Tremendous progress has been made in characterizing the bidirectional interactions between the central nervous system, the enteric nervous system, and the gastrointestinal tract. A series of provocative preclinical studies have suggested a prominent role for the gut microbiota in these gut-brain interactions. Based on studies using rodents raised in a germ-free environment, the gut microbiota appears to influence the development of emotional behavior, stress- and pain-modulation systems, and brain neurotransmitter systems. Additionally, microbiota perturbations by probiotics and antibiotics exert modulatory effects on some of these measures in adult animals. Current evidence suggests that multiple mechanisms, including endocrine and neurocrine pathways, may be involved in gut microbiota-to-brain signaling and that the brain can in turn alter microbial composition and behavior via the autonomic nervous system. Limited information is available on how these findings may translate to healthy humans or to disease states involving the brain or the gut/brain axis. Future research needs to focus on confirming that the rodent findings are translatable to human physiology and to diseases such as irritable bowel syndrome, autism, anxiety, depression, and Parkinson's disease.

/pdf/gut-brain-axis-and-the-microbiota-3ksluuopxy.pdf

Gut/brain axis and the microbiota

Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies with features of biliary tract differentiation. CCA is the second most common primary liver tumour and the incidence is increasing worldwide. CCA has high mortality owing to its aggressiveness, late diagnosis and refractory nature. In May 2015, the "European Network for the Study of Cholangiocarcinoma" (ENS-CCA: www.enscca.org or www.cholangiocarcinoma.eu) was created to promote and boost international research collaboration on the study of CCA at basic, translational and clinical level. In this Consensus Statement, we aim to provide valuable information on classifications, pathological features, risk factors, cells of origin, genetic and epigenetic modifications and current therapies available for this cancer. Moreover, future directions on basic and clinical investigations and plans for the ENS-CCA are highlighted.

/pdf/expert-consensus-document-cholangiocarcinoma-current-1ot5rctd8a.pdf

Expert consensus document: Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA)

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.25657

Source and characterization of hepatic macrophages in acetaminophen-induced acute liver failure in humans.

Cholangiocarcinoma (CC) is typically diagnosed at an advanced stage and is refractory to surgical intervention and chemotherapy. Despite a global increase in the incidence of CC, little progress has been made toward the development of treatments for this cancer. Here we utilized human tissue; CC cell xenografts; a p53-deficient transgenic mouse model; and a non-transgenic, chemically induced rat model of CC that accurately reflects both the inflammatory and regenerative background associated with human CC pathology. Using these systems, we determined that the WNT pathway is highly activated in CCs and that inflammatory macrophages are required to establish this WNT-high state in vivo. Moreover, depletion of macrophages or inhibition of WNT signaling with one of two small molecule WNT inhibitors in mouse and rat CC models markedly reduced CC proliferation and increased apoptosis, resulting in tumor regression. Together, these results demonstrate that enhanced WNT signaling is a characteristic of CC and suggest that targeting WNT signaling pathways has potential as a therapeutic strategy for CC.

/pdf/wnt-signaling-drives-cholangiocarcinoma-growth-and-can-be-3zx7m28izs.pdf

WNT signaling drives cholangiocarcinoma growth and can be pharmacologically inhibited

Multidimensional analyses have demonstrated the presence of a unique tumor microenvironment (TME) in liver cancer. Tumor‐associated macrophages (TAMs) are among the most abundant immune cells infiltrating the TME and are present at all stages of liver cancer progression, and targeting TAMs has become one of the most favored immunotherapy strategies. In addition, macrophages and liver cancer cells have distinct origins. At the early stage of liver cancer, macrophages can provide a niche for the maintenance of liver cancer stem cells. In contrast, cancer stem cells (CSCs) or poorly differentiated tumor cells are key factors modulating macrophage activation. In the present review, we first propose the origin connection between precursor macrophages and liver cancer cells. Macrophages undergo dynamic phenotypic transition during carcinogenesis. In this course of such transition, it is critical to determine the appropriate timing for therapy and block specific markers to suppress pro‐tumoral TAMs. The present review provides a more detailed discussion of transition trends of such surface markers than previous reviews. Complex crosstalk occurs between TAMs and liver cancer cells. TAMs play indispensable roles in tumor progression, angiogenesis, and autophagy due to their heterogeneity and robust plasticity. In addition, macrophages in the TME interact with other immune cells by directing cell‐to‐cell contact or secreting various effector molecules. Similarly, tumor cells combined with other immune cells can drive macrophage recruitment and polarization. Despite the latest achievements and the advancements in treatment strategies following TAMs studies, comprehensive discussions on the communication between macrophages and cancer cells or immune cells in liver cancer are currently lacking. In this review, we discussed the interactions between TAMs and liver cancer cells (from cell origin to maturation), the latest therapeutic strategies (including chimeric antigen receptor macrophages), and critical clinical trials for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) to provide a rationale for further clinical investigation of TAMs as a potential target for treating patients with liver cancer.

Tumor‐associated macrophages in liver cancer: From mechanisms to therapy

Chronic inflammation as a risk factor for cancer development is driven in part by monocyte/macrophages, which in many cancers exhibit pro-tumorigenic activity. In this study we identified elevation in CD14(+) CD16(+) , a minor blood monocyte subpopulation in cholangiocarcinoma (CCA) patients, compared to normal and biliary disease patient specimens. Tumour association was suggested by the observation that this elevated level decreased to normal after tumour resection. Moreover, the elevated level of CD14(+) CD16(+) monocytes in CCA patient blood correlated with degree of MAC387-positive (recent blood-derived macrophage migrant-specific marker) tumour-associated macrophage infiltration as determined by immunohistochemistry. These CD14(+) CD16(+) monocytes were suggested to enhance tumour progression as this subpopulation possesses (i) high expression of adhesion molecules (CD11c, CD49d, and CD54) and scavenger receptor (CD163), which enable them to adhere strongly to endothelial cells, and (ii) that peripheral blood monocytes from CCA patients express high levels of growth and angiogenic factor-related genes (epiregulin, VEGF-A and CXCL3). Elevation of peripheral CD14(+) CD16(+) monocyte levels was associated with features associated with poor prognosis CCA parameters (non-papillary type and high number of tissue macrophages). These data indicate that the CD14(+) CD16(+) monocytes from CCA patients with pro-tumorigenic characteristics may associate with rapid tumour progression and poor patient outcome. If confirmed in subsequent studies, the level of CD14(+) CD16(+) monocytes may serve as a marker for disease activity in CCA patients and serve as a target for pathogenic macrophage specific drug development.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2249.2010.04200.x

Circulating CD14(+) CD16(+) monocyte levels predict tissue invasive character of cholangiocarcinoma.

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Circulating CD14(+) CD16(+) monocyte levels predict tissue invasive character of cholangiocarcinoma.