Protective and aggressive bacterial subsets and metabolites modify hepatobiliary inflammation and fibrosis in a murine model of PSC

Awoniyi, Muyiwa; Wang, Jeremy; Ngo, Billy; Meadows, Vik; Tam, Jason W.; A, Viswanathan; Lai, Yunjia; Montgomery, Stephanie A.; Farmer, Morgan; Kummen, Martin; Thingholm, Louise B.; Schramm, Christoph; Bang, Corinna; Franke, André; Lü, Kun; Zhou, Huiping; Bajaj, Jasmohan S.; Hylemon, Phillip B.; Ting, Jenny P.‐Y.; Popov, Yury; Hov, Johannes R.; Francis, Heather; Sartor, R. Balfour

doi:10.1136/gutjnl-2021-326500

Cited by 46 publications

(41 citation statements)

References 36 publications

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“…Importantly, it has been known since the 1970s that GF conditions but also antibiotics increase the bile acid pool size in rodents 9. In this respect, the current findings of Awoniyi et al 6 are therefore in line with previous observations,10 but the rescue of the liver phenotype with Lachnospiraceae and purified SCFAs is new and fascinating! However, we have to consider that it remains an unresolved question whether biliary bile acids play a role in bile duct injury in PSC, since patients with PSC show regular bile composition in this respect 11.…”

supporting

confidence: 87%

“…In Gut , Awoniyi et al 6 show that germ-free (GF) conditions cause 100% mortality in Mdr2 (Abcb4) −/− mice and that selective pathogen-free faecal microbiota transplantation rescued mice. In addition, treating the mice with vancomycin exaggerated liver injury in parallel with reduction of Lachnospiraceae and increase of Enterococcus and Enterobacteriaceae abundance, together with increased bacterial translocation, presumably from the gut to the liver, of Enterococcus faecalis and Escherichia coli strains.…”

mentioning

confidence: 99%

“…Awoniyi et al 6 have to be congratulated for their inspiring paper! The jury is still out whether ‘bugs will be hype or hope’ for patients with PSC.…”

mentioning

confidence: 99%

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confidence: 87%

mentioning

confidence: 99%

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Bacteria as key players in primary sclerosing cholangitis?

Fickert

2022

Gut

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“…In addition to the effects of antibiotics on bile acid homeostasis at the levels investigated in the present study, it was reported that depletion of gut microbiota by antibiotics may result in induction of Cyp7a1 expression in the liver, thereby enhancing bile acid synthesis (Awoniyi et al 2022;Schneider et al 2021). Development of a new approach methodology (NAM) to capture these effects is an interesting topic for future studies.…”

Section: Discussionmentioning

confidence: 89%

In vitro models to detect in vivo bile acid changes induced by antibiotics

et al. 2022

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Bile acid homeostasis plays an important role in many biological activities through the bile–liver–gut axis. In this study, two in vitro models were applied to further elucidate the mode of action underlying reported in vivo bile acid changes induced by antibiotics (colistin sulfate, tobramycin, meropenem trihydrate, and doripenem hydrate). 16S rRNA analysis of rat fecal samples anaerobically incubated with these antibiotics showed that especially tobramycin induced changes in the gut microbiota. Furthermore, tobramycin was shown to inhibit the microbial deconjugation of taurocholic acid (TCA) and the transport of TCA over an in vitro Caco-2 cell layer used as a model to mimic intestinal bile acid reuptake. The effects induced by the antibiotics in the in vitro model systems provide novel and complementary insight explaining the effects of the antibiotics on microbiota and fecal bile acid levels upon 28-day in vivo treatment of rats. In particular, our results provide insight in the mode(s) of action underlying the increased levels of TCA in the feces upon tobramycin exposure. Altogether, the results of the present study provide a proof-of-principle on how in vitro models can be used to elucidate in vivo effects on bile acid homeostasis, and to obtain insight in the mode(s) of action underlying the effect of an antibiotic, in this case tobramycin, on bile acid homeostasis via effects on intestinal bile acid metabolism and reuptake.

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“… 49 Studies have demonstrated that short chain fatty acids (SCFAs), have a role in reducing inflammatory immune responses. 51 …”

Section: Discussionmentioning

confidence: 99%

Short- and Long-Term Effects of Different Antibiotics on the Gut Microbiota and Cytokines Level in Mice

Wang¹,

Xiang²,

Gu³

et al. 2022

IDR

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Background Antibiotics are the first line of treatment for infectious diseases. However, their overuse can increase the spread of drug-resistant bacteria. The present study analyzed the impact of different types of antibiotics on the gut microbiome and cytokines level of mice. Methods A total of five groups of 8-week-old male BALB/c mice (n = 35) were treated with piperacillin-tazobactam (TZP), ceftriaxone (CRO), tigecycline (TGC), levofloxacin (LEV) or normal saline (Ctrl), respectively, for up to 4 weeks. Fecal samples were analyzed by bacterial 16S rRNA gene sequencing for bacterial identification. Blood samples were used for the determination of 23 serum cytokines using multiplex immunoassay. Results Exposure to antibiotics was shown to affect the normal weight gain of mice. Significant changes in gut composition caused by TZP, CRO and TGC treatment included the decreased abundance of Bacteroidetes (p < 0.01), Muribaculaceae (p < 0.01) and Lachnospiraceae (p < 0.01), and the increased abundance of Proteobacteria (p < 0.05), Enterobacteriaceae (including Klebsiella and Enterobacter ) (p < 0.01) and Enterococcaceae (including Enterococcus ) (p < 0.01). After 4-week treatment, the TZP, CRO and LEV groups had significantly lower concentrations of several serum cytokines. Correlation analysis of the top 30 bacterial genera and cytokines showed that Enterococcus and Klebsiella were strongly positively correlated with tumor necrosis factor-α (TNF-α), interleukins (IL) IL-12p70 and IL-1β. Desulfovibrio, Candidatus Saccharimonas, norank_f__norank_o__Clostridia_UCG-014, Lactobacillus , and Roseburi a were strongly negatively correlated with these cytokines. Conclusion This study demonstrates the effects of various antibiotics on the intestinal microflora and immune status of mice. Compared with TZP, CRO and TGC, LEV had minimal impact on the gut microbiota. In addition to TGC, long-term TZP, CRO and LEV intervention can lead to a decrease in serum cytokine levels, which may depend on the intestinal microflora, antibiotic used and the duration of treatment.

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Protective and aggressive bacterial subsets and metabolites modify hepatobiliary inflammation and fibrosis in a murine model of PSC

Cited by 46 publications

References 36 publications

Bacteria as key players in primary sclerosing cholangitis?

Bacteria as key players in primary sclerosing cholangitis?

In vitro models to detect in vivo bile acid changes induced by antibiotics

Short- and Long-Term Effects of Different Antibiotics on the Gut Microbiota and Cytokines Level in Mice

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