ABSTRACT
OBJECTIVE: There is substantial inter-individual diversity in the susceptibility of alcoholics to liver injury. Alterations of intestinal microbiota (IM) have been reported in alcoholic liver disease (ALD), but the extent to which they are merely a consequence or a cause is unknown. We aimed to demonstrate that a specific dysbiosis contributes to the development of alcoholic hepatitis (AH). DESIGN: We humanised germ-free and conventional mice using human IM transplant from alcoholic patients with or without AH. The consequences on alcohol-fed recipient mice were studied. RESULTS: A specific dysbiosis was associated with ALD severity in patients. Mice harbouring the IM from a patient with severe AH (sAH) developed more severe liver inflammation with an increased number of liver T lymphocyte subsets and Natural Killer T (NKT) lymphocytes, higher liver necrosis, greater intestinal permeability and higher translocation of bacteria than mice harbouring the IM from an alcoholic patient without AH (noAH). Similarly, CD45+ lymphocyte subsets were increased in visceral adipose tissue, and CD4(+)T and NKT lymphocytes in mesenteric lymph nodes. The IM associated with sAH and noAH could be distinguished by differences in bacterial abundance and composition. Key deleterious species were associated with sAH while the Faecalibacterium genus was associated with noAH. Ursodeoxycholic acid was more abundant in faeces from noAH mice. Additionally, in conventional mice humanised with the IM from an sAH patient, a second subsequent transfer of IM from an noAH patient improved alcohol-induced liver lesions. CONCLUSIONS: Individual susceptibility to ALD is substantially driven by IM. It may, therefore, be possible to prevent and manage ALD by IM manipulation.
Subject(s)
Dysbiosis/complications , Gastrointestinal Microbiome , Liver Diseases, Alcoholic/microbiology , Animals , Disease Susceptibility/microbiology , Female , Humans , Mice , Mice, Inbred C57BLABSTRACT
Oligometastatic prostate cancer is among the most studied oligometastatic cancers in the literature. However few prospective studies have assessed stereotactic body radiotherapy (SBRT) for prostate cancer oligometastases. Two randomised phase II trials show a progression-free survival benefit compared with observation. Prospective registry data show very good local control and low toxicity too. Inclusion in ongoing trials should be strongly encouraged to define the role of SBRT in addition to systemic therapy. Radiation therapy to the primary tumour has been studied in randomised trials and provides an overall survival benefit in patients with low metastatic burden. The benefit is inversely correlated with the number of bone lesions using conventional imaging, up to three metastases. Radiotherapy to the primary tumour is recommended by the learned societies for patients with low metastatic burden. Its role in combination with second generation anti androgen therapy needs to be clarified.