Inhibition of NF-κB by a PXR-dependent pathway mediates counter-regulatory activities of rifaximin on innate immunity in intestinal epithelial cells

Mencarelli, Andrea; Renga, Barbara; Palladino, Giuseppe; D’Amore, Claudio; Ricci, Patrizia; Distrutti, Eleonora; Barbanti, M.; Baldelli, Franco; Fiorucci, Stefano

doi:10.1016/j.ejphar.2011.06.058

Cited by 102 publications

(64 citation statements)

References 27 publications

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“…In particular, rifaximin can down-regulate the inflammatory response triggered by the gut microbes by inhibiting the activation of the nuclear factor (NF)-κB via the pregnane X receptor (PXR) and by reducing the expression of the pro-inflammatory cytokines interleukin (IL)-1B and tumor necrosis factor-alpha (TNFα)[67-71]. …”

Section: Rifaximin: a Poorly Absorbed Antibiotic With Non-traditionalmentioning

confidence: 99%

Eubiotic properties of rifaximin: Disruption of the traditional concepts in gut microbiota modulation

Ponziani

Zocco

D’Aversa

et al. 2017

WJG

137

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Antibiotics are usually prescribed to cure infections but they also have significant modulatory effects on the gut microbiota. Several alterations of the intestinal bacterial community have been reported during antibiotic treatment, including the reduction of beneficial bacteria as well as of microbial alpha-diversity. Although after the discontinuation of antibiotic therapies it has been observed a trend towards the restoration of the original condition, the new steady state is different from the previous one, as if antibiotics induced some kind of irreversible perturbation of the gut microbial community. The poorly absorbed antibiotic rifaximin seem to be different from the other antibiotics, because it exerts non-traditional effects additional to the bactericidal/bacteriostatic activity on the gut microbiota. Rifaximin is able to reduce bacterial virulence and translocation, has anti-inflammatory properties and has been demonstrated to positively modulate the gut microbial composition. Animal models, culture studies and metagenomic analyses have demonstrated an increase in Bifidobacterium, Faecalibacterium prausnitzii and Lactobacillus abundance after rifaximin treatment, probably consequent to the induction of bacterial resistance, with no major change in the overall gut microbiota composition. Antibiotics are therefore modulators of the symbiotic relationship between the host and the gut microbiota. Specific antibiotics, such as rifaximin, can also induce eubiotic changes in the intestinal ecosystem; this additional property may represent a therapeutic advantage in specific clinical settings.

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Section: Rifaximin: a Poorly Absorbed Antibiotic With Non-traditionalmentioning

confidence: 99%

Eubiotic properties of rifaximin: Disruption of the traditional concepts in gut microbiota modulation

Ponziani

Zocco

D’Aversa

et al. 2017

WJG

137

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“…It is poorly absorbed on oral administration (15) Rifaximin, a non-absorbable antibiotic, inhibits the release of pro-angiogenic mediators in colon cancer cells through a pregnane X receptor-dependent pathway and as such has an optimum safety profile. Apart from its antibiotic potential, rifaximin has also been studied for its anti-inflammatory effects; several studies have highlighted the anti-inflammatory potential of rifaximin, which is mainly attributed to the inhibition of the NF-κB signaling and NO release via activation of intestinal human pregnane X (PXR) receptors (16,17). The aim of the present study was to explore the anti-proliferative and anti-migration effects of rifaximin, and to evaluate the possible control of the angiogenic mediator release by rifaximin using a human intestinal epithelial cell line to model the intestinal barrier.…”

Section: Introductionmentioning

confidence: 99%

Rifaximin, a non-absorbable antibiotic, inhibits the release of pro-angiogenic mediators in colon cancer cells through a pregnane X receptor-dependent pathway

