Colorectal Neoplasia and the Colorectal Microbiome: Dysplasia, Probiotics, and Fusobacteria

By Martin H. Floch

Colorectal Neoplasia and the Microbiome: Dysplasia, Probiotics, and Fusobacteria provides foundational knowledge on the gut microbiome and evidence for an association with colorectal neoplasia. It covers the role of microbiota in causing adenomatous polyps and colorectal cancer as well as the modulatory effect of diet and probiotics. Chapters explain a foundational history of microbiology in the colon, the epidemiology of colon polyps and cancer, dysbiosis, the role of immunology and bacteria, and the diet. The book combines medical and scientific aspects to show mechanistic aspects between microbiota and hosts, clearly presenting the association between microbiota, colonic lesions and possible causal links.

The book is essential reading for everyone working with human microbiota including basic scientists, physiologists of the intestine, experts in intestinal microbiota, gastroenterologists, oncologists and surgeon.

• Provides foundational background on the complete history of microbiology in the colon
• Offers thorough coverage of the connection between fusobacterium nucleatum, diet and bacteria on colon health
• Presents the connection between immunology and bacteria in the colon

• Language: English
• Publisher: Academic Press
• Release date: Aug 15, 2020
• ISBN: 9780128225615

Book preview

States

Preface

Martin H. Floch

The role of bacteria in colon cancer has been endlessly questioned by scientists. The colon is full of bacteria, and colon neoplasia is the third most common cancer in the world. Therefore why not look for a connection?

In this past century, there has been much literature on this subject but never has any significant clinical conclusions come forth. Only more questions. We published our experience on this subject four decades ago, and now we are drawing together a group of authorities to bring the subject up-to-date in this book. As a major stimulus to do this is the publication by Liu plus 34 coauthors in the most popular Gastroenterology journal on the effect of the diet and Fusobacteria organisms in colon carcinoma [1].

Diet is still believed to be the major risk factor for colorectal neoplasia. There may be those that will want to eat the diet suggested by Liu. In this book, Comelli and Jenkins carefully review this type of diet and the risk factor of a low-fiber diet and how to use high-fiber foods.

Also in this book, recent bacteriology of the intestine is reviewed followed by the epidemiological factors known in colorectal cancer by Pitchumoni. Then the history of the literature on bacteria is discussed: streptococci by Galiano et al., Bacteroides by Purcell, and the microbiology of Fusobacterium nucleatum by Emma Allen-Vercoe et al.. Coleman and Haller discuss physiologic effects of Fusobacteria, and then Housseu reviews the entire role of the immunology in colorectal cancer. Walker discusses dysbiosis in the intestine, and Floch and Bonfilio review the medical recommendations for colorectal cancer screening plus the recommendation of adding F. nucleatum culturing of oral and fecal secretions to the colonoscopy procedure—A new epidemiologic approach!!! We hope you will enjoy and use this book. I am grateful to the staff of Elsevier, Candy Peabody, and particularly Stacy Masucci for her guidance in developing this book.

Reference

1. Liu L, Tabung FK, Zhang X, et al. Diets that promote colon inflammation associate with risk of colorectal carcinomas that contain Fusobacterium nucleatum. Clin Gastroenterol Hepatol. 2018;16:1622–1631.

Chapter 1

History of bacteriology in the intestine

Martin Floch,    Section of Gastroenterology and Nutrition, Yale, University School of Medicine, Norwalk Hospital, Norwalk, CT, United States

Abstract

The bacteriology of the intestine has a relatively short history. It started with the observations of smudges by Leuwenhoek in the 19th century and now into the recent magnitude of the vast realm of the microbiota. The microbiota consists of at least as many cells as in the body with hundreds of species. In the initial history, Pasteur identified disease with organisms, but the era of Koch identified details of infection. Koch’s work became the leadership philosophy as evidenced by his work in tuberculosis. This led to the era of realization that anaerobic organisms predominated in the intestine. We now appreciate that anaerobes predominate in humans.

