Abstract:Inflammatory bowel disease patients have a greatly increased risk of developing colitisassociated colon cancer (CAC); however, the basis for inflammation-induced genetic damage requisite for neoplasia is unclear. Using three models of CAC, we find that sustained inflammation triggers 8-oxoguanine DNA lesions. Strikingly, antioxidants or iNOS inhibitors reduce 8-oxoguanine and polyps in CAC models. Because the mismatch repair (MMR) system repairs 8-oxoguanine and is frequently defective in colorectal cancer (CR… Show more
“…Notably, we observed the significant enrichment of butyric acid in the streptomycin-conditioned FW (Fig. 5 f, g), a possible indication for reactive oxygen species (ROS) production and accumulation of 8-oxoG lesions [ 37 – 39 ] despite the role of butyrate in regulating homeostatic immune responses [ 40 , 41 ]. Fig.…”
Section: Resultsmentioning
confidence: 99%
“…This effect could be mediated by the antibiotic-induced alteration of bacterial metabolism, since short-term exposure of healthy human microbiota to antibiotics caused alterations of amino acid catabolic products and enrichment of butyric acid. Although microbiota-derived butyrate is an important mediator of intestinal immune homeostasis [40,41], other studies suggest that the gut microbiota, partially through an altered production of butyrate, induces ROS and the accumulation of 8-oxoG lesions, therefore contributing to inflammation and tumorigenesis [37][38][39]. On the other hand, the recipients that received FMT with a metronidazoleconditioned microbiota were able to control inflammation by reducing colitis severity.…”
Background
The gut microbiota plays a central role in host physiology and in several pathological mechanisms in humans. Antibiotics compromise the composition and functions of the gut microbiota inducing long-lasting detrimental effects on the host. Recent studies suggest that the efficacy of different clinical therapies depends on the action of the gut microbiota. Here, we investigated how different antibiotic treatments affect the ability of the gut microbiota to control intestinal inflammation upon fecal microbiota transplantation in an experimental colitis model and in ex vivo experiments with human intestinal biopsies.
Results
Murine fecal donors were pre-treated with different antibiotics, i.e., vancomycin, streptomycin, and metronidazole before FMT administration to colitic animals. The analysis of the gut microbiome, fecal metabolome, and the immunophenotyping of colonic lamina propria immune cells revealed that antibiotic pre-treatment significantly influences the capability of the microbiota to control intestinal inflammation. Streptomycin and vancomycin-treated microbiota failed to control intestinal inflammation and were characterized by the blooming of pathobionts previously associated with IBD as well as with metabolites related to the presence of oxidative stress and metabolism of simple sugars. On the contrary, the metronidazole-treated microbiota retained its ability to control inflammation co-occurring with the enrichment of Lactobacillus and of innate immune responses involving iNKT cells. Furthermore, ex vivo cultures of human intestinal lamina propria mononuclear cells and iNKT cell clones from IBD patients with vancomycin pre-treated sterile fecal water showed a Th1/Th17 skewing in CD4+ T-cell populations; metronidazole, on the other hand, induced the polarization of iNKT cells toward the production of IL10.
Conclusions
Diverse antibiotic regimens affect the ability of the gut microbiota to control intestinal inflammation in experimental colitis by altering the microbial community structure and microbiota-derived metabolites.
“…Notably, we observed the significant enrichment of butyric acid in the streptomycin-conditioned FW (Fig. 5 f, g), a possible indication for reactive oxygen species (ROS) production and accumulation of 8-oxoG lesions [ 37 – 39 ] despite the role of butyrate in regulating homeostatic immune responses [ 40 , 41 ]. Fig.…”
Section: Resultsmentioning
confidence: 99%
“…This effect could be mediated by the antibiotic-induced alteration of bacterial metabolism, since short-term exposure of healthy human microbiota to antibiotics caused alterations of amino acid catabolic products and enrichment of butyric acid. Although microbiota-derived butyrate is an important mediator of intestinal immune homeostasis [40,41], other studies suggest that the gut microbiota, partially through an altered production of butyrate, induces ROS and the accumulation of 8-oxoG lesions, therefore contributing to inflammation and tumorigenesis [37][38][39]. On the other hand, the recipients that received FMT with a metronidazoleconditioned microbiota were able to control inflammation by reducing colitis severity.…”
Background
The gut microbiota plays a central role in host physiology and in several pathological mechanisms in humans. Antibiotics compromise the composition and functions of the gut microbiota inducing long-lasting detrimental effects on the host. Recent studies suggest that the efficacy of different clinical therapies depends on the action of the gut microbiota. Here, we investigated how different antibiotic treatments affect the ability of the gut microbiota to control intestinal inflammation upon fecal microbiota transplantation in an experimental colitis model and in ex vivo experiments with human intestinal biopsies.
