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Rath, E.

Publications and source records attributed to Rath, E..

2 recordsLinked to original sources
bioRxiv2023

Mitochondrial perturbation of the epithelium causes microbial dysbiosis and unresolved tissue injury in intestinal inflammation

Mitochondrial dysfunction is associated with inflammatory bowel diseases (IBD). To understand how microbial-metabolic circuits contribute to intestinal tissue injury, we disrupt mitochondrial function in the epithelium by deleting heat shock protein 60 (Hsp60{Delta}/{Delta}IEC). While metabolic perturbation causes self-resolving tissue injury, regeneration is disrupted in the absence of aryl hydrocarbon receptor (Hsp60{Delta}/{Delta}IEC;AhR-/-) or IL-10 (Hsp60{Delta}/{Delta}IEC;Il10-/-) leading to IBD-like pathology. Injury is absent in the distal colon of germ-free (GF) Hsp60{Delta}/{Delta}IEC mice, highlighting bacterial control of metabolic injury. Selective colonization of GF Hsp60{Delta}/{Delta}IEC mice with the synthetic community OMM12 confirms consistent expansion of metabolically-flexible Bacteroides spp. across all models and mono-colonization with B. caecimuris recapitulates injury. Transcriptional profiling of metabolically-impaired epithelium identifies gene signatures, including Ido1, Nos2, and Duox2, distinguishing active from inactive tissue inflammation in 343 resected samples from Crohns disease patients. In conclusion, mitochondrial perturbation of the epithelium causes microbiota-dependent tissue injury and discriminative inflammatory gene profiles relevant for IBD. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=171 SRC="FIGDIR/small/549844v6_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@240c5forg.highwire.dtl.DTLVardef@a84382org.highwire.dtl.DTLVardef@e829e3org.highwire.dtl.DTLVardef@163625_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract:C_FLOATNO Control of metabolic injury by microbial signals. C_FIG O_LIMitochondrial perturbation of the intestinal epithelium induces tissue injury C_LIO_LILoss of IL-10 and AhR-related host mechanisms accelerate injury and inflammation C_LIO_LIMitochondrial dysfunction induces dysbiosis and expansion of Bacteroides spp. C_LIO_LIMetabolic injury gene signature discriminates inflamed vs. non-inflamed IBD samples C_LI

microbiology↗
bioRxiv2022

Leptospermum extract (QV0) suppresses pleural mesothelioma tumour growth in vitro and in vivo by mitochondrial dysfunction associated apoptosis

Pleural mesothelioma (PM) is a highly aggressive, fast-growing asbestos-induced cancer with limited effective treatments. There has been an interest in using naturally occurring anticancer agents derived from plant materials for the treatment of PM. However, it is unclear if aqueous extract from the Leptospermum polygalifolium (QV0) has activity against PM. Here we investigated the anti-cancer property of QV0 in vitro and in vivo. Animals treated with Defender(R) (QV0 dietary supply) exhibited a reduced tumour size over 30 days, which was associated with an average extended of seven days mouse life. There was no liver toxicity, nor increased blood glucose post-treatment in animals treated with Defender(R). Moreover, QV0 suppressed the growth of 13 cancer cell lines in a dose-dependent manner, effective at concentrations as low as 0.02% w/v. This response was found to be associated with inhibited cell migration, proliferation, and colony formation, but without evident cell cycle alteration. We observed mitochondrial dysfunction post QV0 treatment, as evidenced by significantly decreased basal and maximal oxygen consumption rates. Significantly enhanced tumour apoptosis was observed in the Defender(R)-treated animals, correlating with mitochondrial dysfunction. To the best of our knowledge, this study constitutes the first demonstration of an improved host survival (without adverse effects) response in a QV0-treated PM mouse model, associated with an evident inhibition of PM cell growth and mitochondrial dysfunction-related enhancement of tumour apoptosis. ImportanceA major problem with cancer chemotherapy or immunotherapy is the severe adverse effects associated with normal tissue damage. PM is known to be treatment resistant and has poor a prognosis, therefore new therapeutic treatment options are urgently needed. In the present study, we explored the potential utility of a Leptospermum extract (QV0) as a treatment option for mesothelioma. We demonstrated for the first time that QV0 exhibits an anti-tumour response in mesothelioma, without any associated adverse effects observed in the PM mouse model. These findings provide a rationale for early-stage clinical trials. We anticipate that prospective translational research will lead to the clinical implementation of a novel QV0-based treatment strategy that will ultimately benefit PM patients.

cancer biology↗