Keywords

Microbiology; anaerobes; Pasteur; Koch; microbiota

The goal of this book is to understand the role of bacteria in the development of colorectal cancer. Therefore we will review the history of the recent knowledge available on the bacterial flora of the human intestine, and the following chapters will review the facts of human colorectal cancer, as well as the related bacteriology known about the disease.

Leeuwenhoek and Koch

The initial description of bacteria must be given to a Dutch clothier Leeuwenhoek who recorded observations of life forms using a makeshift microscope in the 17th century [1]. This was indeed very controversial. The next landmark in the history of the science of bacteriology is attributed to Robert Koch [2]. He was born in Germany on December 11, 1843, and his first papers were published in 1876 in English. When we look at the understanding of bacterial relationship to humans, his teaching and work were pivotal. Louis Pasteur had discovered that bacteria caused putrefaction, but Koch held to the theory that disease was caused by living transmissible entities [2]. After a tour in military service, Koch opened and maintained a clinical practice while visiting many research facilities. He was appointed district medical officer but maintained the clinical practice and began to investigate anthrax that was deadly to many humans and animals at that time.

He developed culture techniques, showed that the anthrax bacteria could develop spores, and that the disease was transmitted by inoculation. He had worked out the life cycle of the anthrax bacillus. This was so impressive to German scientists that Koch became a noted leader, and he took his place in history.

His work on cholera and the list of pathogens discovered by his techniques [2] is impressive and crosses paths as the modern history of intestinal bacteria flora advances. Most literature on intestinal bacteria relates to infectious diseases and, hence, the recent papers relating to the pathogens discovered by Koch’s followers.

Interest in the microbiota was stimulated by the publication of the human microbiome project [3] so that scientists around the world [4–6] began to reach the bacteriologic literature.

Our modern knowledge of the flora began with the work of Dubos and Schaedler who showed that anaerobes, not aerobes, were the predominant organisms in the intestine outnumbering the aerobes by 1000 to 1 per colony-forming units. At that time, others in the field headed by Luckey of Missouri, Feldman of California, Moore and Holdeman of Blacksburg, Virginia and Gorbach, and Golden of Boston began to publish their findings [3–11]. In our laboratories at Yale in New Haven and Norwalk, we developed techniques to identify flora and relate it to clinical situations [12,13]. The understanding of the anaerobic flora then extrapolated.

Anaerobes

Cholera and pathogenic E. coli were known aerobes [1] but anaerobic pathophysiology was less understood. Organisms of the Clostridia were isolated, but those such as Fusobacteria or Akkermansia were not yet understood or frequently identified. The textbook definition of an anaerobe is an organism that requires reduced oxygen for growth. This means that an anaerobe fails to grow on the surface of solid media in 10% CO2 in air. In contrast, facultative organisms can grow in the presence or absence of air and microaerophilic bacteria can grow in 10% CO2 air or under aerobic or anaerobic conditions. As opposed to the strict requirement for survival of anaerobic conditions of several anaerobic species inhabiting our bodily surfaces, anaerobes that commonly cause infections are generally aerotolerant and can survive for up to 72 hours in the presence of an oxygenated atmosphere although they will not grow. [1].

Hundreds of anaerobic organisms have been identified in the intestinal flora. The most common ones are listed in Table 1.1.

Table 1.1

The bacteriologists’ works previously noted revealed that anaerobes were predominant in the normal human intestine and were found in numerous human diseases [1–12]. They were found in disorders with immunoglobulin deficiencies, they were stable in stable patients, and were affected by the amount of fiber-containing foods in the diet [14–17].

So, what does the history of bacteriology teach us about cancer?

In summary, we have gone in a few centuries from where we related the scourge of infectious diseases such as cholera to the great discoveries of Leeuwenhoek and Koch but now are trying to relate the scourge of cancers to bacteria. Is this possible? We published a large textbook [18] on the microbiota pathophysiology of human gastrointestinal disease and learned that the microbiota were clearly related to human immunologic and metabolic processes in a wide variety of human diseases and disorders, including the irritable bowel syndrome and functional gastrointestinal disorders, acute infectious diseases, allergic disease, obesity, inflammatory bowel disease, and many liver diseases including nonalcoholic fatty liver and hepato-encephalopathy [18]. In the past, It had been noted that colorectal cancer was related to bacteria [15,19], but most theories that were advanced were based on the metabolism and breakdown substances of bile acids, but Fusobacteria were only noted in one manuscript [19].

