Gut Microbiota in relation to Colorectal Cancer: Difference between revisions

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NOD male mice’s protection to autoimmune disease relative to female mice against diabetes was lost after living in germ-free environment. Also the sex hormone decreased. This suggest a relationship between the sex hormone and the gut microbiota. Antibiotics have found to decrease the stability and diversity of the gut microbiota.Knowing the function of the microbiota in disease may leads to new treatment and therapies for diseases.  
NOD male mice’s protection to autoimmune disease relative to female mice against diabetes was lost after living in germ-free environment. Also the sex hormone decreased. This suggest a relationship between the sex hormone and the gut microbiota. Antibiotics have found to decrease the stability and diversity of the gut microbiota.Knowing the function of the microbiota in disease may leads to new treatment and therapies for diseases.  
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=Colorectal Cancer=
=Colorectal Cancer=
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<br>
<br>
==Overview==
==Overview==
[[Image:Colorectal treat 1.png|thumb|300px|right|Electron micrograph of the Ebola Zaire virus. This was one of the first micrographs taken of the virus, in 1976. By Dr. Frederick Murphy, now at U.C. Davis, then at the [http://wwwnc.cdc.gov/eid/article/21/11/pdfs/et-2111.pdf CDC].]]


Colorectal carcinoma is one of the most common malignant tumor and most common causes of cancer-related death in the world. According to the report of WHO, colorectal cancer is the third common malignant tumor in men and second in women. Approximately 6% of the population will develop colorectal cancer during their lifetime.  
Colorectal carcinoma is one of the most common malignant tumor and most common causes of cancer-related death in the world. According to the report of WHO, colorectal cancer is the third common malignant tumor in men and second in women. Approximately 6% of the population will develop colorectal cancer during their lifetime.  
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==Treatment==
==Treatment==
[[Image:Figure 1 for gut microbe.png‎|thumb|300px|right|Electron micrograph of the Ebola Zaire virus. This was one of the first micrographs taken of the virus, in 1976. By Dr. Frederick Murphy, now at U.C. Davis, then at the [http://wwwnc.cdc.gov/eid/article/21/11/pdfs/et-2111.pdf CDC].]]


For patients with metastatic colorectal cancer, the long-term prognosis is very poor with no active treatment. So that, the operation is very important for colorectal patients. The surgery could only be done in the relatively early stage of patients (stage I-III). We have to diagnose the patients as early as possible. Screen system thus is an effective process for early diagnosis. In developed country, the process is supported by the government. But it is not easy to apply it in the developing countries.
For patients with metastatic colorectal cancer, the long-term prognosis is very poor with no active treatment. So that, the operation is very important for colorectal patients. The surgery could only be done in the relatively early stage of patients (stage I-III). We have to diagnose the patients as early as possible. Screen system thus is an effective process for early diagnosis. In developed country, the process is supported by the government. But it is not easy to apply it in the developing countries.
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==Basic==
==Basic==
   
