RESUMEN

The combination of anti-angiogenic drugs and immune checkpoint inhibitors (ICIs) in the treatment of tumors is emerging as a way to improve ICIs-resistant tumor therapy. In addition, gut microbes (GMs) are involved in angiogenesis in the tumor microenvironment and are also associated with the antitumor function of immune checkpoint inhibitors. However, it is unclear whether gut microbes have a role in anti-tumor function in the combination of anti-angiogenic drugs and immune checkpoint inhibitors for cancer treatment. Endostatin, an angiogenesis inhibitor, has been widely used as an antiangiogenic therapy for cancer. We showed that combined therapy with an adenovirus encoding human endostatin, named Ad-E, and PD-1 blockade dramatically abrogated MC38 tumor growth. The structure of intestinal microbes in mice was changed after combination treatment. We found that the antitumor function of combination therapy was inhibited after the elimination of intestinal microbes. In mice with depleted microbiota, oral gavage of Bacteroides fragilis salvaged the antitumor effects of combination Ad-E and αPD-1 monoclonal antibody (mAb) to a certain extent. Further, Bacteroides fragilis could improve CD3+T cells, NK cells, and IFNγ+CD8+ T cells in the tumor microenvironment to inhibit tumor growth. Besides, Bacteroides fragilis might restore antitumor function by down-regulating isobutyric acid (IBA). Our results suggested that GMs may be involved in the combination of Ad-E and αPD-1 mAb for cancer treatment, which has oncological implications for tumor growth dynamics and cancer immune surveillance.

Asunto(s)

Neoplasias Colorrectales , Endostatinas , Microbioma Gastrointestinal , Inhibidores de Puntos de Control Inmunológico , Receptor de Muerte Celular Programada 1 , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Endostatinas/farmacología , Endostatinas/uso terapéutico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/microbiología , Neoplasias Colorrectales/patología , Ratones , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Humanos , Línea Celular Tumoral , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Ratones Endogámicos C57BL , Inhibidores de la Angiogénesis/farmacología , Inhibidores de la Angiogénesis/uso terapéutico , Inhibidores de la Angiogénesis/administración & dosificación , Femenino

RESUMEN

The giant freshwater prawn (GFP; Macrobrachium rosenbergii), a tropical species cultured worldwide, has high market demand and economic value. Male GFP growth varies considerably; however, the mechanisms underlying these growth differences remain unclear. In this study, we collected gut and hemolymphatic samples of large (ML), medium (MM), and small (MS) male GFPs and used the 16S rRNA sequencing and liquid chromatography-mass spectrometry-based metabolomic methods to explore gut microbiota and metabolites associated with GFP growth. The dominant bacteria were Firmicutes and Proteobacteria; higher growth rates correlated with a higher Firmicutes/Bacteroides ratio. Serum metabolite levels significantly differed between the ML and MS groups. We also combined transcriptomics with integrative multiomic techniques to further elucidate systematic molecular mechanisms in the GFPs. The results revealed that Faecalibacterium and Roseburia may improve gut health in GFP through butyrate release, affecting physiological homeostasis and leading to metabolic variations related to GFP growth differences. Notably, our results provide novel, fundamental insights into the molecular networks connecting various genes, metabolites, microbes, and phenotypes in GFPs, facilitating the elucidation of differential growth mechanisms in GFPs.

RESUMEN

Bile acids (BAs) are synthesized by the host liver from cholesterol and are delivered to the intestine, where they undergo further metabolism by gut microbes and circulate between the liver and intestines through various transporters. They serve to emulsify dietary lipids and act as signaling molecules, regulating the host's metabolism and immune homeostasis through specific receptors. Therefore, disruptions in BA metabolism, transport, and signaling are closely associated with cholestasis, metabolic disorders, autoimmune diseases, and others. Botanical triterpenoids and steroids share structural similarities with BAs, and they have been found to modulate BA metabolism, transport, and signaling, potentially exerting pharmacological or toxicological effects. Here, we have updated the research progress on BA, with a particular emphasis on new-found microbial BAs. Additionally, the latest advancements in targeting BA metabolism and signaling for disease treatment are highlighted. Subsequently, the roles of botanical triterpenoids in BA metabolism, transport, and signaling are examined, analyzing their potential pharmacological, toxicological, or drug interaction effects through these mechanisms. Finally, a research paradigm is proposed that utilizes the gut microbiota as a link to interpret the role of these important natural products in BA signaling.