Esposito

Gigli

Seguella

et al. 2016

International Journal of Oncology

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Abstract. Activation of intestinal human pregnane X receptor (PXR) has recently been proposed as a promising strategy for the chemoprevention of inflammation-induced colon cancer. The present study was aimed at evaluating the effect of rifaximin, a non-absorbable antibiotic, in inhibiting angiogenesis in a model of human colorectal epithelium and investigating the role of PXR in its mechanism of action. Caco-2 cells were treated with rifaximin (0.1, 1.0 and 10.0 µM) in the presence or absence of ketoconazole (10 µM) and assessed for cell proliferation, migration and expression of proliferating cell nuclear antigen (PCNA). The release of vascular endothelial growth factor (VEGF) and nitric oxide (NO), expression of Akt, mechanistic target of rapamycin (mTOR), p38 mitogen activated protein kinases (MAPK), nuclear factor κB (NF-κB) and metalloproteinase-2 and -9 (MMP-2 and -9) were also evaluated. Treatment with rifaximin 0.1, 1.0 and 10.0 µM caused significant and concentration-dependent reduction of cell proliferation, cell migration and PCNA expression in the Caco-2 cells vs. untreated cells. Treatment downregulated VEGF secretion, NO release, VEGFR-2 expression, MMP-2 and MMP-9 expression vs. untreated cells. Rifaximin treatment also resulted in a concentration-dependent decrease in the phosphorylation of Akt, mTOR, p38MAPK and inhibition of hypoxia-inducible factor 1-α (HIF-1α), p70S6K and NF-κB. Ketoconazole (PXR antagonist) treatment inhibited these effects. These findings demonstrated that rifaximin causes PXR-mediated inhibition of angiogenic factors in Caco-2 cell line and may be a promising anticancer tool. IntroductionColorectal cancer (CRC) represents one of the major causes of morbidity and mortality throughout the world and is the third most common form of human cancer worldwide (1,2). Like other forms of cancer, CRC is characterized by angiogenesis, which is a crucial event in promoting cancer growth, progression and metastasis (3). Among the various signaling molecules involved in the angiogenic process, vascular endothelial growth factor (VEGF) and nitric oxide (NO) are thought to be the key signaling molecules responsible for neo-vascularization (4-6). Once hypersecreted, VEGF binds to its type 2 receptor (VEGFR-2) and mediates the regulation of different pathways in the target cells, mainly the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway (7,8) and the phosphop38 mitogen activated protein kinase (MAPK)-dependent activation of nuclear factor κB (NF-κB) (9,10). Activation of the NF-κB and Akt/mTOR pathways increases the levels of the inducible nitric oxide synthase (iNOS) isoform, leading to the release and accumulation of nitric oxide (NO) that acts as a pro-angiogenic stimulus on the blood vessels and favors neo-vascularization in solid tumors (5,11). Thus, targeting the angiogenic and mitogenic pathways is a rational and potentially effective strategy in the treatment of CRC (12).Rifaximin is a semi-synthetic antibiotic largely used fo...

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“…Rifaximin, an antimicrobial agent used in the treatment of IBD, mediates its effects by increasing the expression of PXR. It has been shown to abrogate the DNA binding of NF-κB caused by LPS, to reduce mRNA levels of IL-8, RANTES, MIP-3α and TNFα [305]. Chrysin, a naturally occurring flavonoid with anti-inflammation activity, prevents DSS-induced colitis, an effect largely mediated by PXR [306].…”

Section: Nuclear Receptorsmentioning

confidence: 99%

Enteric Microbiota–Gut–Brain Axis from the Perspective of Nuclear Receptors

Duszka

Wahli

2018

IJMS

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Nuclear receptors (NRs) play a key role in regulating virtually all body functions, thus maintaining a healthy operating body with all its complex systems. Recently, gut microbiota emerged as major factor contributing to the health of the whole organism. Enteric bacteria have multiple ways to influence their host and several of them involve communication with the brain. Mounting evidence of cooperation between gut flora and NRs is already available. However, the full potential of the microbiota interconnection with NRs remains to be uncovered. Herewith, we present the current state of knowledge on the multifaceted roles of NRs in the enteric microbiota–gut–brain axis.

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Inhibition of NF-κB by a PXR-dependent pathway mediates counter-regulatory activities of rifaximin on innate immunity in intestinal epithelial cells

Cited by 102 publications

References 27 publications

Eubiotic properties of rifaximin: Disruption of the traditional concepts in gut microbiota modulation

Eubiotic properties of rifaximin: Disruption of the traditional concepts in gut microbiota modulation

Rifaximin, a non-absorbable antibiotic, inhibits the release of pro-angiogenic mediators in colon cancer cells through a pregnane X receptor-dependent pathway

Enteric Microbiota–Gut–Brain Axis from the Perspective of Nuclear Receptors

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