   
[[Image:Figure 1 for gut microbe.png‎|thumb|300px|right|Electron micrograph of the Ebola Zaire virus. This was one of the first micrographs taken of the virus, in 1976. By Dr. Frederick Murphy, now at U.C. Davis, then at the [http://wwwnc.cdc.gov/eid/article/21/11/pdfs/et-2111.pdf CDC].]]
Human microbiota is great in size in both quantitative mass and qualitative diversity. Human contains a huge number of bacteria that are metabolical. The location of the bacteria is very stable however they vary greatly in numbers. In bacterial community anaerobe are more abundant than aerobes. A majority of microbes can be put into 2 categories: bacteroidetes and firmicutes. Recently, eukaryotic fungal species have been identifies as a member of the human microbiota. Microbial composition start to develop since birth and varies in different individual. Altered configuration of microbita has been associated with a number of disorders such as obesity and cancer. It was believed to be more a consequence of the disorder rather than causation. However, the correlation between the change of microbiotal composition and diseases is under investigation.
Human microbiota is great in size in both quantitative mass and qualitative diversity. Human contains a huge number of bacteria that are metabolical. The location of the bacteria is very stable however they vary greatly in numbers. In bacterial community anaerobe are more abundant than aerobes. A majority of microbes can be put into 2 categories: bacteroidetes and firmicutes. Recently, eukaryotic fungal species have been identifies as a member of the human microbiota. Microbial composition start to develop since birth and varies in different individual. Altered configuration of microbita has been associated with a number of disorders such as obesity and cancer. It was believed to be more a consequence of the disorder rather than causation. However, the correlation between the change of microbiotal composition and diseases is under investigation.
First defense of the GI track is a continuous tube that begins at the mouth and end at the anus. The small and the large intestines are held in place by the mesentery. The intestines contain a barrier of mucous and epithelial cells that prevent the translocation of the bacteria in the lumen to other site in the body.
First defense of the GI track is a continuous tube that begins at the mouth and end at the anus. The small and the large intestines are held in place by the mesentery. The intestines contain a barrier of mucous and epithelial cells that prevent the translocation of the bacteria in the lumen to other site in the body.
Line 42: Line 54:


==Metabolic role==
==Metabolic role==
[[Image:Figure 1 for gut microbe.png‎|thumb|300px|right|Electron micrograph of the Ebola Zaire virus. This was one of the first micrographs taken of the virus, in 1976. By Dr. Frederick Murphy, now at U.C. Davis, then at the [http://wwwnc.cdc.gov/eid/article/21/11/pdfs/et-2111.pdf CDC].]]


microbes have great metabolic capacities such as vitamin synthesis, bile salt metabolism and xenobiotic degradation. Researchers use metabolonic approach to identify different gut microbiotal population and their consequence metabolic process. Research on germ free mice showed less body fat tissue than regular mice suggest the role of microbiota in energy homeostasis. Observation of reduction in bacteroidetes and increase in firmicates in obese human suggested that the microbiota of an obesed person extract more energy from the diet. Microbital population changes has also been linked to other metabolic conditions such as non-insulin-dependent diabetes, non-alcoholic hepatosteatosis, and atherosclerosis.   
microbes have great metabolic capacities such as vitamin synthesis, bile salt metabolism and xenobiotic degradation. Researchers use metabolonic approach to identify different gut microbiotal population and their consequence metabolic process. Research on germ free mice showed less body fat tissue than regular mice suggest the role of microbiota in energy homeostasis. Observation of reduction in bacteroidetes and increase in firmicates in obese human suggested that the microbiota of an obesed person extract more energy from the diet. Microbital population changes has also been linked to other metabolic conditions such as non-insulin-dependent diabetes, non-alcoholic hepatosteatosis, and atherosclerosis.   
Line 56: Line 70:


==Regulation of adaptive immunity==
==Regulation of adaptive immunity==
[[Image:Figure 1 for gut microbe.png‎|thumb|300px|right|Electron micrograph of the Ebola Zaire virus. This was one of the first micrographs taken of the virus, in 1976. By Dr. Frederick Murphy, now at U.C. Davis, then at the [http://wwwnc.cdc.gov/eid/article/21/11/pdfs/et-2111.pdf CDC].]]


adaptive immunity is referred to an immune response specific to antigens. Thisthe immune response in more complex and more specific than the innate reponse. Factors of the level of the adaptive immune response include the ecological fitness antigenic degeneration and pathogeniticity. The gut microbiota plays an impotant role in the mucosal adaptive immune system. The major components of the system is mainly found in the small intestines and are strongly influenced by microbita.  
adaptive immunity is referred to an immune response specific to antigens. Thisthe immune response in more complex and more specific than the innate reponse. Factors of the level of the adaptive immune response include the ecological fitness antigenic degeneration and pathogeniticity. The gut microbiota plays an impotant role in the mucosal adaptive immune system. The major components of the system is mainly found in the small intestines and are strongly influenced by microbita.  
Line 67: Line 83:
<br>
<br>
==Intestinal Inflammation Targets Cancer-Inducing Activity of the Microbiota==
==Intestinal Inflammation Targets Cancer-Inducing Activity of the Microbiota==
[[Image:Figure 1 for gut microbe.png‎|thumb|300px|right|Electron micrograph of the Ebola Zaire virus. This was one of the first micrographs taken of the virus, in 1976. By Dr. Frederick Murphy, now at U.C. Davis, then at the [http://wwwnc.cdc.gov/eid/article/21/11/pdfs/et-2111.pdf CDC].]]