RESUMEN

Inflammatory bowel disease (IBD) refers to long-term medical conditions that involve inflammation of the digestive tract, and the global incidence and prevalence of IBD are on the rise. Gut microbes play an important role in maintaining the intestinal health of the host, and the occurrence, development, and therapeutic effects of IBD are closely related to the structural and functional changes of gut microbes. Published studies have shown that the natural products from traditional Chinese medicine have direct or indirect regulatory impacts on the composition and metabolism of the gut microbes. In this review, we summarize the research progress of several groups of natural products, i.e., flavonoids, alkaloids, saponins, polysaccharides, polyphenols, and terpenoids, for the therapeutic activities in relieving IBD symptoms. The role of gut microbes and their intestinal metabolites in managing the IBD is presented, with focusing on the mechanism of action of those natural products. Traditional Chinese medicine alleviated IBD symptoms by regulating gut microbes, providing important theoretical and practical basis for the treatment of variable inflammatory intestinal diseases.

RESUMEN

Mandarin fish (Siniperca chuatsi) represents a typical carnivorous freshwater economic fish in China. Recently, the study of their feeding behavior to acclimate formulated diets has become a research focus. This study evaluated the effects of various diets on the body composition, nutritional content, digestive enzyme activity, gene expression, and gut microbiota of mandarin fish. Firstly, no significant differences were found in the muscle's basic nutritional components (moisture, crude protein, crude fat, and crude ash), as well as in the fatty acid and amino acid content, between the live feed group (LFSC) and the compound feed group (CFSC). However, mandarin fish in the LFSC group exhibited significantly higher lipase activity in the liver and intestine compared to the CFSC group, while amylase activity in the intestine showed an opposite pattern. Additionally, intestinal transcriptome analysis revealed 6238 differentially expressed genes and identified several differentially expressed clock genes associated with diet type. Furthermore, gut microbiota analysis indicated that different feeding regimens influenced microbial composition, revealing correlations between bacterial genera and intestinal gene expression levels. These findings provided novel insights into the gut microbiota and transcriptomic responses of mandarin fish to different dietary types.

RESUMEN

Akkermansia muciniphila (A. muciniphila) is a 'star strain' that has attracted much attention in recent years. A. muciniphila can effectively regulate host metabolism, significantly affect host immune function, and play an important role in balancing host health and disease. As one of the organs most closely related to the gut (the two can communicate through the hepatic portal vein and bile duct system), liver is widely affected by intestinal microorganisms. A growing body of evidence suggests that A. muciniphila may alleviate liver-related diseases by improving the intestinal barrier, energy metabolism and regulating inflammation through its protein components and metabolites. This paper systematically reviews the key roles of A. muciniphila and its derivatives in maintaining liver health and improving liver disease.

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[Box: see text].

Asunto(s)

Akkermansia , Microbioma Gastrointestinal , Hígado , Humanos , Akkermansia/fisiología , Hígado/microbiología , Hígado/metabolismo , Microbioma Gastrointestinal/fisiología , Animales , Hepatopatías/microbiología , Verrucomicrobia/fisiología , Probióticos