The following chapters discuss and report on the functional relationship of individual bacteria species such as Streptococcus, Bacteroides, and Fusobacteria to colorectal neoplasia.

References

1. Mandell GL, Bennett JE, Dolan R. Principles and practice of infectious diseases 6th ed. Philadelphia, PA: Elsevier; 2005.

2. Blevens SM, Bronze MS. Robert Koch and the ‘golden age’ of bacteriology. Int J Infect Dis. 2010;14:e744–e751.

3. Turnbaugh PJ, Ley RE, Hamady M, et al. The human microbiome project. Nature. 2007;449:804–810.

4. Aries V, Crowther JS, Draser BS, et al. Bacteria and the aetiology of cancer of the large bowel. Gut. 1969;10:334–335.

5. Moore WE, Moore LH. Intestinal floras of populations that have a high risk of colon cancer. Appl Environ Microbiol. 1995;61:3202–3207.

6. Jandhyala SM, Talukdar R, Subramanyam C, et al. Role of the normal gut microbiota. World J Gastroenterol. 2015;21:8787–8803.

7. Moore WE, Holdeman LV. Human fecal flora: the normal flora of 20 Japanese-Hawaiians. Appl Microbiol. 1974;27:961–979.

8. Finegold SM. Intestinal bacteria The role they play in normal physiology, pathologic physiology, and infection. Calif Med. 1969;110:455–459.

9. Floch MH, Gorbach SL, Luckey TD. Intestinal microflora Introduction. Am J Clin Nutr. 1970;23:1425–1426.

10. Clarke JS. Bacteriology of the gut and its clinical implications. West J Med. 1974;121:390–403.

11. Gorbach SL. On the intestinal flora. Gastroenterology. 1969;57:239.

12. Fuchs -M, Dorfman S, Floch MH. The effect of dietary fiber supplementation in man Alteration in fecal physiology and bacterial flora. Am J Clin Nutr. 1976;29:1443–1447.

13. Floch MH, Gershengoren W, Freedman LR. Methods for the quantitative study of the aerobic and anaerobic bacterial flora of man. Yale J Biol Med. 1968;41:50–61.

14. Eastwood MA, Kirkpatrick JR, Mitchell WD, et al. Effects of dietary supplements of wheat bran and cellulose on faeces and bowel function. Br Med J. 1973;4:392–394.

15. Draser BS, Hill MJ. Intestinal bacteria and cancer. Am J Clin Nutr. 1972;25:1399–1404.

16. Finegold SM, Atteberry HR, Sutten VL. Effect of diet on human fecal flora: comparison of Japanese and American diets. Am J Clin Nutr. 1974;27:1456–1469.

17. Floch MH. Editorial: Human gut microecology. West J Med. 1974;121:423–424.

18. Floch MH, Ringel Y, Walker WA. The microbiota in gastrointestinal pathophysiology; implications for human health, prebiotics, probiotics, and dysbiosis Philadelphia, PA: Academic Press (Elsevier); 2017.

19. Vargo D, Moskovitz M, Floch MH. Faecal bacterial flora in cancer of the colon. Gut. 1980;21:701–705.

Chapter 2

Epidemiology of colorectal cancer

C.S. Pitchumoni¹, ², ³ and Arkady Broder¹, ⁴,    ¹1Division of Gastroenterology and Hepatology, Saint Peter’s University Hospital, New Brunswick, NJ, United States,    ²2Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, United States,    ³3New York Medical College, Valhalla, NY, United States,    ⁴4Saint Peter’s University Hospital, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, United States

