Influence of Fluconazole Administration on Gut Microbiome, Intestinal Barrier, and Immune Response in Mice

Heng, Xing; Jiang, Yuanhe; Chu, Weihua

doi:10.1128/aac.02552-20

Cited by 27 publications

(22 citation statements)

References 29 publications

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“…Phylum Patescibacteria appeared to be among the most affected phylum in the murine gut during amoxicillin treatment since a significant reduction was detected during treatment in group D ( Fig 4 ). A reduction of Patescibacteria has previously been demonstrated during treatment with the antifungal compound fluconazole [ 69 ] and it has also been demonstrated as highly sensitive to inorganic contamination in drinking water [ 70 ]. However, little information regarding the potential health related effects of these bacterial phyla in the gut is found.…”

Section: Discussionmentioning

confidence: 99%

Effects of different amoxicillin treatment durations on microbiome diversity and composition in the gut

Lekang

Shekhar²,

Berild³

et al. 2022

PLoS ONE

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Antibiotics seize an effect on bacterial composition and diversity and have been demonstrated to induce disruptions on gut microbiomes. This may have implications for human health and wellbeing, and an increasing number of studies suggest a link between the gut microbiome and several diseases. Hence, reducing antibiotic treatments may be beneficial for human health status. Further, antimicrobial resistance (AMR) is an increasing global problem that can be counteracted by limiting the usage of antibiotics. Longer antibiotic treatments have been demonstrated to increase the development of AMR. Therefore, shortening of antibiotic treatment durations, provided it is safe for patients, may be one measure to reduce AMR. In this study, the objective was to investigate effects of standard and reduced antibiotic treatment lengths on gut microbiomes using a murine model. Changes in the murine gut microbiome was assessed after using three different treatment durations of amoxicillin (3, 7 or 14 days) as well as a control group not receiving amoxicillin. Fecal samples were collected before and during the whole experiment, until three weeks past end of treatment. These were further subject for 16S rRNA Illumina MiSeq sequencing. Our results demonstrated significant changes in bacterial diversity, richness and evenness during amoxicillin treatment, followed by a reversion in terms of alpha-diversity and abundance of major phyla, after end of treatment. However, a longer restitution time was indicated for mice receiving amoxicillin for 14 days, and phylum Patescibacteria did not fully recover. In addition, an effect on the composition of Firmicutes was indicated to last for at least three weeks in mice treated with amoxicillin for 14 days. Despite an apparently reversion to a close to original state in overall bacterial diversity and richness, the results suggested more durable changes in lower taxonomical levels. We detected several families, genera and ASVs with significantly altered abundance three weeks after exposure to amoxicillin, as well as bacterial taxa that appeared significantly affected by amoxicillin treatment length. This may strengthen the argument for shorter antibiotic treatment regimens to both limit the emergence of antibiotic resistance and risk of gut microbiome disturbance.

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Section: Discussionmentioning

confidence: 99%

Effects of different amoxicillin treatment durations on microbiome diversity and composition in the gut

Lekang

Shekhar²,

Berild³

et al. 2022

PLoS ONE

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“…Indeed, miconazole is a broad-spectrum azole antifungal against candidiasis, with some activity against Gram-positive bacteria as well [ 17 ]. There are few reports of antifungal drugs affecting intestinal mucosal morphology, gut microbiota and immunity [ 36 ]. Therefore, further studies are needed to evaluate the influence of the antifungal miconazole on the gut microbiota and immune system.…”

Section: Discussionmentioning

confidence: 99%

Miconazole Mitigates Acetic Acid-Induced Experimental Colitis in Rats: Insight into Inflammation, Oxidative Stress and Keap1/Nrf-2 Signaling Crosstalk

Alsharif

Fayed

Abdel-Rahman

et al. 2022

Biology

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Ulcerative colitis (UC) is the most common type of inflammatory bowel disease, characterized by oxidative stress and elevated pro-inflammatory cytokines. Miconazole is an azole antifungal that stimulates the expression of antioxidant enzymes via Nrf2 activation, which consequently inhibits ROS formation and NF-κB activation. Hence, the present study aimed to investigate the protective effect of miconazole, sulfasalazine (as a reference drug) and their combination on acetic acid (AA)-induced UC in a rat model which was induced by intra-rectal administration of 4% AA. Rats were pretreated with miconazole (20 and 40 mg/kg, orally) or sulfasalazine (100 mg/kg, orally), or their combination (20 mg/kg miconazole and 50 mg/Kg of sulfasalazine, orally). Pretreatment with miconazole significantly reduced wet colon weight and macroscopic scores, accompanied by a significant amelioration of the colonic architecture disorder. Moreover, the treatment also significantly decreased the malondialdehyde (MDA) level and prevented the depletion of superoxide dismutase (SOD) activity and GSH content in inflamed colons. Additionally, the treatment showed suppressive activities on pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and C-reactive protein (CRP), and upregulated the anti-inflammatory cytokine interleukin-10 (IL-10). Moreover, the treatment upregulated the protein levels of Nrf-2 and heme oxygenase-1 (HO-1) in the colon tissue. Taken together, miconazole is effective in alleviating AA-induced colitis in rats, and the mechanism of its action is associated with the activation of Nrf2-regulated cytoprotective protein expression.

