGFB. The expression of inflammatory genes such as IL-1B and IL-6 was also increased. The expression of inflammatory genes such as Toll-like receptor, C3, and IL-1B in the intestine also increased with ischemia time. In the fecal microbiota, the total read percentage of Bacteroides acidifaciens at the species level increased with increasing ischemia time. Conclusion The observed shifts in gut microbiota composition may serve as a critical indicator of chronic kidney disease (CKD)-induced gut dysbiosis secondary to AKI. This finding highlights the need for further research into the identification and migration patterns of the gut microbiota, which represents a promising avenue for early detection, prevention, and therapeutic intervention in AKI. Future investigations elucidating the mechanisms by which the microbiota influence IRI-induced AKI and the development of practical therapeutic strategies have the potential to significantly improve clinical outcomes in patients suffering from IRI-induced AKI.

Donepezil ameliorates gut barrier disruption in doxorubicin-treated rats

An impact of donepezil against doxorubicin-induced gut barrier disruption and gut dysbiosis has never been investigated. Twenty-four male Wistar rats were divided into three groups. Each group was treated with either vehicle as a control, doxorubicin, or doxorubicin-cotreated with donepezil. Heart rate variability was assessed to reflect the impact of doxorubicin and donepezil. Then, animals were euthanized, and the ileum and its contents were collected in each case to investigate the gut barrier and gut microbiota, respectively. The microbiota-derived endotoxin, trimethylamine N-oxide (TMAO), and short-chain fatty acids (SCFAs) in the serum were determined. An increase in the sympathetic tone, endotoxins, and TMAO levels with disruption of the gut barrier and a decrease in SCFAs levels were observed in doxorubicin-treated rats. Gut microbiota of doxorubicin-treated rats was significantly different from that of the control group. Donepezil treatment significantly decreased the sympathetic tone, restored the gut barrier, and reduced endotoxin and TMAO levels in doxorubicin-treated rats. Nonetheless, donepezil administration did not alter the gut microbiota profile and levels of SCFAs in doxorubicin-treated rats. Doxorubicin impaired the autonomic balance and the gut barrier, and induced gut dysbiosis, resulting in gut toxicity. Donepezil partially improved the doxorubicin-induced gut toxicity through balancing the autonomic disturbance.

L. plantarum and L. casei synergistically mitigate Gastro-Intestinal Acute Radiation Syndrome (GI-ARS)

Introduction: Incidental or accidental acute exposure to ionizing radiation causes radiation toxicity, for which there are no known medical countermeasures (MCMs). Ionizing radiation alters host gut epithelium as well as the gut microbiome. We sought to investigate if radiation induced gut dysbiosis occurred as a result of depletion of gut-protective bacteria, and if probiotic supplementation of such bacteria could help mitigate GI-ARS post ionizing radiation exposure. Methods: Adult C57BL/6 mice were subjected to total body irradiation, and a defined concentration of probiotics (either individually or combined) were given 24 h after radiation exposure. Mice were sacrificed 24 hours post treatment (i.e., 48 h post irradiation). Vascular-to-luminal flux of FITC-inulin was measured to evaluate intestinal mucosal permeability and endotoxemia by measuring plasma lipopolysaccharide. Gut microbiota was analyzed by 16S rRNA sequencing. Intestinal epithelial junctions were analyzed by immunofluorescence confocal microscopy and mucosal inflammatory response by RT-PCR for cytokine expression. Systemic inflammation was evaluated by ELISA for plasma cytokines. Results and conclusion: Our data show that radiation altered the taxonomic composition of the microbiota compared to age-matched sham treated mice. Shannon index analysis showed a significant decrease in α-diversity in irradiated mice. Bray-Curtis analysis indicated significant differences in microbiota composition between Sham and IR groups. E. coli abundance was increased whereas Lactobacillus abundance was decreased, particularly L. plantarum and L. casei. Probiotic supplementation with individual Lactobacillus species each mitigated radiation induced intestinal barrier dysfunction, gut specific as well as systemic inflammatory cytokine expression and endotoxemia. Our preliminary data further indicates that L. plantarum affects Epidermal Growth Factor Receptor (EGFR)-mediated signaling whereas L. casei was EGFR-independent. Interestingly, combined supplementation in a 1:1 ratio further enhanced recovery compared to adding the individual effects. Individual supplementation of L. plantarum and L. casei to irradiated mice reduced intestinal (ileal) permeability by 2-fold and 3-fold respectively, whereas combined supplementation reduced ileal permeability almost 8-fold compared to irradiated but untreated mice. This data indicates that L. plantarum and L. casei mitigate GI-ARS by distinct cellular mechanisms. Furthermore, data show that a mixture of these probiotic species is more effective in radio-mitigation than individually. Further mechanistic analysis will be required to identify cross-talking targets between mechanisms of these probiotics and synergistic radio-mitigation. In conclusion, Lactobacillus species are potential MCMs for the treatment of GI-ARS. Funding acknowledgements: NIH/NIAID, UO1-AI170019, UO1-AI172991. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Gut dysbiosis induced by florfenicol increases susceptibility to Aeromonas hydrophila infection in Zebrafish Danio rerio after the recommended withdrawal period.

Florfenicol (FFC) is a broad-spectrum antibiotic approved by the U.S. Food and Drug Administration to treat both systemic and external bacterial infections in food fish. The objective of this study was to evaluate the effect of FFC-medicated feed on the gut microbiota of Zebrafish Danio danio to determine (1) if the therapeutic dose of FFC-medicated feed induces dysbiosis and (2) if fish with altered gut microbiota were more susceptible to subsequent infection by the common opportunistic fish pathogen Aeromonas hydrophila. Zebrafish that were treated with regular and FFC-medicated feeds were artificially challenged with A. hydrophila at the end of the recommended 15-day antibiotic withdrawal period. The gut microbiota of the Zebrafish at different stages was analyzed using 16S ribosomal RNA gene sequencing. Our results found that FFC-medicated feed induced disruption of the gut microbiota. Dysbiosis was observed in all treated groups, with a significant increase in bacterial diversity, and was characterized by a remarkable bloom of Proteobacteria and a drastic decline of Mycoplasma and Cetobacterium in treated animals but without noticeable clinical signs or mortalities. In addition, the increase of Proteobacteria was not significantly reduced after the recommended 15-day withdrawal period, and the Zebrafish treated with FFC-medicated feed exhibited a significantly higher mortality rate when they were subsequently challenged with A. hydrophila compared to the control (regular feed) groups. Interestingly, the most dramatic changes in the gut microbiome composition occurred at the transition time between the late stage of the medicated treatment and the beginning of the withdrawal period instead of the time during the Aeromonas infection. The administration of FFC-medicated feed at the recommended dose induced gut dysbiosis in Zebrafish, and fish did not recover to the baseline after the recommended withdrawal period. Our findings suggest that the use of antibiotics in fish elicits a response similar to those previously described in mammals and possibly makes the host more susceptible to subsequent infections of opportunistic pathogens. This study using a controlled model system suggests that antibiotics in aquaculture may have long-term effects on the general well-being of the fish.