Inflammation promotes carcinogenesis by modifying the host physiology and the microbiota. Arthur et al. introduced the two-hit model of inflammation action where inflammation creates microbiota consisting of abundant bacteria populations that synthesize genotoxins. One genotoxin called pks, synthesized by E. coli, leads to DNA damage and tumorigenesis in mice lacking the gene for IL10 (an anti-inflammatory cytokine) and treated with AOM (colon-specific carcinogen). Their experiments showed that pks by itself has the ability to cause DNA damage, and the E.coli abundance in mice IL10-/- mice increases pks production and causes further damage to DNA. The presence of both pks and AOM leads to tumorigenesis. In the second part of the model, inflammation enhances the ability of genotoxin-producing bacteria to attach to the colonal mucosa by disrupting the natural protective process that exists in WT mice.
Inflammation promotes carcinogenesis by modifying the host physiology and the microbiota. Arthur et al. introduced the two-hit model of inflammation action where inflammation creates microbiota consisting of abundant bacteria populations that synthesize genotoxins. One genotoxin called pks, synthesized by E. coli, leads to DNA damage and tumorigenesis in mice lacking the gene for IL10 (an anti-inflammatory cytokine) and treated with AOM (colon-specific carcinogen). Their experiments showed that pks by itself has the ability to cause DNA damage, and the E.coli abundance in mice IL10-/- mice increases pks production and causes further damage to DNA. The presence of both pks and AOM leads to tumorigenesis. In the second part of the model, inflammation enhances the ability of genotoxin-producing bacteria to attach to the colonal mucosa by disrupting the natural protective process that exists in WT mice.
Line 79: Line 97:


==Inflammation, microbita and CRC==
==Inflammation, microbita and CRC==
[[Image:Figure 1 for gut microbe.png‎|thumb|300px|right|Electron micrograph of the Ebola Zaire virus. This was one of the first micrographs taken of the virus, in 1976. By Dr. Frederick Murphy, now at U.C. Davis, then at the [http://wwwnc.cdc.gov/eid/article/21/11/pdfs/et-2111.pdf CDC].]]


==Microbiota disbiosis and CRC==
==Microbiota disbiosis and CRC==
[[Image:Figure 1 for gut microbe.png‎|thumb|300px|right|Electron micrograph of the Ebola Zaire virus. This was one of the first micrographs taken of the virus, in 1976. By Dr. Frederick Murphy, now at U.C. Davis, then at the [http://wwwnc.cdc.gov/eid/article/21/11/pdfs/et-2111.pdf CDC].]]


In study by Gao et al, comparison between healthy controls’ and cancer patients’ colon microbiota using the 16S RNA V3 sequence showed siginificant differences. A significant over presentation of Firmicutes and Fusobacteria and relative under representation of Proteobacteria were observed in cancerous tissues. Firmicutes is associate with energy resorption indicate metabolic change in gut mocrobiota in CRC patient. Fusobacteria is thought to be associated with inflammatory bowel diseases, including both ulcerative colitis and Crohn’s disease which are known factor of colorectal cancer.
In study by Gao et al, comparison between healthy controls’ and cancer patients’ colon microbiota using the 16S RNA V3 sequence showed siginificant differences. A significant over presentation of Firmicutes and Fusobacteria and relative under representation of Proteobacteria were observed in cancerous tissues. Firmicutes is associate with energy resorption indicate metabolic change in gut mocrobiota in CRC patient. Fusobacteria is thought to be associated with inflammatory bowel diseases, including both ulcerative colitis and Crohn’s disease which are known factor of colorectal cancer.


