Over the past decades the food industry has been revolutionized toward the production of functional foods due to an increasing awareness of the consumers on the positive role of food in wellbeing and health. By definition probiotic foods must contain live microorganisms in adequate amounts so as to be beneficial for the consumer's health. There are numerous probiotic foods marketed today and many probiotic strains are commercially available. However, the question that arises is how to determine the real probiotic potential of microorganisms. This is becoming increasingly important, as even a superficial search of the relevant literature reveals that the number of proclaimed probiotics is growing fast. While the vast majority of probiotic microorganisms are food-related or commensal bacteria that are often regarded as safe, probiotics from other sources are increasingly being reported raising possible regulatory and safety issues. Potential probiotics are selected after in vitro or in vivo assays by evaluating simple traits such as resistance to the acidic conditions of the stomach or bile resistance, or by assessing their impact on complicated host functions such as immune development, metabolic function or gut-brain interaction. While final human clinical trials are considered mandatory for communicating health benefits, rather few strains with positive studies have been able to convince legal authorities with these health claims. Consequently, concern has been raised about the validity of the workflows currently used to characterize probiotics. In this review we will present an overview of the most common assays employed in screening for probiotics, highlighting the potential strengths and limitations of these approaches. Furthermore, we will focus on how the advent of omics technologies has reshaped our understanding of the biology of probiotics, allowing the exploration of novel routes for screening and studying such microorganisms.

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Discovering probiotic microorganisms: in vitro, in vivo, genetic and omics approaches.

Colorectal cancer (CRC) is the third leading cause of cancer deaths worldwide and the fourth most common cancer diagnosed among men and women in the United States. Considering the risk factors of CRC, dietary therapy has become one of the most effective approaches in reducing CRC morbidity and mortality. The use of probiotics is increasing in popularity for both the prevention and treatment of a variety of diseases. As the most common types of microbes used as probiotics, lactic acid bacteria (LAB) are comprised of an ecologically diverse group of microorganisms united by formation of lactic acid as the primary metabolite of sugar metabolism. LAB have been successfully used in managing diarrhea, food allergies, and inflammatory bowel disease. LAB also demonstrated a host of properties in preventing colorectal cancer development by inhibiting initiation or progression through multiple pathways. In this review, we discuss recent insights into cellular and molecular mechanisms of LAB in CRC prevention including apoptosis, antioxidant DNA damages, immune responses, and epigenetics. The emerging experimental findings from clinical trials as well as the proposed mechanisms of gut microbiota in carcinogenesis will also be briefly discussed.

Emerging roles of lactic acid bacteria in protection against colorectal cancer.

Probiotic microorganisms such as lactic acid bacteria (LAB) exert a number of strain-specific health-promoting activities attributed to their immunomodulatory, anti-inflammatory and anti-carcinogenic properties. Despite recent attention, our understanding of the biological processes involved in the beneficial effects of LAB strains is still limited. To this end, the present study investigated the growth-inhibitory effects of Lactobacillus casei ATCC 393 against experimental colon cancer. Administration of live Lactobacillus casei (as well as bacterial components thereof) on murine (CT26) and human (HT29) colon carcinoma cell lines raised a significant concentration- and time-dependent anti-proliferative effect, determined by cell viability assays. Specifically, a dramatic decrease in viability of colon cancer cells co-incubated with 109 CFU/mL L. casei for 24 hours was detected (78% for HT29 and 52% for CT26 cells). In addition, live L. casei induced apoptotic cell death in both cell lines as revealed by annexin V and propidium iodide staining. The significance of the in vitro anti-proliferative effects was further confirmed in an experimental tumor model. Oral daily administration of 109 CFU live L. casei for 13 days significantly inhibited in vivo growth of colon carcinoma cells, resulting in approximately 80% reduction in tumor volume of treated mice. Tumor growth inhibition was accompanied by L. casei-driven up-regulation of the TNF-related apoptosis-inducing ligand TRAIL and down-regulation of Survivin. Taken together, these findings provide evidence for beneficial tumor-inhibitory, anti-proliferative and pro-apoptotic effects driven by this probiotic LAB strain.

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Lactobacillus casei Exerts Anti-Proliferative Effects Accompanied by Apoptotic Cell Death and Up-Regulation of TRAIL in Colon Carcinoma Cells.

Colorectal cancer (CRC), the third major cause of mortality among various cancer types in United States, has been increasing in developing countries due to varying diet and dietary habits and occupational hazards. Recent evidences showed that composition of gut microbiota could be associated with the development of CRC and other gut dysbiosis. Modulation of gut microbiota by probiotics and prebiotics, either alone or in combination could positively influence the cross-talk between immune system and microbiota, would be beneficial in preventing inflammation and CRC. In this review, role of probiotics and prebiotics in the prevention of CRC has been discussed. Various epidemiological and experimental studies, specifically gut microbiome research has effectively improved the understanding about the role of probiotics and microbial treatment as anticarcinogenic agents. A few human studies support the beneficial effect of probiotics and prebiotics; hence, comprehensive understanding is urgent to realize the clinical applications of probiotics and prebiotics in CRC prevention.

Probiotics, prebiotics and colorectal cancer prevention

The Mediterranean diet (MD) is considered one of the healthiest dietary models. Many of the characteristic components of the MD have functional features with positive effects on health and wellness. The MD adherence, calculated through various computational scores, can lead to a reduction of the incidence of major diseases (e.g., cancers, metabolic and cardiovascular syndromes, neurodegenerative diseases, type 2 diabetes and allergy). Furthermore, eating habits are the main significant determinants of the microbial multiplicity of the gut, and dietary components influence both microbial populations and their metabolic activities from the early stages of life. For this purpose, we present a study proposal relying on the generation of individual gut microbiota maps from MD-aware children/adolescents. The maps, based on meta-omics approaches, may be considered as new tools, acting as a systems biology-based proof of evidence to evaluate MD effects on gut microbiota homeostasis. Data integration of food metabotypes and gut microbiota “enterotypes” may allow one to interpret MD adherence and its effects on health in a new way, employable for the design of targeted diets and nutraceutical interventions in childcare and clinical management of food-related diseases, whose onset has been significantly shifted early in life.

