Mouse models for unraveling the importance of diet in colon cancer prevention

Diet and genetics are both considered important risk determinants for colorectal cancer, a leading cause of death worldwide. Several genetically engineered mouse models have been created, including the Apc^Min mouse, to aid in the identification of key cancer related processes and to assist with the characterization of environmental factors, including the diet, which influence risk. Current research using these models provides evidence that several bioactive food components can inhibit genetically predisposed colorectal cancer, while others increase risk. Specifically, calorie restriction or increased exposure to n-3 fatty acids, sulforaphane, chafuroside, curcumin and dibenzoylmethane were reported protective. Total fat, calories and all-trans retinoic acid are associated with an increased risk. Unraveling the importance of specific dietary components in these models is complicated by the basal diet used, the quantity of test components provided and interactions among food components. Newer models are increasingly available to evaluate fundamental cellular processes, including DNA mismatch repair, immune function and inflammation as markers for colon cancer risk. Unfortunately, these models have been used infrequently to examine the influence of specific dietary components. The enhanced use of these models can shed mechanistic insights about the involvement of specific bioactive food and components and energy as determinants of colon cancer risk. However, the use of available mouse models to exactly represent processes important to human gastrointestinal cancers will remain a continued scientific challenge.     

Exploring mechanisms of diet-colon cancer associations through candidate molecular interaction networks

Background

Epidemiological studies in the recent years have investigated the relationship between dietary habits and disease risk demonstrating that diet has a direct effect on public health. Especially plant-based diets -fruits, vegetables and herbs- are known as a source of molecules with pharmacological properties for treatment of several malignancies. Unquestionably, for developing specific intervention strategies to reduce cancer risk there is a need for a more extensive and holistic examination of the dietary components for exploring the mechanisms of action and understanding the nutrient-nutrient interactions. Here, we used colon cancer as a proof-of-concept for understanding key regulatory sites of diet on the disease pathway.

Results

We started from a unique vantage point by having a database of 158 plants positively associated to colon cancer reduction and their molecular composition (~3,500 unique compounds). We generated a comprehensive picture of the interaction profile of these edible and non-edible plants with a predefined candidate colon cancer target space consisting of ~1,900 proteins. This knowledge allowed us to study systematically the key components in colon cancer that are targeted synergistically by phytochemicals and identify statistically significant and highly correlated protein networks that could be perturbed by dietary habits.

Conclusion

We propose here a framework for interrogating the critical targets in colon cancer processes and identifying plant-based dietary interventions as important modifiers using a systems chemical biology approach. Our methodology for better delineating prevention of colon cancer by nutritional interventions relies heavily on the availability of information about the small molecule constituents of our diet and it can be expanded to any other disease class that previous evidence has linked to lifestyle.     

The Role of Intestinal Microbiota in Development of Irinotecan Toxicity and in Toxicity Reduction through Dietary Fibres in Rats

CPT-11 is a drug used as chemotherapy for colorectal cancer. CPT-11 causes toxic side-effects in patients. CPT-11 toxicity has been attributed to the activity of intestinal microbiota, however, intestinal microbiota may also have protective effects in CP!-11 chemotherapy. This study aimed to elucidate mechanisms through which microbiota and dietary fibres could modify host health. Rats bearing a Ward colon carcinoma were treated with a two-cycle CPT-11/5-fluorouracil therapy recapitulating clinical therapy of colorectal cancer. Animals were fed with a semi-purified diet or a semi-purified diet was supplemented with non-digestible carbohydrates (isomalto-oligosaccharides, resistant starch, fructo-oligosaccharides, or inulin) in 3 independent experiments. Changes in intestinal microbiota, bacteria translocating to mesenteric lymphnodes, cecal GUD activity, and cecal SCFA production, and the intestinal concentration of CPT-11 and its metabolites were analysed. Non-digestible carbohydrates significantly influenced feed intake, body weight and other indicators of animal health. The identification of translocating bacteria and their quantification in cecal microbiota indicated that overgrowth of the intestine by opportunistic pathogens was not a major contributor to CPT-11 toxicity. Remarkably, fecal GUD activity positively correlated to body weight and feed intake but negatively correlated to cecal SN-38 concentrations and IL1-β. The reduction in CPT-11 toxicity by non-digestible carbohydrates did not correlate to stimulation of specific bacterial taxa. However, cecal butyrate concentrations and feed intake were highly correlated. The protective role of intestinal butyrate production was substantiated by a positive correlation of the host expression of MCT1 (monocarboxylate transporter 1) with body weight as well as a positive correlation of the abundance of bacterial butyryl-CoA gene with cecal butyrate concentrations. These correlations support the interpretation that the influence of dietary fibre on CPT-11 toxicity is partially mediated by an increased cecal production of butyrate.     