==Diet, micorbiota and CRC==
==Diet, micorbiota and CRC==
[[Image:Figure 1 for gut microbe.png‎|thumb|300px|right|Electron micrograph of the Ebola Zaire virus. This was one of the first micrographs taken of the virus, in 1976. By Dr. Frederick Murphy, now at U.C. Davis, then at the [http://wwwnc.cdc.gov/eid/article/21/11/pdfs/et-2111.pdf CDC].]]


Influence on and of gut microbiota is considered to be the primary mechanism that connect the non-genetic factors together in mediating gene expression. This research studied dietary factor on composition of gut microbiota thus influence human health and disease, particularly cancer. The molecular interaction of gut microbiota is greatly influenced by diet. The production of butyrate, folate, propionate and biotin from digestion lead to epigenetic modification such as changes in DNA methylation and histone acetylation or more indirectly inhibit certain enzymes.  
Influence on and of gut microbiota is considered to be the primary mechanism that connect the non-genetic factors together in mediating gene expression. This research studied dietary factor on composition of gut microbiota thus influence human health and disease, particularly cancer. The molecular interaction of gut microbiota is greatly influenced by diet. The production of butyrate, folate, propionate and biotin from digestion lead to epigenetic modification such as changes in DNA methylation and histone acetylation or more indirectly inhibit certain enzymes.  
Line 91: Line 115:


=Conclusion=
=Conclusion=
[[Image:Figure 1 for gut microbe.png‎|thumb|300px|right|Electron micrograph of the Ebola Zaire virus. This was one of the first micrographs taken of the virus, in 1976. By Dr. Frederick Murphy, now at U.C. Davis, then at the [http://wwwnc.cdc.gov/eid/article/21/11/pdfs/et-2111.pdf CDC].]]
<br>Now we have fully understand the relationship between gut microbiota and the host is essential to the hosts’ health. And the manipulation of the gut microbiota might help treat some disease therapeutically. Understanding the optimal gut microbiota might help prevent colorectal cancer and many other diseases. Further research is being conducted on this topic.<br>
<br>Now we have fully understand the relationship between gut microbiota and the host is essential to the hosts’ health. And the manipulation of the gut microbiota might help treat some disease therapeutically. Understanding the optimal gut microbiota might help prevent colorectal cancer and many other diseases. Further research is being conducted on this topic.<br>



Revision as of 23:28, 18 November 2015

This is a curated page. Report corrections to Microbewiki.

Introduction


By [Yingqi Li]

Electron micrograph of the Ebola Zaire virus. This was one of the first micrographs taken of the virus, in 1976. By Dr. Frederick Murphy, now at U.C. Davis, then at the CDC.



Scientists believe the bodies’ biological functions are carried out by not only human genes but also the genes of the microorganisms in our bodies. The bacteria and viruses we carry serves as a buffer and interpreter of our environment. Gut microbes play an important role on immunological, metabolic, and neurological diseases. However, the mechanisms remain unknown. The gut bacteria supply nutrients, help with digestion, and fight against foreign opportunistic pathogens. It is hard to distinguish the good bacteria from the bad ones since normal gut bacteria can also trigger diseases. The over representation of one kind can leads to imbalance which induce inflammation and trigger disease in the body. The immune cells circulate throughout the body and the gut microbiota environment determines their behavior. The gut microbiota is also believed to relate to neuropsychiatric disorders as they have similar molecular structure with neuropeptides. NOD male mice’s protection to autoimmune disease relative to female mice against diabetes was lost after living in germ-free environment. Also the sex hormone decreased. This suggest a relationship between the sex hormone and the gut microbiota. Antibiotics have found to decrease the stability and diversity of the gut microbiota.Knowing the function of the microbiota in disease may leads to new treatment and therapies for diseases.




Colorectal Cancer


Overview

Electron micrograph of the Ebola Zaire virus. This was one of the first micrographs taken of the virus, in 1976. By Dr. Frederick Murphy, now at U.C. Davis, then at the CDC.

