Dataset Information

N-(1-carbamoyl-2-phenylethyl) butyramide reduces antibiotic-induced intestinal injury, innate immune activation and modulates microbiota composition.

ABSTRACT: The use/misuse of antibiotics leads to pathological features referring to antibiotic-induced intestinal injury (AIJ), a clinical issue that plays a prominent role in the development of severe digestive disturbances. AIJ is characterized by loss of intestinal architecture and function, dysbiosis and bacterial translocation into the liver, triggering hepatic inflammation. This study aimed at determining the beneficial effect of N-(1-carbamoyl-2-phenylethyl) butyramide (FBA), a butyrate releasing compound, in ceftriaxone-induced intestinal injury. To this purpose, mice receiving ceftriaxone (8?g?kg^-1/die, per os) for five days, were treated with FBA (212,5?mg?kg^-1/die, per os) for five or fifteen days. FBA modulated key players of innate immunity in antibiotic-injured gut tissues, reducing inflammatory process and improving the anti-inflammatory and resolving pattern. FBA also improved colonic architecture and intestinal integrity. Interestingly, we also observed a remodeling of gut microbiota composition related to an increase of metabolic pathways related to lactate and butyrate production. At mechanistic level, FBA induced histone acetylation and increased the expression of GPR43 and monocarboxylate transporter 1 in colon. Our data clearly demonstrated that FBA has multiple converging mechanisms in limiting intestinal and hepatic alterations to counteract AIJ.

SUBMITTER: Lama A

PROVIDER: S-EPMC6423286 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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N-(1-carbamoyl-2-phenylethyl) butyramide reduces antibiotic-induced intestinal injury, innate immune activation and modulates microbiota composition.

Lama Adriano A Annunziata Chiara C Coretti Lorena L Pirozzi Claudio C Di Guida Francesca F Nitrato Izzo Allegra A Cristiano Claudia C Mollica Maria Pina MP Chiariotti Lorenzo L Pelagalli Alessandra A Lembo Francesca F Meli Rosaria R Mattace Raso Giuseppina G

Scientific reports 20190318 1

The use/misuse of antibiotics leads to pathological features referring to antibiotic-induced intestinal injury (AIJ), a clinical issue that plays a prominent role in the development of severe digestive disturbances. AIJ is characterized by loss of intestinal architecture and function, dysbiosis and bacterial translocation into the liver, triggering hepatic inflammation. This study aimed at determining the beneficial effect of N-(1-carbamoyl-2-phenylethyl) butyramide (FBA), a butyrate releasing c ...[more]

PMID: 30886232

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Project description:BackgroundNormal mammalian development and homeostasis are dependent upon the gut microbiota. Antibiotics, essential for the treatment and prophylaxis of bacterial infections, can have collateral effects on the gut microbiota composition, which can in turn have far-reaching and potentially deleterious consequences for the host. However, the magnitude and duration of such collateral effects appear to vary between individuals. Furthermore, the degree to which such perturbations affect the host response is currently unclear. We aimed to test the hypothesis that different human microbiomes have different responses to a commonly prescribed antibiotic and that these differences may impact the host response.MethodsGerm-free mice (n = 30) humanized with the microbiota of two unrelated donors (A and B) were subjected to a 7-day antibiotic challenge with amoxicillin-clavulanate ("co-amoxiclav"). Microbiome and colonic transcriptome analysis was performed, pre (day 0) and post antibiotics (day 8) and subsequently into recovery (days 11 and 18).ResultsUnique community profiles were evident depending upon the donor, with donor A recipient mice being dominated by Prevotella and Faecalibacterium and donor B recipient mice dominated by Bacteroides and Parabacteroides. Donor A mice underwent a marked destabilization of their microbiota following antibiotic treatment, while donor B mice maintained a more stable profile. Dramatic and overlapping alterations in the host transcriptome were apparent following antibiotic challenge in both groups. Despite this overlap, donor A mice experienced a more significant alteration in gene expression and uniquely showed correlations between host pathways and key microbial genera.ConclusionsGerm-free mice humanized by different donor microbiotas maintain distinct microbiome profiles, which respond in distinct ways to antibiotic challenge and evince host responses that parallel microbiome disequilibrium. These results suggest that inter-individual variation in the gut microbiota may contribute to personalized host responses following microbiota perturbation.