Results
Murine fecal donors were pre-treated with different antibiotics, i.e., vancomycin, streptomycin, and metronidazole before FMT administration to colitic animals. The analysis of the gut microbiome, fecal metabolome, and the immunophenotyping of colonic lamina propria immune cells revealed that antibiotic pre-treatment significantly influences the capability of the microbiota to control intestinal inflammation. Streptomycin and vancomycin-treated microbiota failed to control intestinal inflammation and were characterized by the blooming of pathobionts previously associated with IBD as well as with metabolites related to the presence of oxidative stress and metabolism of simple sugars. On the contrary, the metronidazole-treated microbiota retained its ability to control inflammation co-occurring with the enrichment of Lactobacillus and of innate immune responses involving iNKT cells. Furthermore, ex vivo cultures of human intestinal lamina propria mononuclear cells and iNKT cell clones from IBD patients with vancomycin pre-treated sterile fecal water showed a Th1/Th17 skewing in CD4+ T-cell populations; metronidazole, on the other hand, induced the polarization of iNKT cells toward the production of IL10.
Conclusions
Diverse antibiotic regimens affect the ability of the gut microbiota to control intestinal inflammation in experimental colitis by altering the microbial community structure and microbiota-derived metabolites.
“…Not only bacterial virulence factors, but also specific microbial metabolites, such as butyrate, were shown to severely affect CRC development [ 63 , 64 , 65 , 66 ], with the metabolome being a dominant factor responsible for variations in the gut microbiota communities in CRC [ 67 ]. These shifts in the CRC tumor microenvironment facilitate the assembly of a microbial community that is specific for CRC late-stage tumor, supporting a “driver–passenger” conceptual model, where CRC driver bacteria possess specific oncogenic properties that may drive tumorigenesis, while CRC passenger bacteria respond to changes in the tumor environment and are thus enriched in CRC tumor tissue [ 68 , 69 ].…”
Section: Hereditary and Sporadic Colorectal Cancer And Their Link mentioning
confidence: 99%
“…These shifts in the CRC tumor microenvironment facilitate the assembly of a microbial community that is specific for CRC late-stage tumor, supporting a “driver–passenger” conceptual model, where CRC driver bacteria possess specific oncogenic properties that may drive tumorigenesis, while CRC passenger bacteria respond to changes in the tumor environment and are thus enriched in CRC tumor tissue [ 68 , 69 ]. It has been recently demonstrated that the catabolism of microbial metabolites like butyrate can induce the production of reactive oxygen species, the accumulation of the 8-oxo-7,8-dihydro-2′-deoxyguanosine lesions and double-strand DNA breaks in MMR-deficient cells [ 63 , 70 ]. This will lead to further accumulation of mutations that will eventually drive neoplasia.…”
Section: Hereditary and Sporadic Colorectal Cancer And Their Link mentioning
confidence: 99%
“…This will lead to further accumulation of mutations that will eventually drive neoplasia. LS patients, harboring mutations in MMR genes, represent approximately 5% of all CRC cases [ 71 ], and an additional 15% of sporadic CRC patients carry mutations or have epigenetically silenced MMR genes, thus highlighting the risk associated to DNA damage induced by pathogens and gut-associated microorganisms [ 63 ]. A separate study showed that, in a genetic model of CRC (i.e., genetically sensitized MSH2 and MLH1 -deficient mice), the gut microbiota stimulated polyp formation by providing butyrate that induced hyper-proliferation and transformation of colon epithelial cells, suggesting a role of butyrate-producing gut microbes in the etiology of CRC [ 72 ].…”
Section: Hereditary and Sporadic Colorectal Cancer And Their Link mentioning
Colorectal cancer (CRC) is the fourth most common cause of cancer-related death and the third most common cancer in the world. Depending on the origin of the mutation, colorectal carcinomas are classified as sporadic or hereditary. Cancers derived from mutations appearing during life, affecting individual cells and their descendants, are called sporadic and account for almost 95% of the CRCs. Less than 5% of CRC cases result from constitutional mutations conferring a very high risk of developing cancer. Screening for hereditary-related cancers is offered to individuals at risk for hereditary CRC, who have either not undergone genetic evaluation or have uncertain genetic test results. In this review, we briefly summarize the main findings on the correlation between sporadic CRC and the gut microbiota, and we specifically focus on the few evidences about the role that gut microorganisms have on the development of CRC hereditary syndromes. The characterization of a gut microbiota associated with an increased risk of developing CRC could have a profound impact for prevention purposes. We also discuss the potential role of the gut microbiota as therapeutic treatment.
Recurrent bacterial infections, impenetrable microbial biofilms, and irremediable antibiotic resistance are the most perilous threats in orthopedic implant‐associated infections (IAIs). Recently, chemodynamic therapy (CDT) has been considered a promising therapy, while the clinical practices for existing CDT agents are limited by the low therapeutic efficiency in physiological circumstances. Herein, it is demonstrated that silica‐copper nanosheets (Si@Cu NSs) exhibit a combined therapeutic photothermal‐chemodynamic strategy for IAIs treatment with superior capacity and biocompatibility. This unique design endows the nanostructure with enhanced copper‐based Fenton‐like properties via p‐d orbital hybridization by incorporating copper nanoclusters (Cu NCs) on silicene nanosheets (Si NSs) matrix, integrating inherent photothermal performance of Si NSs with specific catalytic anti‐infection of Cu NCs against planktonic bacteria and biofilms both in vitro and in vivo. This study not only reveals the promising bio‐application prospects of 2D nanocatalytic biomaterials but also demonstrates the feasibility of constructing novel CDT agents by orbital hybridization for the catalytic treatment of IAIs.
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