Bidirectional interactions between indomethacin and the murine intestinal microbiota

Liang, Xue; Bittinger, Kyle; Li, Xuanwen; Abernethy, Darrell R.; Bushman, Frederic D.; FitzGerald, Garret A.

doi:10.7554/elife.08973

Cited by 82 publications

(72 citation statements)

References 91 publications

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“…Though a previous study showed a different gut microbial alteration after indomethacin treatment in mice14, the present study differs by employing 16S rRNA sequencing on serial samples from the same mouse, reducing individual variations to visualize the gut microbial alteration. And these compositional changes in microbiota are consistent with another sequencing study15.…”

Section: Discussionsupporting

confidence: 90%

“…The composition after this adaptive change is significantly different from the original commensals; nevertheless, we also acknowledge that our experiments have not provided mechanistic insights to small bowel enteropathy. In a recent study, antibiotic pretreatment was shown to reduce gut de-glucuronidation and result in increased indomethacin elimination, therefore preventing the mucosae from injury15. Antibiotic pretreatment may affect the pathogenesis through altering the drug metabolism.…”

Section: Discussionmentioning

confidence: 99%

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Gut Microbiota Mediates Protection Against Enteropathy Induced by Indomethacin

Xiao

Nakatsu

Wong

et al. 2017

Sci Rep

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Non-steroidal anti-inflammatory drugs (NSAIDs) can cause significant small bowel injuries. The role of gut microbiota in this NSAID-induced enteropathy is poorly understood. We studied the dynamic changes in gut microbiota following indomethacin administration in mice, and investigated the effects of these adaptive changes on subsequent NSAID-induced enteropathy. The changes in gut microbiota were studied using 16S rRNA sequencing, and the effects of such changes were investigated using antibiotics and a faecal transplantation model. After indomethacin treatment, significant adaptive changes in gut microbiota were observed, including increased abundance of Firmicutes and decreased abundance in that of Bacteroidetes. Depletion of gut microbiota with antibiotics led to a higher mortality (P = 0.0021) in mice compared to controls. Mice pre-transplanted with adaptively changed microbiota showed less small bowel injury and lower levels of pro-inflammatory cytokines when exposed to indomethacin. In summary, this study identifies adaptive changes in the gut microbiota upon indomethacin administration, which can in turn ameliorate further NSAID-induced injury. The heightened mortality with antibiotic depletion of the adaptively changed microbiota suggests its important role in protecting against such injury. This study provides insight for future efforts to target the microbiota as a therapeutic strategy.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Gut Microbiota Mediates Protection Against Enteropathy Induced by Indomethacin

Xiao

Nakatsu

Wong

et al. 2017

Sci Rep

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“…This difference between mice and rats may in part be related to the absence of a gall bladder in rats, but obviously, other species-related differences may play a role. A recent study reported on the acute and chronic effects of indomethacin supplementation in BL6 mice based on 16S ribosomal RNA (rRNA) gene amplicon sequencing [38]. Using an acute dose about 10 times higher than the dosage used in the present experiments, the authors found that the abundance of Peptococcaceae in the fecal samples increased already after 6 h. Exposure for 7 days using a dosage similar to the one used here resulted in no significant changes in the fecal microbiome, whereas an increased abundance of Peptococcaceas was observed in samples from cecum and the large intestine [38].…”

Section: Discussionmentioning

confidence: 99%

“…A recent study reported on the acute and chronic effects of indomethacin supplementation in BL6 mice based on 16S ribosomal RNA (rRNA) gene amplicon sequencing [38]. Using an acute dose about 10 times higher than the dosage used in the present experiments, the authors found that the abundance of Peptococcaceae in the fecal samples increased already after 6 h. Exposure for 7 days using a dosage similar to the one used here resulted in no significant changes in the fecal microbiome, whereas an increased abundance of Peptococcaceas was observed in samples from cecum and the large intestine [38]. This finding and the clear effects of the microbiota on the metabolism of indomethacin suggest that some of the strain-specific effects of indomethacin supplementation may relate to differences in composition of the microbiota and changes in the gut not reflected in fecal samples.…”