Project description:The acquisition and development of infant gut microbiota can be influenced by numerous factors, of which early antibiotic treatment is an important one. However, studies on the effects of antibiotic treatment in early life on clinical outcomes and establishment and development of the gut microbiota of term infants are limited. Disturbed microbiota composition is hypothesized to be an underlying mechanism of an aberrant development of the immune system. This study aims to investigate the potential clinical and microbial consequences of empiric antibiotic use in early life.450 term born infants, of whom 150 are exposed to antibiotic treatment in early life and 300 are not (control group), are included in this observational cohort study with a one-year follow-up. Clinical outcomes, including coughing, wheezing, fever >38 °C, runny nose, glue ear, rash, diarrhea and >3 crying hours a day, are recorded daily by parents and examined by previously defined doctor's diagnosis. A blood sample is taken at closure to investigate the infant's vaccination response and sensitization for food and inhalant allergens. Fecal samples are obtained at eight time points during the first year of life. Potential differences in microbial profiles of infants treated with antibiotics versus healthy controls will be determined by use of 16S-23S rRNA gene analysis (IS-pro). Microbiota composition will be described by means of abundance, diversity and (dis)similarity. Diversity is calculated using the Shannon index. Dissimilarities between samples are calculated as the cosine distance between each pair of samples and analyzed with principal coordinate analysis. Clinical variables and possible associations are assessed by appropriate statistics.Both clinical quantitative and qualitative microbial effects of antibiotic treatment in early life may be demonstrated. These findings can be important, since there is evidence that manipulation of the infant microbiota by using pre- or probiotics can restore the ecological balance of the microbiota and may mitigate potential negative effects on the developing immune system, when use of antibiotics cannot be avoided.ClinicalTrials.gov NCT02536560. Registered 28 August 2015.

Project description:UnlabelledCholine is a water-soluble nutrient essential for human life. Gut microbial metabolism of choline results in the production of trimethylamine (TMA), which upon absorption by the host is converted in the liver to trimethylamine-N-oxide (TMAO). Recent studies revealed that TMAO exacerbates atherosclerosis in mice and positively correlates with the severity of this disease in humans. However, which microbes contribute to TMA production in the human gut, the extent to which host factors (e.g., genotype) and diet affect TMA production and colonization of these microbes, and the effects TMA-producing microbes have on the bioavailability of dietary choline remain largely unknown. We screened a collection of 79 sequenced human intestinal isolates encompassing the major phyla found in the human gut and identified nine strains capable of producing TMA from choline in vitro. Gnotobiotic mouse studies showed that TMAO accumulates in the serum of animals colonized with TMA-producing species, but not in the serum of animals colonized with intestinal isolates that do not generate TMA from choline in vitro. Remarkably, low levels of colonization by TMA-producing bacteria significantly reduced choline levels available to the host. This effect was more pronounced as the abundance of TMA-producing bacteria increased. Our findings provide a framework for designing strategies aimed at changing the representation or activity of TMA-producing bacteria in the human gut and suggest that the TMA-producing status of the gut microbiota should be considered when making recommendations about choline intake requirements for humans.ImportanceCardiovascular disease (CVD) is the leading cause of death and disability worldwide, and increased trimethylamine N-oxide (TMAO) levels have been causally linked with CVD development. This work identifies members of the human gut microbiota responsible for both the accumulation of trimethylamine (TMA), the precursor of the proatherogenic compound TMAO, and subsequent decreased choline bioavailability to the host. Understanding how to manipulate the representation and function of choline-consuming, TMA-producing species in the intestinal microbiota could potentially lead to novel means for preventing or treating atherosclerosis and choline deficiency-associated diseases.

Dataset Information

N-(1-carbamoyl-2-phenylethyl) butyramide reduces antibiotic-induced intestinal injury, innate immune activation and modulates microbiota composition.

Publications

N-(1-carbamoyl-2-phenylethyl) butyramide reduces antibiotic-induced intestinal injury, innate immune activation and modulates microbiota composition.

Similar Datasets

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