消化道微生物区系与肥胖关系的研究进展

肥胖以及与肥胖相关的一些疾病威胁着发达国家和发展中国家,这些疾病包括Ⅱ型糖尿病、高血压、心血管疾病、非酒精型脂肪肝。最新研究表明消化道微生物区系(microbiota,指一个特定区域中所有活的微生物群落的统称。)可能与宿主肥胖相关。目前此类研究尚处于起步阶段,作者总结了以往研究结果,对消化道微生物区系的组成和作用、与宿主能量代谢相关的消化道微生物种类和作用、消化道微生物区系影响宿主能量储存的途径作了较为详细的介绍。并探讨了目前研究中存在的问题,总结了本实验室已有研究成果,以及今后可能的研究方向。     

Nutrition Facts in Multiple Sclerosis

The question whether dietary habits and lifestyle have influence on the course of multiple sclerosis (MS) is still a matter of debate, and at present, MS therapy is not associated with any information on diet and lifestyle. Here we show that dietary factors and lifestyle may exacerbate or ameliorate MS symptoms by modulating the inflammatory status of the disease both in relapsing-remitting MS and in primary-progressive MS. This is achieved by controlling both the metabolic and inflammatory pathways in the human cell and the composition of commensal gut microbiota. What increases inflammation are hypercaloric Western-style diets, characterized by high salt, animal fat, red meat, sugar-sweetened drinks, fried food, low fiber, and lack of physical exercise. The persistence of this type of diet upregulates the metabolism of human cells toward biosynthetic pathways including those of proinflammatory molecules and also leads to a dysbiotic gut microbiota, alteration of intestinal immunity, and low-grade systemic inflammation. Conversely, exercise and low-calorie diets based on the assumption of vegetables, fruit, legumes, fish, prebiotics, and probiotics act on nuclear receptors and enzymes that upregulate oxidative metabolism, downregulate the synthesis of proinflammatory molecules, and restore or maintain a healthy symbiotic gut microbiota. Now that we know the molecular mechanisms by which dietary factors and exercise affect the inflammatory status in MS, we can expect that a nutritional intervention with anti-inflammatory food and dietary supplements can alleviate possible side effects of immune-modulatory drugs and the symptoms of chronic fatigue syndrome and thus favor patient wellness.     

Importance of probiotics in the prevention and treatment of colorectal cancer

Colorectal cancer (CRC) remains one of the most common and deadly cancers. Intestinal gut microflora is important to maintain and contributes to several intestinal functions, including the development of the mucosal immune system, absorption of complex macromolecules, synthesis of amino acids/vitamins and the protection against pathogenic microorganisms. It is well known that the gut microbiota changes or dysbiosis may have an essential impact in the initiation and promotion of chronic inflammatory pathways and also have a profound different genetic and epigenetic alterations leading to dysplasia, clonal expansion, and malignant transformation. Probiotic bacteria has antitumor activity with various mechanisms such as nonspecific physiological and immunological mechanisms. This review evaluates the effects of microbiota and probiotics in clinical trials, in vitro and animal model studies that have explored how probiotic against cancer development and also discusses the possible immunomodulatory mechanisms. Several mechanisms alteration of the intestinal microflora; inactivation of cancerogenic compounds; competition with putrefactive and pathogenic microbiota; improvement of the host's immune response; antiproliferative effects via regulation of apoptosis and cell differentiation; fermentation of undigested food; inhibition of tyrosine kinase; reduces the enteropathogenic complications before and after colon cancer surgery and improve diarrhea and it's have been able to create the integrity of gut mucosal and have stimulatory effects on the systemic immune system and prevent the CRC metastasis. Research in clinical trials encouraging findings that support a role of probiotics in CRC prevention and improve the safety and effectiveness of cancer therapy even though additional clinical research is still necessary.     