Colorectal carcinoma is one of the most common malignant tumor and most common causes of cancer-related death in the world. According to the report of WHO, colorectal cancer is the third common malignant tumor in men and second in women. Approximately 6% of the population will develop colorectal cancer during their lifetime. It was reported that in the majority of patients with colorectal cancer (about 40% to 70%), tumor cells will eventually transfer to remote organ, most of liver metastasis and then lung as second during the natural course of the disease. Liver metastases occupy 25% of patients at the time of diagnosis. About 50% of patients will develop metastasis even after operation, especially in late stage of patients. Dietary and environmental factor play a leading role in colorectal cancer. Especially in western countries where the diet is high in fat and low in fibers, colorectal cancer are more common. Another important factor is genetic alteration which can be inherited or acquired. Colorectal cancer can be a result of combined effect of multiple genetic mutations. Mechanisms include alteration of colonic flora, altered gastrointestinal tract transitional time and modulation of bile acid recycling could lead to the excess exposure to potential carcinogens within the lumen to the colonic mucosa. Recent observation in mosaic animals showed that mucosa in colon is polyclonal in its composition and each clonal progeny contains cells from a single stem cell. And the daughter cells will not extend beyond the region of confluence at the mucosal surface. Colorectal cancer formation arises from clonal expansion of a single progenitor.

Treatment

Electron micrograph of the Ebola Zaire virus. This was one of the first micrographs taken of the virus, in 1976. By Dr. Frederick Murphy, now at U.C. Davis, then at the CDC.

For patients with metastatic colorectal cancer, the long-term prognosis is very poor with no active treatment. So that, the operation is very important for colorectal patients. The surgery could only be done in the relatively early stage of patients (stage I-III). We have to diagnose the patients as early as possible. Screen system thus is an effective process for early diagnosis. In developed country, the process is supported by the government. But it is not easy to apply it in the developing countries. The average overall survival is only a few months in late stage of patients if not treated. Therefore, it’s rather important to choose the appropriate treatment strategies to improve the survival time. Review of large sample studies and randomized controlled studies have shown that the R0 (without remain of tumor) resection provide the patients the chance of the long-term survival. Even in some metastatic patients (with limited metastasis), the complete resection are recommend to performed. Even though surgical resection remains the mainstay of potentially curative therapy, the role of systemic chemotherapy has been gradually recognized for prolongation of life time in very late stage of colorectal cancer patients. Standard chemotherapy agents include 5-fluorouracil, Oxalipaltin and Irinotican. The regimens for late stage of colorectal cancer comprising 5-fluorouracil (5-FU) plus leucovorin (LV) in combination with irinotecan (FOLFIRI) or oxaliplatin (FOLFOX). It have been reported that the chemotherapy could provide 20-22 monthes of survival time. Moreover, mounting evidence suggests that the additional targeted agents (Bevacizumab and Cetuximab) might be even more effective [8]. In treating colorectal cancer, three most important strategies include surgery, chemotherapy and targeted therapy. The combination of chemotherapeutic agents and targeted agents ensured the survival time nearly 3 years. Even in late stage of patients, chemotherapy and the emergence of molecular targeted drugs can effectively control the tumor and the shrinkage of the tumor make the cancer operable. The improved complete resection will definitely provide the opportunity of survival to the patients. It was a big step for human being in treating colorectal cancer in the past several decades.

Gut Microbiota


Basic

Electron micrograph of the Ebola Zaire virus. This was one of the first micrographs taken of the virus, in 1976. By Dr. Frederick Murphy, now at U.C. Davis, then at the CDC.