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Mediterranean diet and health: food effects on gut microbiota and disease control.

Background: Colorectal cancer represents the most common malignancy of the gastrointestinal tract. Owing to differences in dietary habits and lifestyle, this neoplasm is more common in industrialized countries than in developing ones. Evidence from a wide range of sources supports the assumption that the link between diet and colorectal cancer may be due to an imbalance of the intestinal microflora. Discussion: Probiotic bacteria are live microorganisms that, when administered in adequate amounts, confer a healthy benefit on the host, and they have been investigated for their protective anti-tumor effects. In vivo and molecular studies have displayed encouraging findings that support a role of probiotics in colorectal cancer prevention. Summary: Several mechanisms could explain the preventive action of probiotics against colorectal cancer onset. They include: alteration of the intestinal microflora; inactivation of cancerogenic compounds; competition with putrefactive and pathogenic microbiota; improvement of the host’s immune response; anti-proliferative effects via regulation of apoptosis and cell differentiation; fermentation of undigested food; inhibition of tyrosine kinase signaling pathways.

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Potential role of probiotics on colorectal cancer prevention

Biliary tract carcinomas are relatively rare, representing less than 1% of cancers. However, their incidence has increased in Japan and in industrialized countries like the USA. Biliary tract tumors have a poor prognosis and a high mortality rate because they are usually detected late in the course of the disease; therapeutic treatment options are often limited and of minimal utility. Recent studies have shown the importance of serum and molecular markers in the diagnosis and follow up of biliary tract tumors. This review aims to introduce the main features of the most important serum and molecular markers of biliary tree tumors. Some considerable tumor markers are cancer antigen 125, carbohydrate antigen 19-9, carcinoembryonic antigen, chromogranin A, mucin 1, mucin 5, alpha-fetoprotein, claudins and cytokeratins.

Markers of bile duct tumors

Context: Studies on experimental animals have shown liver is a common target of chemical carcinogens; this might suggest that occupational exposure to chemicals is another risk factor for HCC. However, the relationship between occupation and liver cancer has not been extensively studied, with the exception of the known association between vinyl chloride and angiosarcoma of the liver. Evidence Acquisition: A MEDLINE and conventional search of the past 50 years of the medical literature was performed to identify relevant articles on incidence and mechanisms of HCC due to occupational exposure to chemicals. Several important edited books and monographs were also identified and reviewed. Results: While laboratory data clearly indicate that the liver is an important target of chemical carcinogenesis, epidemiological studies provide very limited evidence on occupational risk factors for HCC. Nevertheless, we found some case reports and epidemiological data showing a moderately increased risk of HCC development in people exposed to vinyl chloride, organic solvents, pesticides, polychlorinated biphenyls, and arsenic. Conclusions: Occupational exposure to chemicals may be another risk factor for HCC development, but the interpretation of currently available findings is limited by the small number of studies, questionable accuracy of the diagnosis of liver cancer, and potential confounding or modifying factors such as chronic hepatitis virus infection and alcohol consumption. Further relevant investigations are required for clarifying the actual contribution of occupational exposure to chemicals in HCC development.

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Risk of hepatocellular carcinoma in workers exposed to chemicals.

The residual liver function is a major clinical index in hepatocellular carcinoma (HCC) patients. As the liver plays a crucial role in lipid and lipoprotein metabolism, the significant impairment of the hepatic function occurring during chronic liver diseases, such as HCC, can influence plasma lipoprotein profiles. Although, lipoprotein(a) (Lp(a)) circulating concentrations are mostly determined by genetic factors, in the majority of reports they have shown a correlation with the hepatic status and a significant decrease in HCC and liver cirrhosis patients than among the controls. In such a way, Lp(a) may represent a new additional and useful marker for a more complete assessment and monitoring of the liver function in patients with HCC and liver cirrhosis. Further studies are needed in order to evaluate the clinical significance of Lp(a) in HCC.

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Lipoprotein(a) as a potential marker of residual liver function in hepatocellular carcinoma.

The skeleton is the most common site of tumor metastasis. The detection of metastatic bone disease is critical for primary cancer staging because it will condition the therapeutic decision and the prognosis. For the diagnosis of bone metastases, imaging techniques are usually employed, even if these techniques have some limitations in terms of accuracy and costs. An innovative, cheaper method for the screening of skeletal metastases could be the measurement of bone turnover markers. This article is aimed at providing a literature review on the clinical significance of increased serum levels of bone sialoprotein (BSP) observed in patients suffering from metastatic bone lesions. In addition, we have briefly summarized recent studies reporting the biological and pathological roles of BSP in bone remodeling and bone metastasis. Some studies have demonstrated that serum BSP can be considered as an early marker and a prognostic factor for the development of bone metastases. BSP may help in assessing osteolytic bone disease, in evaluating additional prognostic information and in monitoring treatment modalities.

Mario Uccello

Papers

Potential role of probiotics on colorectal cancer prevention

Markers of bile duct tumors

Risk of hepatocellular carcinoma in workers exposed to chemicals.

Lipoprotein(a) as a potential marker of residual liver function in hepatocellular carcinoma.

Serum bone sialoprotein levels and bone metastases.