Nutritional modulation of leptin expression and leptin action in obesity and obesity-associated complications

In obesity, an elevated accumulation and dysregulation of adipose tissue, due to an imbalance between energy intake and energy expenditure, usually coexists with the loss of responsiveness to leptin in central nervous system, and subsequently with hyperleptinemia. Leptin, a peptide hormone mainly produced by white adipose tissue, regulates energy homeostasis by stimulating energy expenditure and inhibiting food intake. Human obesity is characterized by increased plasma leptin levels, which have been related with different obesity-associated complications, such as chronic inflammatory state (risk factor for diabetes, cardiovascular and autoimmune diseases), as well as infertility and different types of cancer. Besides, leptin is also produced by placenta, and high leptin levels during pregnancy may be related with some pathological conditions such as gestational diabetes. This review focuses on the current insights and emerging concepts on potentially valuable nutrients and food components that may modulate leptin metabolism. Notably, several dietary food components, such as phenols, peptides, and vitamins, are able to decrease inflammation and improve leptin sensitivity by up- or down-regulation of leptin signaling molecules. On the other hand, some food components, such as saturated fatty acids may worsen chronic inflammation increasing the risk for pathological complications. Future research into nutritional mechanisms that restore leptin metabolism and signals of energy homeostasis may inspire new treatment options for obesity-related disorders.     

The intestinal microbiota, gastrointestinal environment and colorectal cancer: a putative role for probiotics in prevention of colorectal cancer?

Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the United States, and, even though 5-15% of the total CRC cases can be attributed to individual genetic predisposition, environmental factors could be considered major factors in susceptibility to CRC. Lifestyle factors increasing the risks of CRC include elevated body mass index, obesity, and reduced physical activity. Additionally, a number of dietary elements have been associated with higher or lower incidence of CRC. In this context, it has been suggested that diets high in fruit and low in meat might have a protective effect, reducing the incidence of colorectal adenomas by modulating the composition of the normal nonpathogenic commensal microbiota. In addition, it has been demonstrated that changes in abundance of taxonomic groups have a profound impact on the gastrointestinal physiology, and an increasing number of studies are proposing that the microbiota mediates the generation of dietary factors triggering colon cancer. High-throughput sequencing and molecular taxonomic technologies are rapidly filling the knowledge gaps left by conventional microbiology techniques to obtain a comprehensive catalog of the human intestinal microbiota and their associated metabolic repertoire. The information provided by these studies will be essential to identify agents capable of modulating the massive amount of gut bacteria in safe noninvasive manners to prevent CRC. Probiotics, defined as "live microorganisms which, when administered in adequate amounts, confer a health benefit on the host" (219), are capable of transient modulation of the microbiota, and their beneficial effects include reinforcement of the natural defense mechanisms and protection against gastrointestinal disorders. Probiotics have been successfully used to manage infant diarrhea, food allergies, and inflammatory bowel disease; hence, the purpose of this review was to examine probiotic metabolic activities that may have an effect on the prevention of CRC by scavenging toxic compounds or preventing their generation in situ. Additionally, a brief consideration is given to safety evaluation and production methods in the context of probiotics efficacy.     

Bacteria,phages and pigs: the effects of in-feed antibiotics on the microbiome at different gut locations