RESUMEN

Parkinson's disease is a progressive neurodegenerative disorder marked by the death of dopaminergic neurons in the substantia nigra region of the brain. Aggregation of alpha-synuclein (α-synuclein) is a contributing factor to Parkinson's disease pathogenesis. The objective of this study is to investigate the neuroprotective effects of gut microbes on α-synuclein aggregation using both in silico and in vivo approaches. We focussed on the interaction between α-synuclein and metabolites released by gut bacteria that protect from PD. We employed three probiotic microbe strains against α-synuclein protein: Lactobacillus casei, Escherichia coli, and Bacillus subtilis, with their chosen PDB IDs being Dihydrofolate reductase (3DFR), methionine synthetase (6BM5), and tryptophanyl-tRNA synthetase (3PRH), respectively. Using HEX Dock 6.0 software, we examined the interactions between these proteins. Among the various metabolites, methionine synthetase produced by E. coli showed potential interactions with α-synuclein. To further evaluate the neuroprotective benefits of E. coli, an in vivo investigation was performed using a rotenone-induced Parkinsonian mouse model. The motor function of the animals was assessed through behavioural tests, and oxidative stress and neurotransmitter levels were also examined. The results demonstrated that, compared to the rotenone-induced PD mouse model, the rate of neurodegeneration was considerably reduced in mice treated with E. coli. Additionally, histopathological studies provided evidence of the neuroprotective effects of E. coli. In conclusion, this study lays the groundwork for future research, suggesting that gut bacteria may serve as potential therapeutic agents in the development of medications to treat Parkinson's disease. fig. 1.

Asunto(s)

Bacillus subtilis , Escherichia coli , Microbioma Gastrointestinal , Simulación del Acoplamiento Molecular , Estrés Oxidativo , Probióticos , Rotenona , alfa-Sinucleína , Animales , Ratones , Microbioma Gastrointestinal/fisiología , Probióticos/uso terapéutico , Probióticos/farmacología , alfa-Sinucleína/metabolismo , Estrés Oxidativo/efectos de los fármacos , Rotenona/toxicidad , Lacticaseibacillus casei/fisiología , Metionina-ARNt Ligasa , Triptófano-ARNt Ligasa/fisiología , Masculino , Tetrahidrofolato Deshidrogenasa/metabolismo , Simulación por Computador , Trastornos Parkinsonianos/microbiología , Humanos , Fármacos Neuroprotectores/uso terapéutico , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Enfermedad de Parkinson Secundaria/inducido químicamente , Neuronas Dopaminérgicas/efectos de los fármacos , Enfermedad de Parkinson/microbiología

RESUMEN

Gut microbe dysbiosis increases repetitive inflammatory responses, leading to an increase in the incidence of colorectal cancer. Recent studies have revealed that specific microbial species directly instigate mutations in the host nucleus DNA, thereby accelerating the progression of colorectal cancer. Given the well-established role of mitochondrial dysfunction in promoting colorectal cancer, it is reasonable to postulate that gut microbes may induce mitochondrial gene mutations, thereby inducing mitochondrial dysfunction. In this review, we focus on gut microbial genotoxins and their known and potential targets in mitochondrial genes. Consequently, we propose that targeted disruption of genotoxin transport pathways may effectively reduce the rate of mitochondrial gene mutations and yield substantial benefits for the prevention of colorectal carcinogenesis.

Asunto(s)

Carcinogénesis , Neoplasias Colorrectales , Microbioma Gastrointestinal , Mitocondrias , Mutágenos , Mutación , Humanos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/microbiología , Mitocondrias/metabolismo , Mitocondrias/genética , Microbioma Gastrointestinal/genética , Mutágenos/toxicidad , Carcinogénesis/genética , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Disbiosis/genética , Animales

RESUMEN

Type 2 diabetes (T2D) is the predominant metabolic epidemic posing a major threat to global health. Growing evidence indicates that gut microbiota (GM) may critically influence the progression from normal glucose tolerance, to pre-diabetes, to T2D. On the other hand, regular exercise contributes to the prevention and/or treatment of the disease, and evidence suggests that a possible way regular exercise favorably affects T2D is by altering GM composition toward health-promoting bacteria. However, research regarding this potential effect of exercise-induced changes of GM on T2D and the associated mechanisms through which these effects are accomplished is limited. This review presents current data regarding the association of GM composition and T2D and the possible critical GM differentiation in the progression from normal glucose, to pre-diabetes, to T2D. Additionally, potential mechanisms through which GM may affect T2D are presented. The effect of exercise on GM composition and function on T2D progression is also discussed.