Abstract

Colorectal cancer (CRC) is the third most commonly occurring cancer in men and the second most commonly occurring cancer in women. Worldwide there were over 1.8 million new cases in 2018. In the United States, CRC is the third deadliest of all cancers. The incidence and mortality rates vary up to 10-fold worldwide, the lowest incidences are in many Afro-Asian countries with low human development index (HDI) and high incidence in economically advanced countries. CRC shows one of the clearest markers of epidemiological and nutritional transition. The incidence of CRC is expected to rise worldwide since the risk of developing CRC increases with age and most countries have an ever-growing aging population. Countries with historically low rates of CRC are now experiencing increased risk along with better HDI, change in diet, decrease in exercise, and increase in obesity. Initial studies show that the increased risk of developing CRC is related to a Westernized lifestyle that broadly encompasses obesity, sedentary behavior, and a high-meat, high-calorie, fat-rich, fiber-deficient diet, high alcohol consumption, and cigarette smoking. This chapter aims to provide a basic knowledge of the epidemiology and pathogenesis of CRC. There is growing evidence that the gut microbiota comprising a large population of microorganisms in the colon plays a major role in the pathogenesis of CRC. There is justifiable optimism that, through further research, we will identify the best ways to modulate the gut microbiota with substantial short- and long-term benefits in reducing the burden of CRC.

Keywords

Colorectal cancer; colonoscopy; adenoma; HNPCC; FAP; Peutz–Jeghers disease; MUTH; juvenile polyposis; vitamin D; calcium; fiber; smoking; red meat; obesity; gut microbiota

Key points

1. Colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the fourth leading cause of cancer-related deaths in the world. About 71% of cases arise in the colon and about 29% in the rectum.

2. The lifetime risk is about 1 in 23 (4.5%) and varies worldwide according to individual risk factors.

3. Incidence and mortality rates vary widely worldwide. The incidence is much lower in many Afro-Asian countries with low human development index (HDI).

4. Rapid increases in incidence and mortality are found in many medium to high HDI countries that share similar lifestyles and diet, particularly in Eastern Europe, Asia, and South America.

5. The incidence and mortality rates have been stabilizing or declining in the United States, a phenomenon attributed to screening colonoscopy in asymptomatic patients.

6. The global burden is expected to increase by 60% and reach more than 2.2 million new cases and 1.1 million cancer deaths by 2030.

7. Increasing age, male gender, and a family history of CRC are the greatest risk factors for the disease.

8. A heterogeneous disease influenced by external factors (carcinogens, dietary deficiencies, and smoking) and hereditary factors that result in genetic changes triggering unregulated epithelial proliferation.

9. The series of genetic changes starting from adenoma to carcinoma takes place in 10 or more years.

10. Most of the inherited syndromes of CRC (familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, Peutz–Jeghers syndrome, juvenile polyposis, and others) are transmitted by an autosomal dominant pathway, except MUTH that is a recessive trait.

11. Screening strategies include structural- and stool-based exams. These included fecal occult blood tests, fecal immunochemical (or immunohistochemical) test, sigmoidoscopy, colonoscopy, capsule colonoscopy, barium enema, and CT-based imaging studies.

12. The sporadic type of CRC is preventable by early screening and polyp detection.

13. Other preventive measures involve dietary and lifestyle changes. These changes include a high-fiber diet, and reduction of the intake of high animal fat, avoidance of smoking, and alcoholism are some common examples.

Introduction

In the United States, colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer death in men and women [1]. According to the American Institute for Cancer Research, CRC is considered one of the clearest markers of epidemiological and nutritional transition [2]. The incidence rates of CRC, often linked to Western lifestyles, are increasing as previous high rates of infection-related cancers decline in countries that are undergoing rapid societal and economic changes [3]. Sporadic CRC is a heterogeneous disease that evolves through a complex, long term (usually greater than 10 years), gradual process wherein the development and transformation of polyps (the usual precursor lesions for CRC) are determined by a combination of inheritance (individual susceptibility) and lifestyle factors [2]. Table 2.1 outlines these two groups of factors. The development of CRC in patients with inflammatory bowel disease (IBD), consisting of Crohn’s and ulcerative colitis, is unique and is believed not to involve an origin from a precancerous polyp [4].

Table 2.1

FAP, Familial adenomatous polyposis; IBD, inflammatory bowel disease; MAP, MUTYH-associated polyposis.

