Investigation of the gut microbiome, bile acid composition and host immunoinflammatory response in a model of azoxymethane-induced colon cancer at discrete timepoints.

BACKGROUND: Distinct sets of microbes contribute to colorectal cancer (CRC) initiation and progression. Some occur due to the evolving intestinal environment but may not contribute to disease. In contrast, others may play an important role at particular times during the tumorigenic process. Here, we describe changes in the microbiota and host over the course of azoxymethane (AOM)-induced tumorigenesis. METHODS: Mice were administered AOM or PBS and were euthanised 8, 12, 24 and 48 weeks later. Samples were analysed using 16S rRNA gene sequencing, UPLC-MS and qRT-PCR. RESULTS: The microbiota and bile acid profile showed distinct changes at each timepoint. The inflammatory response became apparent at weeks 12 and 24. Moreover, significant correlations between individual taxa, cytokines and bile acids were detected. One co-abundance group (CAG) differed significantly between PBS- and AOM-treated mice at week 24. Correlation analysis also revealed significant associations between CAGs, bile acids and the bile acid transporter, ASBT. Aberrant crypt foci and adenomas were first detectable at weeks 24 and 48, respectively. CONCLUSION: The observed changes precede host hyperplastic transformation and may represent early therapeutic targets for the prevention or management of CRC at specific timepoints in the tumorigenic process.

Microbial Metabolites as Molecular Mediators of Host-Microbe Symbiosis in Colorectal Cancer.

The symbiosis between the gut microbiota and the host has been identified as an integral part of normal human physiology and physiological development. Research in germ-free or gnotobiotic animals has demonstrated the importance of this symbiosis in immune, vascular, hepatic, respiratory and metabolic systems. Disruption of the microbiota can also contribute to disease, and the microbiota has been implicated in numerous intestinal and extra-intestinal pathologies including colorectal cancer. Interactions between host and microbiota can occur either directly or indirectly, via microbial-derived metabolites. In this chapter, we focus on two major products of microbial metabolism, short-chain fatty acids and bile acids, and their role in colorectal cancer. Short-chain fatty acids are the products of microbial fermentation of complex carbohydrates and confer protection against cancer risk, while bile acids are compounds which are endogenous to the host, but undergo microbial modification in the large intestine leading to alterations in their bioactivity. Lastly, we discuss the ability of microbial modulation to mediate cancer risk and the potential to harness this ability as a prophylactic or therapeutic treatment in colorectal cancer.

Feline leukemia virus in a captive bobcat.

An 11-mo-old captive-bred male neutered bobcat (Felis rufus) presented with lethargy, anorexia, leukopenia, neutropenia, lymphopenia, and nonregenerative anemia. The animal was diagnosed as feline leukemia virus (FeLV) positive by immunofluorescent antibody and enzyme-linked immunosorbant assay (ELISA) testing. It died despite supportive care. Pathologic examination revealed multifocal non-suppurative encephalitis, diffuse interstitial pneumonia, multifocal hepatocellular necrosis, non-suppurative peritonitis, and lymphoid depletion. FeLV was isolated from peripheral blood mononuclear cells, bone marrow, spleen, and lymph node. FeLV-specific gag sequences were amplified by DNA polymerase chain reaction (PCR) and aligned with known domestic cat FeLV's. The source of the virus was speculated to be a domestic cat that was a surrogate nurse. Case reports of FeLV in nondomestic felids are few, and FeLV does not appear to be enzootic in wild felids, except European wildcats (Felis silvestris) in France and Scotland. Introduction of FeLV into free-living and captive nondomestic felid populations could have serious consequences for their health and survival. Measures to prevent the introduction of this virus to nondomestic felids are warranted.

The effect of normalization of plasma amino acids on hepatic encephalopathy in man.

Previous work from this laboratory has suggested that the plasma amino acid pattern, known to be deranged in hepatic encephalopathy, may be related causally. In order to test this hypothesis, 23% dextrose and a special amino acid solution whose components were calculated to normalize the plasma amino acid pattern were infused in 11 patients, eight with chronic cirrhosis and acute exacerbation (Group 1) and three patients with fulminant hepatitis (Group 2), in amounts of up to 120 Gm. of protein equivalent per 24 hours. Plasma amino acids were abnormal but different in both groups. In Group 1 (cirrhosis) changes in plasma amino acid pattern including elevated phenylalanine, tyrosine, glutamate, aspartate, and methionine and decreased valine, leucine, and isoleucine. In Group 2 all amino acids were elevated, with the exception of the branched chains which were normal. Hepatic encephalopathy improved in all patients in Group 1 and in one of three patients in Group 2 following the infusion. The ratio (see article) showed an excellent correlation with a grade of encephalopathy. When this ratio, previously 1.0 in the presence of encephalopathy, returned to the normal value near 3.0 to 3.5, encephalopathy improved. An excellent correlation was obtained between the ratio and the grade of encephalopathy and was dose related as well. The results suggest that different amino acid patterns in hepatic encephalopathy of differing etiologies require treatment modalities which may differ for the two types of encephalopathy. Whereas amino acid infusion appears to be a valuable, efficacious way of providing nutrition in treating hepatic encephalopathy in patients with cirrhosis and acute deterioration and coma, other means of therapy such as plasms "laundering" appear to be necessary in patients with fulminant hepatitis.

Primary adenovillous carcinoma of the bladder.

Two cases of primary adenovillous carcinoma of the bladder are presented: one in a normally placed bladder and the other in an exstrophied bladder. The close association of these 2 neoplasms with coexistent cystitis glandularis would seem to support the possible precancerous nature of the latter entity. The remarkable similarity of these neoplasms to villous adenocarcinomas of the rectum is also described, a finding which may reflect the close embryologic origin of the rectum and bladder neck. A brief review of the classification of vesical adenocarcinomas is also given.

The role of plasma amino acids in hepatic encephalopathy.

The dog with an end-to-side portacaval shunt has a plasma amino acid pattern similar to that in man with chronic liver disease and encephalopathy. When dogs with end-to-side portacaval shunts manifested symptoms of hepatic encephalopathy, superior caval catheters were placed and one of three solutions was infused. Whereas almost all animals given a commercially available synthetic amino acid mixture died, a special mixture formulated to normalize plasma amino acids was associated with 100 percent survival and few neurological symptoms. The results suggest that manipulation and normalization of plasma amino acids in animals with hepatic failure may be efficacious in providing adequate nutrition while minimizing hepatic encephalopathy. Moreover, these experiments may shed some light on the mechanism of human hepatic encephalopathy.

[New evaluation of effect of total colectomy and intestinal sterilization following portacaval shunt]. / Neubewertung der Wirkung der totalen Colektomie und der intestinalen Sterilisation nach portocavalem Shunt

The effect of total colectomy and "intestinal sterilisation" following chronic portocaval shunt was investigated in 96 Sprague-Dawley rats: while both therapeutic procedures are of no significant impact on serum ammonia concentrations there is a significant reduction of brain octopamine, a known false neuro-chemical transmitter, and a clear response on aromatic amino acid levels in brain and plasma. The interference with central and peripheral neurotransmitters is suggested as an alternative mechanism in experimental encephalopathy.