Human microbiota is great in size in both quantitative mass and qualitative diversity. Human contains a huge number of bacteria that are metabolical. The location of the bacteria is very stable however they vary greatly in numbers. In bacterial community anaerobe are more abundant than aerobes. A majority of microbes can be put into 2 categories: bacteroidetes and firmicutes. Recently, eukaryotic fungal species have been identifies as a member of the human microbiota. Microbial composition start to develop since birth and varies in different individual. Altered configuration of microbita has been associated with a number of disorders such as obesity and cancer. It was believed to be more a consequence of the disorder rather than causation. However, the correlation between the change of microbiotal composition and diseases is under investigation. First defense of the GI track is a continuous tube that begins at the mouth and end at the anus. The small and the large intestines are held in place by the mesentery. The intestines contain a barrier of mucous and epithelial cells that prevent the translocation of the bacteria in the lumen to other site in the body. The connective tissue below the intestinal epithelia called lamina propria (LP) contains a large number of intenstinal immune cell. A specialized region in small intestine called Peyer’s patches is where naïve immune cells differentiate into various mature immune cells. The physical barrier and the immune cells give response when the pathogen invade though the gut. Physical barriers: mucus layer is the front line of the physical barrier. This layer contains glycoprotein and mucin which creates a very viscous mucus. In the epithelial layer, the tight junction protein complexes adhere the cell to each other create the second barrier. The complexes contains transmembrane, scaffold and adapting proteins. These complexes form a paracellular seal and perform as a selectively permeable barrier.

Metabolic role

Electron micrograph of the Ebola Zaire virus. This was one of the first micrographs taken of the virus, in 1976. By Dr. Frederick Murphy, now at U.C. Davis, then at the CDC.

microbes have great metabolic capacities such as vitamin synthesis, bile salt metabolism and xenobiotic degradation. Researchers use metabolonic approach to identify different gut microbiotal population and their consequence metabolic process. Research on germ free mice showed less body fat tissue than regular mice suggest the role of microbiota in energy homeostasis. Observation of reduction in bacteroidetes and increase in firmicates in obese human suggested that the microbiota of an obesed person extract more energy from the diet. Microbital population changes has also been linked to other metabolic conditions such as non-insulin-dependent diabetes, non-alcoholic hepatosteatosis, and atherosclerosis. Normal microbiota exist in the mostly anaerobic luminal environment the gut microbiota generate energy through fermentation of complex carbohydrates and thus producing organic acid including SCFAs which are important energy source for colonic epithelium. Firmicutes such as clostridium species and bifidobacterium species are more efficient at producing SCFAs compare to other species in gut. They are also found more abundant in in obese mice and human again supporting the correlation between microbital composition change and human phenotype. SCFAs serves not only as energy source but also have immunomodulatory effects such as suppressing inflammatory cytokine secretion in mice. For example, butyrate induce epithelial production of ROS and plays a role in NF-KB suppression. NF-kB is short for nuclear factor kB, a protein complex controls DNA transcription, cytokine production and cell survival. It plays a big role in inflammatory and immunie system. It is involved in cellular response to stimuli such as cytokine, free radical and bacterial antigen. Malfunction of this protein has shown to be linked to cancer and other immune disease. Addition to suppression of NF-kB, luminal instillation of butyrate has shown promising result in human ulcerative colitis and other related inflammatory disorder. Much more research need to be done in the metabolic role of microbiota in order to understand the relationship of composition change and GI disorder thus purposing more therapeutic strategies.