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“…Fungal infections can occur in oncology patients due to decreased immunity and often require the use of systemic antifungal agents. While many studies have examined the impact of antibiotic use on the GIT microbiome far fewer have examined antifungal use on the microbiome, with most using mouse models ( Qiu et al., 2015 ; Sam et al., 2017 ; Udawatte et al., 2020 ; Heng et al., 2021 ). Past mouse studies looking at antifungal use identified Bacteroides , Alistipes , Lactobacillus , some Firmicutes, and Proteobacteria taxa to be increased while members of the Clostridium XIVa were decreased ( Qiu et al., 2015 ; Udawatte et al., 2020 ; Heng et al., 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…While many studies have examined the impact of antibiotic use on the GIT microbiome far fewer have examined antifungal use on the microbiome, with most using mouse models ( Qiu et al., 2015 ; Sam et al., 2017 ; Udawatte et al., 2020 ; Heng et al., 2021 ). Past mouse studies looking at antifungal use identified Bacteroides , Alistipes , Lactobacillus , some Firmicutes, and Proteobacteria taxa to be increased while members of the Clostridium XIVa were decreased ( Qiu et al., 2015 ; Udawatte et al., 2020 ; Heng et al., 2021 ). We however identified significantly decreased Bacteroidetes taxa ( Bacteroides , Parabacteroides , and Alistipes ) as well as Lachnospiraceae, and Ruminococcaceae, including butyrogenic ( Faecalibacterium, Subdoligranulum , and Anaerostipes ), and acetogenic taxa ( Blautia ) among patients treated with antifungals.…”

Section: Discussionmentioning

confidence: 99%

Antibiotic and antifungal use in pediatric leukemia and lymphoma patients are associated with increasing opportunistic pathogens and decreasing bacteria responsible for activities that enhance colonic defense

Dunn

MacDonald

Rodrigues

et al. 2022

Front. Cell. Infect. Microbiol.

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Due to decreased immunity, both antibiotics and antifungals are regularly used in pediatric hematologic-cancer patients as a means to prevent severe infections and febrile neutropenia. The general effect of antibiotics on the human gut microbiome is profound, yielding decreased diversity and changes in community structure. However, the specific effect on pediatric oncology patients is not well-studied. The effect of antifungal use is even less understood, having been studied only in mouse models. Because the composition of the gut microbiome is associated with regulation of hematopoiesis, immune function and gastrointestinal integrity, changes within the patient gut can have implications for the clinical management of hematologic malignancies. The pediatric population is particularly challenging because the composition of the microbiome is age dependent, with some of the most pronounced changes occurring in the first three years of life. We investigated how antibiotic and antifungal use shapes the taxonomic composition of the stool microbiome in pediatric patients with leukemia and lymphoma, as inferred from both 16S rRNA and metagenome data. Associations with age, antibiotic use and antifungal use were investigated using multiple analysis methods. In addition, multivariable differential abundance was used to identify and assess specific taxa that were associated with multiple variables. Both antibiotics and antifungals were linked to a general decline in diversity in stool samples, which included a decrease in relative abundance in butyrate producers that play a critical role in host gut physiology (e.g., Faecalibacterium, Anaerostipes, Dorea, Blautia),. Furthermore, antifungal use was associated with a significant increase in relative abundance of opportunistic pathogens. Collectively, these findings have important implications for the treatment of leukemia and lymphoma patients. Butyrate is important for gastrointestinal integrity; it inhibits inflammation, reinforces colonic defense, mucosal immunity. and decreases oxidative stress. The routine use of broad-spectrum anti-infectives in pediatric oncology patients could simultaneously contribute to a decline in gastrointestinal integrity and colonic defense while promoting increases in opportunistic pathogens within the patient gut. Because the gut microbiome has been linked to both short-term clinical outcomes, and longer-lasting health effects, systematic characterization of the gut microbiome in pediatric patients during, and beyond, treatment is warranted.

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Influence of Fluconazole Administration on Gut Microbiome, Intestinal Barrier, and Immune Response in Mice

Cited by 27 publications

References 29 publications

Effects of different amoxicillin treatment durations on microbiome diversity and composition in the gut

Effects of different amoxicillin treatment durations on microbiome diversity and composition in the gut

Miconazole Mitigates Acetic Acid-Induced Experimental Colitis in Rats: Insight into Inflammation, Oxidative Stress and Keap1/Nrf-2 Signaling Crosstalk

Antibiotic and antifungal use in pediatric leukemia and lymphoma patients are associated with increasing opportunistic pathogens and decreasing bacteria responsible for activities that enhance colonic defense

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