Over 95% of CRCs are adenocarcinomas, associated with a high cure rate when detected and managed early [5]. Colon and rectal cancers (RCs) share several common epidemiological and etiological factors and are hence discussed together here. Although discussed together, we recognize that there are differences based on the blood supply, drainage, and innervation resulting in differences in the invasive growth of the primary tumor. These biologic differences between rectal and colon cancers often result in distinct surgical approaches and medical treatment outcomes. The difference between rectal and colon cancer is perhaps best exemplified in varying local recurrence, survival, and, therefore, management approach between the two cancer types.

Epidemiology

A brief description is provided here based on many epidemiological studies conducted from throughout the world.

Global epidemiology

CRC is the third most common cancer in men (746,000 cases, 10.0% of the total) and the second in women (614,000 cases, 9.2% of the total) worldwide [6]. This incidence contributes to 693,000 deaths [2,7]. There is substantial geographical variation in incidences across the world. The wide variability in the global pattern of incidence is strongly linked to the human development index, interpreted by experts as a reflection of adoption of Western lifestyles [8]. See Figs. 2.1–2.3 for further details.

Figure 2.1 Variations in incidence of colorectal cancer. These variations demonstrate considerable increases in developed nations. Adapted from the World Health Organization.

Figure 2.2 Incidence of colorectal cancer throughout the world: (A) colon and (B) rectum. From GLOBOCAN (IARC) (2012).

Figure 2.3 Adenoma-to-carcinoma sequence.

There are distinct gradients across economic development levels, with the highest incidence being in rich countries, lowest in developing nations, and in-between in countries in transition [9]. This concept is further highlighted by the highest estimated mortality rates (per 100,000 population) reported in central and eastern Europe (20.3 deaths in men and 11.7 in women), and the lowest in Western Africa (3.5 deaths in men and 3.0 in women) [8]. A number of interesting and important features are further highlighted in multiple epidemiological studies. In addition, there is a clear etiological association to lifestyle changes, including dietary changes and physical activity [10].

Overall, the CRC incidence and mortality rates are rising rapidly in many low- and middle-income countries where incidence rates were historically low (Latin America and Asia); stabilizing or decreasing trends tend to be seen in highly developed countries. The International Agency for Research on Cancer (IARC) has estimated that one in five men and one in six women worldwide will develop cancer throughout their lifetime [11]. Further, IARC reported that 1 in 8 men and 1 in 11 women would die from their disease. In the period 1998–2002 the incidence of CRC was reported to range from a very low rate of 4.1 (in some regions of India) to 59.1 in the Czech Republic. Regions with the highest incidence rates were located in Europe, North America, and Oceania. In contrast, the lowest rates were observed from registries in Asia, Africa, and South America. With economic growth and better living conditions and probably associated with Westernized diet dietary, rapid increases in both CRC incidence and mortality are being observed in many countries such as Eastern Europe, Asia, and South America [11,12].

An analysis of CRC incidence in seven high-income countries by Araghi et al. indicates that despite overall declines or stabilizations of incidence in some countries, there have been substantial increases in the incidence of CRC in individuals under the age of 50 [13]. In the most recent 10-year period, significant increases were noted in the incidence of colon cancer in people younger than 50 years in Denmark (by 3.1% per year), New Zealand (2.9% per year), Australia (2.9% per year), and the United Kingdom (1.8% per year). Significant increases in the average annual percentage change in the incidence of RC were also noted in this age group in Canada (by 3.4% per year), Australia (2.6% per year), and the United Kingdom (1.4% per year) [7,14,15]. During the same period in people aged 50–74 years, the average the incidence of colon cancer decreased significantly in Australia (by 1.6% per year), Canada (1.9% per year), and New Zealand (3.4% per year) and of RC in Australia (2.4% per year), Canada (1.2% per year), and the United Kingdom (1.2% per year) [11,16]. Increases in the incidence of CRC in people younger than 50 years were mainly driven by increases in the left-sided tumors of the colon [13]. The increasing incidence of early-onset CRC is of concern and needs further analysis and investigation of possible