Immunomodulation

germ free animals are used for probiotic researches where these animals have no microorganisms living in or in them. It is known that the germ free mice have abnormal immune cell type and immune cell products. They also have a reduced level of secreted immunoglobulin and an irregular cytokine level. These observations suggested the key role of gut microbiota in the development of immune system. This is not surprising considering that intestinal mucosa has the largest surface area that is in contact with the antigens of the external environment. Also most of the antigens that are presented to the resident immune cells as well as stimulating the pattern recognition receptors like toll like receptor and nod like receptors of the intestinal epithelial cell lie in gut microbiota. The intestinal mucosal is composed of gut-associated lymphoid tissue (GALT), including PP and small intestine lymphoid tissue (SILT) in the small intestine, lymphoid aggregate in the large intestine, and diffusely spread immune cell in the lamina propria of the GIT. The mucosal immune system needs to fulfill the seemingly contradict functions. It need to tolerant the microbiota to prevent overt immune response as well as control the over growth and the translocation of the gut microbiota. Effects on inflammatory signaling: the epithelia can suppress TLR signaling or limit TLR expression to prevent induction of overt inflammation. Members of microbiota including nonpathogenic prokaryotes, intestinal symbiont B thetaiotamicron and symbiotic bacterial in general influence signaling intensity. Nonpathogenic prokaryotes are able to suppress inflammatory signaling pathways mediated by either intact viable organisms or secreted products. B thetaiotamicron influence the inflammatory sigl\naling by inhibiting NF-kB pathway through the regulation of translocation of the P65 unit. Symbiotic bacteria influence inflammatory pathway by manipulating the ubiquitin system. The ubiquitin system is involved in the immune response, development and programmed cell death. The targeted cell is ligated to the ubiquitin during the process of degradation. An example of symbiotic bacteria influence is the blocking of IkB ubiquitination which regulate NF-kB activation. IkB is the inhibitory component of the NF-kB pathway.

Regulation of adaptive immunity

Electron micrograph of the Ebola Zaire virus. This was one of the first micrographs taken of the virus, in 1976. By Dr. Frederick Murphy, now at U.C. Davis, then at the CDC.

adaptive immunity is referred to an immune response specific to antigens. Thisthe immune response in more complex and more specific than the innate reponse. Factors of the level of the adaptive immune response include the ecological fitness antigenic degeneration and pathogeniticity. The gut microbiota plays an impotant role in the mucosal adaptive immune system. The major components of the system is mainly found in the small intestines and are strongly influenced by microbita. The collective gut-associate lymphoids tissue (GALT) structured as Peyer’s patch is the largest immune organ in the human body. The Peyer’s patch is mucosal lymph nodes covered with M cells, a cell type that engulf specific antigens from the gut lumen. As the normal mocrobiota is constantly sampled by the M cells, the mucosal immune system developed tolerance to these gut residents. Other than the M cells, the dendritic cells and the regulatory CD4+ T-cell population (Treg) are also involved in this process. Treg is also known as suppressor T-cells that helps maintain tolerance to self-antigens. Treg works through the elaboration of cytokine that suppress effector lymphocytes, including interleukin (IL)-10, transforming growth factor B etc. This distinctive characteristic of the adaptive immune system regulates the response towards antigens which abrogates autoimmune diseases. And importantly, these processes are restrictied to GALT and vicinal mesenteric lymph nodes. In study of germ free animals, the introduction of a representation member of the normal microbiota bateroids fragilis induced the remediation of the undeveloped GALT, reduced CD4 T-cell population and the unbalanced Th cell subsets which indicate the importance of gut microbita in development of the mucosal adaptive immune system. As oppose to the cell-mediated immunity, mucosal adaptive immune response also undergoes another mechanism, the humoral immunity, through secretory immunoglobulin A (IgA). Secretion of IgA is also restricted to the confines of the mucosal GALT, again illustrate the importance of gut microbita in immune system.

Relationship between Gut Microbiota and Colorectal Cancer


Intestinal Inflammation Targets Cancer-Inducing Activity of the Microbiota

Electron micrograph of the Ebola Zaire virus. This was one of the first micrographs taken of the virus, in 1976. By Dr. Frederick Murphy, now at U.C. Davis, then at the CDC.

Inflammation promotes carcinogenesis by modifying the host physiology and the microbiota. Arthur et al. introduced the two-hit model of inflammation action where inflammation creates microbiota consisting of abundant bacteria populations that synthesize genotoxins. One genotoxin called pks, synthesized by E. coli, leads to DNA damage and tumorigenesis in mice lacking the gene for IL10 (an anti-inflammatory cytokine) and treated with AOM (colon-specific carcinogen). Their experiments showed that pks by itself has the ability to cause DNA damage, and the E.coli abundance in mice IL10-/- mice increases pks production and causes further damage to DNA. The presence of both pks and AOM leads to tumorigenesis. In the second part of the model, inflammation enhances the ability of genotoxin-producing bacteria to attach to the colonal mucosa by disrupting the natural protective process that exists in WT mice. Microbial influence on colorectal cancer:

DNA damaged has shown to contribute to cancer development. In 1960s, exposure to methylazoximethanol of the germ free mice showed development of intestinal tumor. This study demonstrated the enzyme activity of B-glucosidase on formation of methylazoximethanol. Azoxymethane (AOM), known as a colon carcinogen, was first hydrolyzed to methylazoximethanol in the liver and later converted in to methyl carbon ion by B-glucosidase. Lactobacillales such as L. Casei and L. Acidophilus has shown to have anti-carcinogenic effect by suppressing the microbial enzyme activities. In intestinal hemostasis, a proposed mechanism of the protective role of SCFA is that SCFA, especially butyrate induce apoptosis in colorectal cancer through inhibition of histone deacetylase and activation of mitochondrial apoptosis. Study showed that Helicobacter hepaticus and Bacteroides fragilis are wide spread intestinal bacteria that induce the development of colon tumorigenesis. Mucosa-associated microbiota:

Chen et al’s research suggested that the risk of colorectal cancer is influenced by the metabolic exchange. Through the analysis of 16S rRNA genes, they determined the overall structure of microbiota of the CRC patients. Results showed abundance of Firmicutes and less abundance of Bacteroide and Protebacteria in the lumen. Although the overall structure showed little differences between the cancerous tissue and non-cancerous tissue, lower diversity of the cancerous tissue was observed. In comparison to the healthy controls, reduced Bifidobacterium, Faecalibacterium and Blautia in the mucosa-adherent microbiota of CRC patients were observed whereas Fusobacterium, Porphyomonas, Peptostreptococcus and Mogibacterium were enriched.

Inflammation, microbita and CRC

Electron micrograph of the Ebola Zaire virus. This was one of the first micrographs taken of the virus, in 1976. By Dr. Frederick Murphy, now at U.C. Davis, then at the CDC.

Microbiota disbiosis and CRC

Electron micrograph of the Ebola Zaire virus. This was one of the first micrographs taken of the virus, in 1976. By Dr. Frederick Murphy, now at U.C. Davis, then at the CDC.

In study by Gao et al, comparison between healthy controls’ and cancer patients’ colon microbiota using the 16S RNA V3 sequence showed siginificant differences. A significant over presentation of Firmicutes and Fusobacteria and relative under representation of Proteobacteria were observed in cancerous tissues. Firmicutes is associate with energy resorption indicate metabolic change in gut mocrobiota in CRC patient. Fusobacteria is thought to be associated with inflammatory bowel diseases, including both ulcerative colitis and Crohn’s disease which are known factor of colorectal cancer.

Diet, micorbiota and CRC

Electron micrograph of the Ebola Zaire virus. This was one of the first micrographs taken of the virus, in 1976. By Dr. Frederick Murphy, now at U.C. Davis, then at the CDC.

Influence on and of gut microbiota is considered to be the primary mechanism that connect the non-genetic factors together in mediating gene expression. This research studied dietary factor on composition of gut microbiota thus influence human health and disease, particularly cancer. The molecular interaction of gut microbiota is greatly influenced by diet. The production of butyrate, folate, propionate and biotin from digestion lead to epigenetic modification such as changes in DNA methylation and histone acetylation or more indirectly inhibit certain enzymes.


Conclusion

Electron micrograph of the Ebola Zaire virus. This was one of the first micrographs taken of the virus, in 1976. By Dr. Frederick Murphy, now at U.C. Davis, then at the CDC.


Now we have fully understand the relationship between gut microbiota and the host is essential to the hosts’ health. And the manipulation of the gut microbiota might help treat some disease therapeutically. Understanding the optimal gut microbiota might help prevent colorectal cancer and many other diseases. Further research is being conducted on this topic.

References

[1]



Authored for BIOL 291.00 Health Service and Biomedical Analysis, taught by Joan Slonczewski, 2016, Kenyon College.