RESUMEN

Antimicrobial peptides (AMPs) offer a potential solution to the antibiotic crisis owing to their antimicrobial properties, and the human gut biome may be a source of these peptides. However, the potential AMPs and antimicrobial peptide resistance genes (AMPRGs) of gut microbes in different age groups has not been thoroughly assessed. Here, we investigated the potential development of AMPs and the distribution pattern of AMPRGs in the gut microbiome at different ages by analyzing the intestinal metagenomic data of healthy individuals at different life stages (CG: centenarians group n=20; OAG: older adults group n=15; YG: young group n=15). Age-related increases were observed in the potential AMPs within the gut microbiome, with centenarians showing a greater diversity of these peptides. However, the gut microbiome of the CG group had a lower level of AMPRGs compared to that of the OAG group, and it was similar to the level found in the YG group. Additionally, conventional probiotic strains showed a significant positive correlation with certain potential AMPs and were associated with a lower detection of resistance genes. Additionally, comparing potential AMPs with existing libraries revealed limited similarity, indicating that current machine-learning models can identify novel peptides in the gut microbiota. These results indicate that longevity may benefit from diversity of AMPs and lower resistance genes. Our findings help explain the age advantage of the centenarians and identify the potential for antimicrobial peptide biosynthesis in the human gut microbiome, offering insights into the development of antimicrobial peptide resistance and the screening of probiotic strains.

RESUMEN

Insufficient density of red deer has affected the stability of forest ecosystems and the recovery of large carnivores (represented by Amur tiger). Conservation translocations from captivity to the wild has become an important way to restore the red deer populations. However, the difference in gut microbes between pre-release and wild red deer may affect the feeding adaptability of red deer after release. In this study, we clarified the differences in gut microbes between pre-released and wild red deer and screened the key gut microbes of the red deer involved in feeding by using metagenomic sequencing and feeding analysis. The results showed that the microbial difference between pre-released and wild red deer was mainly related to Firmicutes represented by Eubacteriales and Clostridia, and Firmicutes abundance in pre-released red deer (68.23%) was significantly lower than that of wild red deer (74.91%, p < 0.05). The expression of microbial metabolic pathways in pre-released red deer were significantly lower than those in wild red deer (p < 0.05), including carbohydrate metabolism, amino acid metabolism, glycan biosynthesis and metabolism, etc. The combinations of Firmicutes were significantly positively correlated with the intake of plant fiber and carbohydrate (p < 0.05), and were key microbes to help red deer deal with wild plant resources. Additionally, the combinations of Firmicutes represented by Eubacteriales and Clostridia lacking in pre-released red deer contributed the most to expression of microbial metabolic pathways (importance > 1), showing a significant positive correlation (p < 0.05). This study indicates that high abundance of Firmicutes is an important guarantee for red deer to adapt to the wild feeding environment, which provides critical implications for the recovery of red deer populations and the protection of endangered ungulates.

Asunto(s)

Quimioprevención , Humanos , Enfermedad Crónica/prevención & control , Quimioprevención/métodos , Animales , Dieta , Fitoquímicos/uso terapéutico , Fitoquímicos/farmacología

RESUMEN

[This corrects the article DOI: 10.3389/fmicb.2022.1001750.].