Disturbance of the beneficial gut microbial community is a potential collateral effect of antibiotics, which have many uses in animal agriculture (disease treatment or prevention and feed efficiency improvement). Understanding antibiotic effects on bacterial communities at different intestinal locations is essential to realize the full benefits and consequences of in-feed antibiotics. In this study, we defined the lumenal and mucosal bacterial communities from the small intestine (ileum) and large intestine (cecum and colon) plus feces, and characterized the effects of in-feed antibiotics (chlortetracycline, sulfamethazine and penicillin (ASP250)) on these communities. 16S rRNA gene sequence and metagenomic analyses of bacterial membership and functions revealed dramatic differences between small and large intestinal locations, including enrichment of Firmicutes and phage-encoding genes in the ileum. The large intestinal microbiota encoded numerous genes to degrade plant cell wall components, and these genes were lacking in the ileum. The mucosa-associated ileal microbiota harbored greater bacterial diversity than the lumen but similar membership to the mucosa of the large intestine, suggesting that most gut microbes can associate with the mucosa and might serve as an inoculum for the lumen. The collateral effects on the microbiota of antibiotic-fed animals caused divergence from that of control animals, with notable changes being increases in Escherichia coli populations in the ileum, Lachnobacterium spp. in all gut locations, and resistance genes to antibiotics not administered. Characterizing the differential metabolic capacities and response to perturbation at distinct intestinal locations will inform strategies to improve gut health and food safety.     

Intestinal bacteria and ageing

Advancements in science and medicine, as well as improved living standards, have led to a steady increase in life expectancy, and subsequently a rise in the elderly population. The intestinal microbiota is important for maintenance of host health, providing energy, nutrients and protection against invading organisms. Although the colonic microbiota is relatively stable throughout adult life, age-related changes in the gastrointestinal (GI) tract, as well as changes in diet and host immune system reactivity, inevitably affect population composition. Recent studies indicate shifts in the composition of the intestinal microbiota, which may lead to detrimental effects for the elderly host. Increased numbers of facultative anaerobes, in conjunction with a decrease in beneficial organisms such as the anaerobic lactobacilli and bifidobacteria, amongst other anaerobes, have been reported. These changes, along with a general reduction in species diversity in most bacterial groups, and changes to diet and digestive physiology such as intestinal transit time, may result in increased putrefaction in the colon and a greater susceptibility to disease. Therapeutic strategies to counteract these changes have been suggested in ageing people. These include dietary supplements containing prebiotics, probiotics and a combination of both of these, synbiotics. Limited feeding trials show promising results with these supplements, although further longer-term investigations are required to substantiate their use in elderly healthcare fields.     

Human intestinal lumen and mucosa-associated microbiota in patients with colorectal cancer

Recent reports have suggested the involvement of gut microbiota in the progression of colorectal cancer (CRC). We utilized pyrosequencing based analysis of 16S rRNA genes to determine the overall structure of microbiota in patients with colorectal cancer and healthy controls; we investigated microbiota of the intestinal lumen, the cancerous tissue and matched noncancerous normal tissue. Moreover, we investigated the mucosa-adherent microbial composition using rectal swab samples because the structure of the tissue-adherent bacterial community is potentially altered following bowel cleansing. Our findings indicated that the microbial structure of the intestinal lumen and cancerous tissue differed significantly. Phylotypes that enhance energy harvest from diets or perform metabolic exchange with the host were more abundant in the lumen. There were more abundant Firmicutes and less abundant Bacteroidetes and Proteobacteria in lumen. The overall microbial structures of cancerous tissue and noncancerous tissue were similar; however the tumor microbiota exhibited lower diversity. The structures of the intestinal lumen microbiota and mucosa-adherent microbiota were different in CRC patients compared to matched microbiota in healthy individuals. Lactobacillales was enriched in cancerous tissue, whereas Faecalibacterium was reduced. In the mucosa-adherent microbiota, Bifidobacterium, Faecalibacterium, and Blautia were reduced in CRC patients, whereas Fusobacterium, Porphyromonas, Peptostreptococcus, and Mogibacterium were enriched. In the lumen, predominant phylotypes related to metabolic disorders or metabolic exchange with the host, Erysipelotrichaceae, Prevotellaceae, and Coriobacteriaceae were increased in cancer patients. Coupled with previous reports, these results suggest that the intestinal microbiota is associated with CRC risk and that intestinal lumen microflora potentially influence CRC risk via cometabolism or metabolic exchange with the host. However, mucosa-associated microbiota potentially affects CRC risk primarily through direct interaction with the host.     

