Microbiota of MR1 deficient mice confer resistance against Clostridium difficile infection

Smith, Ashley D.; Foss, Elissa D.; Zhang, Irma; Hastie, Jessica L.; Giordano, Nicole; Gasparyan, Lusine; VinhNguyen, Lam Phuc; Schubert, Alyxandria M.; Prasad, Deepika; McMichael, Hannah L.; Sun, Jinchun; Beger, Richard D.; Simonyan, Vahan; Cowley, Siobhán C.; Carlson, Paul E.

doi:10.1371/journal.pone.0223025

Cited by 21 publications

(28 citation statements)

References 43 publications

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“…It has been reported that exposure to Cef via drinking water disrupts the gut microbiota of mice, decreases bacterial load by three orders of magnitude, and alters community composition [24]. Our previous study showed that the stool microbiota of MR1 −/− mice were minimally perturbed by Cef treatment when compared with WT mice [12]. In order to investigate whether antibiotic-induced changes in BA metabolism follow a similar pattern, the total BA intensity levels in cecal content and stool samples from both KO and WT mice were measured and compared.…”

Section: Discussionmentioning

confidence: 96%

“…MR1 and bacterial derived riboflavin derivatives are required for the activation of MAIT cells, which conduct antimicrobial activity. Our previous study [11,12] showed that MR1 −/− mice had inherent differences in microbial composition when compared to WT mice both before and after Cef exposure. Surprisingly, MR1 −/− mice exhibited resistance to CDI, which can be transferrable when the microbiome of MR1 −/− mice is transferred to WT mice via fecal microbiota transplantation.…”

Section: Discussionmentioning

confidence: 99%

“…Our previous study showed the fecal microbiota of KO mice is distinct from wild-type (WT) mice. MR1 −/− mice are resistant to Clostridioides difficile infection (CDI) even following antibiotic treatment, and CDI resistance is transferrable when the microbiome of the KO mice is transferred to WT mice via fecal microbiota transplantation [11,12].…”

Section: Introductionmentioning

confidence: 99%

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Bile Acid Profile and its Changes in Response to Cefoperazone Treatment in MR1 Deficient Mice

et al. 2020

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Mucosal associated invariant T-cells (MAIT cells) are activated following recognition of bacterial antigens (riboflavin intermediates) presented on major histocompatibility complex class I-related molecule (MR1). Our previous study showed that MR1−/− knock-out (KO) mice (lacking MAIT cells) harbor a unique microbiota that is resistant to antibiotic disruption and Clostridioides difficile colonization. While we have characterized the microbiota of this mouse strain, changes in global metabolic activity in these KO mice have not been assessed. Here, LC/MS-based untargeted metabolomics was applied to investigate the differences in the metabolome, specifically in the bile acid (BA) profile of wild-type (WT) and MR1−/− KO mice, as well as how antibiotics change these profiles. BA changes were evaluated in the intestinal content, cecum content, and stool samples from MR1−/− mice and WT mice treated with cefoperazone (Cef). Fecal pellets were collected daily and both intestinal and cecal contents were harvested at predetermined endpoints on day 0 (D0), day 1 (D1), day 3 (D3), and day 5 (D5). KO mice exhibited no changes in 6-hydroxymethyl-8-D-ribityllumazine (rRL-6-CH2OH; an MR1-restricted riboflavin derivative) in the stool samples at either time point vs. D0, while WT mice showed significant decreases in rRL-6-CH2OH in the stool samples on all treatment days vs. D0. Metabolomics analysis from cecal and stool samples showed that KO mice had more total BA intensity (KO/WT = ~1.7 and ~3.3 fold higher) than that from WT mice prior to Cef treatment, while the fold change difference (KO/WT = ~4.5 and ~4.4 fold) increased after five days of Cef treatment. Both KO and WT mice showed decreases in total BA intensity in response to Cef treatment, however, less dramatic decreases were present in KO vs. WT mice. Increases in taurocholic acid (TCA) intensity and decreases in deoxycholic acid (DCA) intensity in the stool samples from WT mice were associated with the depletion of certain gut bacteria, which was consistent with the previously reported microbiome data. Furthermore, the non-detected TCA and relatively higher DCA intensity in the KO mice might be related to Clostridioides difficile infection resistance, although this needs further investigation.