RESUMEN

The heavy metal cadmium (Cd) is a toxic and bioaccumulative metal that can be enriched in the tissues and organs of living organisms through the digestive tract. However, more research is needed to determine whether food-sourced Cd affects the homeostasis of host gut microflora. In this study, the snail Bradybaena ravida (Benson) was used as a model organism fed with mulberry leaves spiked with different concentrations of Cd (0, 0.052, 0.71, and 1.94 mg kg-1). By combining 16S rRNA high-throughput sequencing with biochemical characterization, it was found that there were increases in the overall microbial diversity and abundances of pathogenic bacteria such as Corynebacterium, Enterococcus, Aeromonas, and Rickettsia in the gut of B. ravida after exposure to Cd. However, the abundances of potential Cd-resistant microbes in the host's gut, including Sphingobacterium, Lactococcus, and Chryseobacterium, decreased with increasing Cd concentrations in the mulberry leaves. In addition, there was a significant reduction in activities of energy, nutrient metabolism, and antioxidant enzymes for gut microbiota of snails treated with high concentrations of Cd compared to those with low ones. These findings highlight the interaction of snail gut microbiota with Cd exposure, indicating the potential role of terrestrial animal gut microbiota in environmental monitoring through rapid recognition and response to environmental pollution.

Asunto(s)

Cadmio , Microbioma Gastrointestinal , Caracoles , Animales , Cadmio/toxicidad , Microbioma Gastrointestinal/efectos de los fármacos , Caracoles/efectos de los fármacos , Caracoles/fisiología , ARN Ribosómico 16S , Morus , Hojas de la Planta

RESUMEN

BACKGROUND: There are billions of bacteria in the intestine, most of which are harmless and play important roles in humans. Although only a very small number of bacteria can cause diseases, once the pathogenic bacteria are ingested into the body and multiply in large quantities, it can lead to inflammatory diseases in the intestines and even other organs. Although polymerase chain reaction can specifically detect bacterial nucleic acid. However, the demand for temperature cycling limits its portability. Therefore, it is hoped to establish a high-throughput, highly specific and portable detection platform for directly detecting nucleic acid of intestinal pathogens. RESULTS: Herein, a one-pot chip based on RPA-CRCISPR/Cas12a platform was developed. The chip is the same size as a glass slide and allows detection at the same temperature. Multiple samples could be detected simultaneously on the one chip, achieved high-throughput detection and improved the integration of detection. The specific recognition of CRISPR/Cas12a avoided the influence of non-specific amplification of RPA and enhanced the specificity of the analysis. At the same time, the one-pot chip avoided secondary contamination when the lid was opened during the analysis process. And the bacterial concentration showed good linearity at 102-108 cfu mL-1. The limit of detection could be as low as 0.43 cfu mL-1. This method has been successfully used to detect pollution samples. It can provide a reliable platform for early screening of gastrointestinal and other inflammatory diseases. SIGNIFICANCE: The one-pot chip based on the RPA-CRISPR/Cas12a platform established can directly detect the nucleic acid of intestinal pathogens, with portability and specificity. It is worth noting that the platform has good programmability, can be used for other target detection by changing crRNA and RPA primers, it can achieve multi sample detection on the one chip.

Asunto(s)

Sistemas CRISPR-Cas , Sistemas CRISPR-Cas/genética , Humanos , ADN Bacteriano/análisis , Bacterias/aislamiento & purificación , Bacterias/genética , Límite de Detección , Microbioma Gastrointestinal , Técnicas de Amplificación de Ácido Nucleico

RESUMEN

Unveiling a metabolic mystery, this article explores how 3-O-acylated bile acids, specifically 3-O-succinylated cholic acid (3-sucCA) and 3-acetylated cholic acid (3-acetyCA), modified by gut microbes Bacteroides uniformis and Christensenella minuta, respectively, may either disrupt or harmonize our metabolic processes, offering novel therapeutic avenues for conditions such as metabolic dysfunction-associated steatohepatitis (MASH) and type 2 diabetes mellitus (T2D).