肠道菌群与肥胖关系的研究进展

西方化的高脂饮食方式造成了越来越多的肥胖人群。高脂饮食在一定程度上可以改变肠道菌群的结构组成和功能,促进宿主对食物营养的吸收,从而增加体重形成肥胖。高脂饮食诱导的肥胖者肠道菌群的改变会导致宿主能量吸收增加,肠道通透性和炎症增加,而有减肥功能的短链脂肪酸合成能力下降。最近研究发现肠道菌群也可以通过影响中枢神经系统,尤其是下丘脑相关基因的表达来控制食欲,从而调控肥胖的形成。本文系统介绍了最近几年高脂饮食诱导肥胖的研究,总结了一些与肥胖形成有密切关系的肠道菌群以及其在肥胖形成中的作用机制,为进一步研究肠道菌群与肥胖之间的调控作用奠定了基础。最后总结了肠道菌群可以作为一个预防和治疗肥胖的有效靶点,可以通过在食物中添加有益菌或者通过菌群移植来治疗肥胖。     

Obesity and microbiota: an example of an intricate relationship

It is widely accepted that metabolic disorders, such as obesity, are closely linked to lifestyle and diet. Recently, the central role played by the intestinal microbiota in human metabolism and in progression of metabolic disorders has become evident. In this context, animal studies and human trials have demonstrated that alterations of the intestinal microbiota towards enhanced energy harvest is a characteristic of the obese phenotype. Many publications, involving both animal studies and clinical trials, have reported on the successful exploitation of probiotics and prebiotics to treat obesity. However, the molecular mechanisms underlying these observed anti-obesity effects of probiotics and prebiotic therapies are still obscure. The aim of this mini-review is to discuss the intricate relationship of various factors, including diet, gut microbiota, and host genetics, that are believed to impact on the development of obesity, and to understand how modulation of the gut microbiota with dietary intervention may alleviate obesity-associated symptoms.     

Dairy propionibacteria as probiotics: recent evidences

Nowdays there is evidence that dairy propionibacteria display probiotic properties, which as yet have been underestimated. The aim of this paper is to review the recent highlights of data representing the probiotic potential of dairy propionibacteria, studied both by general selection criteria (useful for all probiotic potentials), and by more specific and innovative approach. Dairy propionibacteria show a robust nature, that makes them able to overcome technological hurdles, allowing their future use in various fermented probiotic foods. In addition to the general selection criteria for probiotics in areas such as food safety, technological and digestive stress tolerance, many potential health benefits have been recently described for dairy propionibacteria, including, production of several active molecules and adhesion capability, that can mean a steady action in modulation of microbiota and of metabolic activity in the gut; their impact on intestinal inflammation, modulation of the immune system, potential modulation of risk factors for cancer development modulation of intestinal absorption.     

Current understanding of microbiota- and dietary-therapies for treating inflammatory bowel disease

Inflammatory bowel disease (IBD) is a result of chronic inflammation caused, in some part, by dysbiosis of intestinal microbiota, mainly commensal bacteria. Gut dysbiosis can be caused by multiple factors, including abnormal immune responses which might be related to genetic susceptibility, infection, western dietary habits, and administration of antibiotics. Consequently, the disease itself is characterized as having multiple causes, etiologies, and severities. Recent studies have identified >200 IBD risk loci in the host. It has been postulated that gut microbiota interact with these risk loci resulting in dysbiosis, and this subsequently leads to the development of IBD. Typical gut microbiota in IBD patients are characterized with decrease in species richness and many of the commensal, and beneficial, fecal bacteria such as Firmicutes and Bacteroidetes and an increase or bloom of Proteobacteria. However, at this time, cause and effect relationships have not been rigorously established. While treatments of IBD usually includes medications such as corticosteroids, 5-aminosalicylates, antibiotics, immunomodulators, and anti-TNF agents, restoration of gut dysbiosis seems to be a safer and more sustainable approach. Bacteriotherapies (now called microbiota therapies) and dietary interventions are effective way to modulate gut microbiota. In this review, we summarize factors involved in IBD and studies attempted to treat IBD with probiotics. We also discuss the potential use of microbiota therapies as one promising approach in treating IBD. As therapies based on the modulation of gut microbiota becomes more common, future studies should include individual gut microbiota differences to develop personalized therapy for IBD.     