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Bile Acid Profile and its Changes in Response to Cefoperazone Treatment in MR1 Deficient Mice

et al. 2020

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“…In our study we treated recipient mice with broad spectrum antibiotics (poorly absorbed) for 1 week to reduce intestinal bacterial load prior to fecal transplantation. A number of studies have used this approach to assess the functional effects of microbiota/fecal transplants . Although other studies have used germ‐free mice as recipient of fecal transplants, we opted to use the antibiotic depletion approach to overcome the dysregulated immune system in the germ‐free mice.…”

Section: Discussionmentioning

confidence: 99%

“…A number of studies have used this approach to assess the functional effects of microbiota/fecal transplants. (115)(116)(117) Although other studies have used germ-free mice as recipient of fecal transplants, we opted to use the antibiotic depletion approach to overcome the dysregulated immune system in the germ-free mice.…”

Section: Discussionmentioning

confidence: 99%

Involvement of the Gut Microbiota and Barrier Function in Glucocorticoid-Induced Osteoporosis

Schepper

Collins

Rios‐Arce

et al. 2019

Journal of Bone and Mineral Research

133

119

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Glucocorticoids (GCs) are potent immune‐modulating drugs with significant side effects, including glucocorticoid‐induced osteoporosis (GIO). GCs directly induce osteoblast and osteocyte apoptosis but also alter intestinal microbiota composition. Although the gut microbiota is known to contribute to the regulation of bone density, its role in GIO has never been examined. To test this, male C57/Bl6J mice were treated for 8 weeks with GC (prednisolone, GC‐Tx) in the presence or absence of broad‐spectrum antibiotic treatment (ABX) to deplete the microbiota. Long‐term ABX prevented GC‐Tx‐induced trabecular bone loss, showing the requirement of gut microbiota for GIO. Treatment of GC‐Tx mice with a probiotic (Lactobacillus reuteri [LR]) prevented trabecular bone loss. Microbiota analyses indicated that GC‐Tx changed the abundance of Verrucomicobiales and Bacteriodales phyla and random forest analyses indicated significant differences in abundance of Porphyromonadaceae and Clostridiales operational taxonomic units (OTUs) between groups. Furthermore, transplantation of GC‐Tx mouse fecal material into recipient naïve, untreated WT mice caused bone loss, supporting a functional role for microbiota in GIO. We also report that GC caused intestinal barrier breaks, as evidenced by increased serum endotoxin level (2.4‐fold), that were prevented by LR and ABX treatments. Enhancement of barrier function with a mucus supplement prevented both GC‐Tx–induced barrier leakage and trabecular GIO. In bone, treatment with ABX, LR or a mucus supplement reduced GC‐Tx–induced osteoblast and osteocyte apoptosis. GC‐Tx suppression of Wnt10b in bone was restored by the LR and high‐molecular‐weight polymer (MDY) treatments as well as microbiota depletion. Finally, we identified that bone‐specific Wnt10b overexpression prevented GIO. Taken together, our data highlight the previously unappreciated involvement of the gut microbiota and intestinal barrier function in trabecular GIO pathogenesis (including Wnt10b suppression and osteoblast and osteocyte apoptosis) and identify the gut as a novel therapeutic target for preventing GIO. © 2019 American Society for Bone and Mineral Research.

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Kidney stone formation and the gut microbiome are altered by antibiotics in genetic hypercalciuric stone-forming rats

Stern

Burk

Asplin³

et al. 2020

Urolithiasis

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Microbiota of MR1 deficient mice confer resistance against Clostridium difficile infection

Cited by 21 publications

References 43 publications

Bile Acid Profile and its Changes in Response to Cefoperazone Treatment in MR1 Deficient Mice

Bile Acid Profile and its Changes in Response to Cefoperazone Treatment in MR1 Deficient Mice

Involvement of the Gut Microbiota and Barrier Function in Glucocorticoid-Induced Osteoporosis

Kidney stone formation and the gut microbiome are altered by antibiotics in genetic hypercalciuric stone-forming rats

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