RESUMEN

Food non-denatured processes, such as freeze-drying and grinding, are commonly applied to raw materials with good bioactive functions. Although the functional components are maintained, whether structural and physical changes impact the in vivo function is often ignored in practical situations. Brasenia schreberi mucilage (BSM) has a significant alleviation effect on DSS-induced colitis. This work focused on the influence of non-denatured manufacture on the colonic benefits of BSM-based products. First, three forms of products including fresh mucilage (FM), freeze-dried products (FS), and freeze-dried powder (FP) were prepared. Then, their in vitro physiochemical properties were compared, analyzing their influence on the gut inflammation degree, microbial composition, and SCFA production in mice. The results suggested that the water retention rate of FS and FP was decreased to 34.59 ± 3.85%, and 9.93 ± 1.76%. The viscosity of FM, FS, and FP was 20.14 Pa∙s, 4.92 Pa∙s, and 0.41 Pa∙s, respectively. The freeze-drying and grinding process also damaged the lamellar microstructure of BSM. Then, animal tests showed that colitis mice intervened with FM, FS, and FP had disease activity scores of 2.03, 3.95, and 4.62. Meanwhile, FM notably changed the gut microbial composition and significantly increased propionate and butyrate levels. It seemed that the distinct colitis alleviation efficacy of BSM-based products is attributed to different hydrodynamic properties in the gut. FM had relatively higher viscosity and correspondingly high nutritional density in the gut lumen, which stimulates Firmicutes growth and promotes butyrate production, and thereby exhibited the best efficiency on protecting from colitis.

RESUMEN

Beauveria bassiana and Metarhizium rileyi are extensively utilized to investigate fungal pathogenic mechanisms and to develop biological control agents. Notwithstanding, notable distinctions exist in their pathogenicity against the same host insect. This study aimed to elucidate the pathogenic differences between M. rileyi and B. bassiana by examining the impact of various ratios of B. bassiana strain AJS91881 and M. rileyi strain SXBN200920 on fifth instar larvae of Spodoptera litura, focusing on early infection stages and intestinal microbial community structure. The lethal time 50 (LT50) for B. bassiana was significantly lower than that for M. rileyi, indicating greater efficacy. Survival analyses in mixed groups (ratios of 1:9, 1:1, and 9:1 M. rileyi to B. bassiana) consistently demonstrated higher virulence of B. bassiana. Intestinal microbial diversity analysis revealed a significant increase in Achromobacter and Pseudomonas in larvae infected with M. rileyi, whereas Weissella was notably higher in those infected with B. bassiana. Additionally, significant shifts in microbial genera abundances were observed across all mixed infection groups. KEGG pathway enrichment analysis indicated that M. rileyi and B. bassiana employ distinct pathogenic strategies during early infection stages. In vitro tests confirmed the superior growth and stress resistance of B. bassiana compared to M. rileyi, but the antifungal ability of M. rileyi was better than that of B. bassiana. In conclusion, our findings provide preliminary insights into the differential pathogenic behaviors of M. rileyi and B. bassiana during the early infection stages in S. litura larvae, enhancing our understanding of their mechanisms and informing biological pest control strategies in agriculture and forestry.