Gut dysbacteriosis and intestinal disease: mechanism and treatment

The gut microbiome functions like an endocrine organ, generating bioactive metabolites, enzymes or small molecules that can impact host physiology. Gut dysbacteriosis is associated with many intestinal diseases including (but not limited to) inflammatory bowel disease, primary sclerosing cholangitis-IBD, irritable bowel syndrome, chronic constipation, osmotic diarrhoea and colorectal cancer. The potential pathogenic mechanism of gut dysbacteriosis associated with intestinal diseases includes the alteration of composition of gut microbiota as well as the gut microbiota–derived signalling molecules. The many correlations between the latter and the susceptibility for intestinal diseases has placed a spotlight on the gut microbiome as a potential novel target for therapeutics. Currently, faecal microbial transplantation, dietary interventions, use of probiotics, prebiotics and drugs are the major therapeutic tools utilized to impact dysbacteriosis and associated intestinal diseases. In this review, we systematically summarized the role of intestinal microbiome in the occurrence and development of intestinal diseases. The potential mechanism of the complex interplay between gut dysbacteriosis and intestinal diseases, and the treatment methods are also highlighted.     

Dietary fibre and colon cancer: epidemiologic and experimental evidence.

Epidemiologic studies have identified two dietary factors, a relatively high intake of fat and a relatively low intake of fibre, that are associated with colon cancer in humans. However, a recent study has shown a low risk of large bowel cancer in a rural Finnish population with a high dietary intake of fat, but also a high intake of fibre. Observations in humans and studies in animals have indicated that dietary fibre may protect against colon carcinogenesis by binding bile acids in the intestinal tract, by a direct effect on the colonic mucosa and by an indirect effect on the metabolism of carcinogens. The strength of protection varies with the type of fibre.     

肠道菌群多糖利用及代谢

宿主与肠道共生菌之间存在一种互利共生的关系。肠道共生菌可以代谢宿主自身不能消化的多糖。进入肠道内的多糖是影响肠道共生菌生理状态和组成的重要因素,这些多糖主要来自饮食和宿主的粘膜分泌物。人类饮食中含有几十种不同的膳食多糖,其中大多数不能被人类基因组中编码的酶降解,并进入大肠,供肠道共生菌利用。肠道共生菌将这些不易消化的多糖转化为短链脂肪酸,作为大肠细胞和其他肠道上皮细胞的营养物质。除此之外,短链脂肪酸对人体健康有着重要的影响。不同的肠道共生菌对进入肠道内的多糖具有不同的偏好性,表明摄入膳食多糖是一种可以直接影响肠道内共生菌物种平衡的策略。因此,研究肠道菌群的多糖代谢机制具有重要的意义。本文从肠道共生菌的组成、利用进入肠道内多糖的机制,以及产生的代谢产物可能对人体健康存在的潜在影响等方面进行了综述,并介绍了代表性的肠道共生菌如拟杆菌和双歧杆菌利用多糖的途径及特征。     

Culture-independent analysis of the gut microbiota in colorectal cancer and polyposis

A role for the intestinal microbiota is routinely cited as a potential aetiological factor in colorectal cancer initiation and progression. As the majority of bacteria in the gut are refractory to culture we investigated this ecosystem in subjects with colorectal cancer and with adenomatous polyposis who are at high risk of developing colorectal cancer, using culture-independent methods. Twenty colorectal cancer and 20 polypectomized volunteers were chosen for this analysis. An exploration of the diversity and temporal stability of the dominant bacteria and several bacterial subgroups was undertaken using 16S rRNA gene denaturing gradient gel electrophoresis and ribosomal intergenic spacer analysis (RISA). Metabonomic analysis of the distal gut microbiota's environment was also undertaken. A significantly reduced temporal stability and increased diversity for the microbiota of subjects with colorectal cancer and polyposis was evident. A significantly increased diversity of the Clostridium leptum and C. coccoides subgroups was also noted for both disease groups. A clear division in the metabonome was observed for the colorectal cancer and polypectomized subjects compared with control volunteers. The intestinal microbiota and their metabolites are significantly altered in both colorectal cancer and polypectomized subjects compared with controls.