Section: Discussionmentioning

confidence: 99%

High-fat feeding rather than obesity drives taxonomical and functional changes in the gut microbiota in mice

et al. 2017

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BackgroundIt is well known that the microbiota of high-fat (HF) diet-induced obese mice differs from that of lean mice, but to what extent, this difference reflects the obese state or the diet is unclear. To dissociate changes in the gut microbiota associated with high HF feeding from those associated with obesity, we took advantage of the different susceptibility of C57BL/6JBomTac (BL6) and 129S6/SvEvTac (Sv129) mice to diet-induced obesity and of their different responses to inhibition of cyclooxygenase (COX) activity, where inhibition of COX activity in BL6 mice prevents HF diet-induced obesity, but in Sv129 mice accentuates obesity.ResultsUsing HiSeq-based whole genome sequencing, we identified taxonomic and functional differences in the gut microbiota of the two mouse strains fed regular low-fat or HF diets with or without supplementation with the COX-inhibitor, indomethacin. HF feeding rather than obesity development led to distinct changes in the gut microbiota. We observed a robust increase in alpha diversity, gene count, abundance of genera known to be butyrate producers, and abundance of genes involved in butyrate production in Sv129 mice compared to BL6 mice fed either a LF or a HF diet. Conversely, the abundance of genes involved in propionate metabolism, associated with increased energy harvest, was higher in BL6 mice than Sv129 mice.ConclusionsThe changes in the composition of the gut microbiota were predominantly driven by high-fat feeding rather than reflecting the obese state of the mice. Differences in the abundance of butyrate and propionate producing bacteria in the gut may at least in part contribute to the observed differences in obesity propensity in Sv129 and BL6 mice.Electronic supplementary materialThe online version of this article (doi:10.1186/s40168-017-0258-6) contains supplementary material, which is available to authorized users.

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“…Whether these types of effects occur following treatment with other NSAIDs or chemopreventive agents with different mechanisms of action should be evaluated. In fact, recently published work by Liang et al ., provides some evidence for this concept by demonstrating that administration of indomethacin to mice induces a shift in the luminal microbiota with a reciprocal effect of the bacteria on drug metabolism (34). Taking into consideration the Liang study as well as the current work, it is possible that several NSAIDs may exert effects on the luminal microbiota, which could explain in part, the chemopreventive efficacy of this class of compounds.…”

Section: Discussionmentioning

confidence: 99%

Celecoxib Alters the Intestinal Microbiota and Metabolome in Association with Reducing Polyp Burden

Montrose

Zhou

McNally

et al. 2016

Cancer Prevention Research

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Treatment with celecoxib, a selective COX-2 inhibitor, reduces formation of premalignant adenomatous polyps in the gastrointestinal tracts of humans and mice. In addition to its chemopreventive activity, celecoxib can exhibit anti-microbial activity. Differing bacterial profiles have been found in feces from colon cancer patients compared with that of normal subjects. Moreover, preclinical studies suggest that bacteria can modulate intestinal tumorigenesis by secreting specific metabolites. In the current study, we determined whether celecoxib treatment altered the luminal microbiota and metabolome in association with reducing intestinal polyp burden in mice. Administration of celecoxib for 10 weeks markedly reduced intestinal polyp burden in APCMin/+ mice. Treatment with celecoxib also altered select luminal bacterial populations in both APCMin/+ and wild-type mice including decreased Lactobacillaceae and Bifidobacteriaceae as well as increased Coriobacteriaceae. Metabolomic analysis demonstrated that celecoxib caused a strong reduction in many fecal metabolites linked to carcinogenesis including glucose, amino acids, nucleotides and lipids. Ingenuity Pathway Analysis suggested that these changes in metabolites may contribute to reduced cell proliferation. To this end, we showed that celecoxib reduced cell proliferation in the base of normal appearing ileal and colonic crypts of APCMin/+ mice. Consistent with this finding, lineage tracing indicated that celecoxib treatment reduced the rate at which Lgr5-positive stem cells gave rise to differentiated cell types in the crypts. Taken together, these results demonstrate that celecoxib alters the luminal microbiota and metabolome along with reducing epithelial cell proliferation in mice. We hypothesize that these actions contribute to its chemopreventive activity.

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Bidirectional interactions between indomethacin and the murine intestinal microbiota

Cited by 82 publications

References 91 publications

Gut Microbiota Mediates Protection Against Enteropathy Induced by Indomethacin

Gut Microbiota Mediates Protection Against Enteropathy Induced by Indomethacin

High-fat feeding rather than obesity drives taxonomical and functional changes in the gut microbiota in mice

Celecoxib Alters the Intestinal Microbiota and Metabolome in Association with Reducing Polyp Burden

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