RESUMEN

Background: The gut microbiota plays a vital role in the development of sepsis and in protecting against pneumonia. Previous studies have demonstrated the existence of the gut-lung axis and the interaction between the gut and the lung, which is related to the prognosis of critically ill patients; however, most of these studies focused on chronic lung diseases and influenza virus infections. The purpose of this study was to investigate the effect of faecal microbiota transplantation (FMT) on Klebsiella pneumoniae-related pulmonary infection via the gut-lung axis and to compare the effects of FMT with those of traditional antibiotics to identify new therapeutic strategies. Methods: We divided the mice into six groups: the blank control (PBS), pneumonia-derived sepsis (KP), pneumonia-derived sepsis + antibiotic (KP + PIP), pneumonia-derived sepsis + faecal microbiota transplantation(KP + FMT), antibiotic treatment control (KP+PIP+PBS), and pneumonia-derived sepsis+ antibiotic + faecal microbiota transplantation (KP + PIP + FMT) groups to compare the survival of mice, lung injury, inflammation response, airway barrier function and the intestinal flora, metabolites and drug resistance genes in each group. Results: Alterations in specific intestinal flora can occur in the gut of patients with pneumonia-derived sepsis caused by Klebsiella pneumoniae. Compared with those in the faecal microbiota transplantation group, the antibiotic treatment group had lower levels of proinflammatory factors and higher levels of anti-inflammatory factors but less amelioration of lung pathology and improvement of airway epithelial barrier function. Additionally, the increase in opportunistic pathogens and drug resistance-related genes in the gut of mice was accompanied by decreased production of favourable fatty acids such as acetic acid, propionic acid, butyric acid, decanoic acid, and secondary bile acids such as chenodeoxycholic acid 3-sulfate, isodeoxycholic acid, taurodeoxycholic acid, and 3-dehydrocholic acid; the levels of these metabolites were restored by faecal microbiota transplantation. Faecal microbiota transplantation after antibiotic treatment can gradually ameliorate gut microbiota disorder caused by antibiotic treatment and reduce the number of drug resistance genes induced by antibiotics. Conclusion: In contrast to direct antibiotic treatment, faecal microbiota transplantation improves the prognosis of mice with pneumonia-derived sepsis caused by Klebsiella pneumoniae by improving the structure of the intestinal flora and increasing the level of beneficial metabolites, fatty acids and secondary bile acids, thereby reducing systemic inflammation, repairing the barrier function of alveolar epithelial cells, and alleviating pathological damage to the lungs. The combination of antibiotics with faecal microbiota transplantation significantly alleviates intestinal microbiota disorder, reduces the selection for drug resistance genes caused by antibiotics, and mitigates lung lesions; these effects are superior to those following antibiotic monotherapy.

Asunto(s)

Antibacterianos , Trasplante de Microbiota Fecal , Microbioma Gastrointestinal , Infecciones por Klebsiella , Klebsiella pneumoniae , Pulmón , Sepsis , Animales , Infecciones por Klebsiella/microbiología , Infecciones por Klebsiella/terapia , Ratones , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Pulmón/microbiología , Pulmón/patología , Sepsis/microbiología , Sepsis/terapia , Pronóstico , Modelos Animales de Enfermedad , Humanos , Masculino , Ratones Endogámicos C57BL

RESUMEN

Metabolites from the gut microbiota define molecules in the gut-kidney cross talks. However, the mechanistic pathway by which the kidneys actively sense gut metabolites and their impact on diabetic chronic kidney disease (DCKD) remains unclear. This study is an attempt to investigate the gut microbiome metabolites, their host targeting genes, and their mechanistic action against DCKD. Gut microbiome, metabolites, and host targets were extracted from the gutMgene database and metabolites from the PubChem database. DCKD targets were identified from DisGeNET, GeneCard, NCBI, and OMIM databases. Computational examination such as protein-protein interaction networks, enrichment pathway, identification of metabolites for potential targets using molecular docking, hubgene-microbes-metabolite-samplesource-substrate (HMMSS) network architecture were executed using Network analyst, ShinyGo, GeneMania, Cytoscape, Autodock tools. There were 574 microbial metabolites, 2861 DCKD targets, and 222 microbes targeting host genes. After screening, we obtained 27 final targets, which are used for computational examination. From enrichment analysis, we found NF-ΚB1, AKT1, EGFR, JUN, and RELA as the main regulators in the DCKD development through mitogen activated protein kinase (MAPK) pathway signalling. The (HMMSS) network analysis found F.prausnitzi, B.adolescentis, and B.distasonis probiotic bacteria that are found in the intestinal epithelium, colonic region, metabolize the substrates like tryptophan, other unknown substrates might have direct interaction with the NF-kB1 and epidermal growth factor receptor (EGFR) targets. On docking of these target proteins with 3- Indole propionic acid (IPA) showed high binding energy affinity of -5.9 kcal/mol and -7.4kcal/mol. From this study we identified, the 3 IPA produced by F. prausnitzi A2-165 was found to have renal sensing properties inhibiting MAPK/NF-KB1 inflammatory pathway and would be useful in treating CKD in diabetics.