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The role of gut microbiota in human metabolism
Vrieze, A.
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Vrieze, A. (2013). The role of gut microbiota in human metabolism
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Download date: 16 Jun 2017
CHAPTER 1
Introduction
Chapter 1
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Introduction
“All disease begins in the gut”
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Hippocrates 460BC
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The human bowel is home to trillions of bacteria, which outnumber the cells of their
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host by a factor of ten to one, and collectively their genes outnumber human genes
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by one hundred-fold. Bacteria colonize the gut soon after birth. Although the initial
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composition of the gut microbiota varies (1), it becomes relatively stable after the age
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of 2 years and onward into adult life (2). Together, the gut microbiota functions as an
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organ, complementing and interacting with human metabolism. Thus, manipulation
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of the gut microbiota can also have detrimental or therapeutic effects on the human
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host. In this respect, although fecal microbiota therapy has only recently gained
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popularity with its success for treating Clostridium difficile infection (3), the use of
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enterically derived material for treatment of disease goes back as far as the 4th
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Century BC. During this period Ge Hong, a traditional Chinese medicine doctor,
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used human fecal suspension given orally to treat food poising and severe diarrhea
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(4). Another Chinese, Li Shizhen, used fermented, fresh, dried or infant feces (for
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esthetic reasons called “yellow soup”) for the treatment of several gastro-intestinal
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related illness, including diarrhea (5). The publication by Eiseman et al. in 1958 was
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the first to report again in the current medical literature on the role of fecal enema’s
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in the treatment of chronic diarrhea (6). However, understanding the composition
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and role of specific intestinal organisms in human disease was initially limited by
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an inability to cultivate most of the microorganisms colonizing the digestive tract.
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The development of next generation culture-independent tools, such as 16S rRNA
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gene sequencing (7), have enabled broader insights into the composition of the gut
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microbiota (8).
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As obesity has become an epidemic worldwide, resulting in an increased prevalence
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of associated disorders such as metabolic syndrome and type 2 diabetes, this thesis
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has focused on studying the relation between gut microbiota composition and human
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obesity as well as glucose metabolism. The causes responsible for the development
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and progression of obesity are complex and involve diverse factors, such as lifestyle
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habits and genetics. The relationship between the human gut microbiota, obesity
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Chapter 1
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and insulin resistance is reviewed in chapters 2 & 3. Antibiotics disturbing the
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gut microbiota may predispose patients to develop recurrent Clostridium difficile
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infections (CDI). There is no evidence-based effective treatment against recurrent
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CDI, but restoring the gut microbiota seems a logical mechanism to repair the host-
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defense against CDI. In chapter 4, treatment with infusion of a donor feces solution
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was compared to vancomycin in patients with recurrent CDI.
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Although convincing in mouse models, it remains difficult to conclude whether
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disturbances in gut microbiota are cause or just consequence of obesity in humans.
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Particularly given the fact that environmental confounding factors, notably dietary
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changes, are known to have a role both in the modulation of the microbiota and
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the development of obesity. Taking a reductionist approach as used in chapter 4,
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restoration of a ‘lean’ gut microbiota may ameliorate obesity and its associated
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diseases. In chapter 5 we examined this hypothesis by infusion of lean donor feces
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in participants with metabolic syndrome. In this double-blind randomised controlled
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trial we investigated the effect of donor feces transplantation on insulin sensitivity.
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Since treatment with oral medication has been described to alter gut microbiota,
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we decided to investigate the effect of short-term oral antibiotics (chapter 6) on gut
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microbiota composition, bile acid metabolism and insulin sensitivity.
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Finally, inflammation of visceral fat plays a key role in the development of insulin
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resistance and subsequent type 2 diabetes, yet the pathophysiological trigger for
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this chronic inflammation remains poorly understood. In chapter 7 we examined
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whether the gut microbiota composition plays a role in the inflammation of visceral
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adipose tissue.
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In chapter 8 we reviewed the role of fecal transplant in clinical practice as well as its
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potential pitfalls.
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Chapter 9 summarises the most important findings of this thesis and advises on
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future directions. Chapter 10 is the Dutch-language summary.
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Introduction
References
1. Penders J, Thijs C, Vink C, et al (2006) Factors influencing the composition of the intestinal
microbiota in early infancy. Pediatrics 118: 511-521
2. Zoetendal EG, Vaughan EE, de Vos WM (2006) A microbial world within us. Mol.Microbiol.
59: 1639-1650
3. Van Nood E, Speelman P, Kuijper EJ, Keller JJ (2009) Struggling with recurrent Clostridium
difficile infections: is donor faeces the solution? Euro.Surveill 14: pii:19316
4. Ge H (Dongjin Dynasty) (2000) Zhou Hou Bei Ji Fang. Tianjijn Science & Technology Press:
Tianjin
5. Li S (Ming Dynasty) (2011) Ben Cao Gang Mu. Huaxia Press: Beijing
6. Eiseman B., Silen W, Bascom G.S, Kauvara AJ (1958) Fecal enema as an adjunct in the
treatment of pseudomembranous enterocolitis. Surgery 44: 854-859
7. Shendure J, Ji H (2008) Next-generation DNA sequencing. Nat.Biotechnol. 26: 1135-1145
8. Turnbaugh PJ, Hamady M, Yatsunenko T, et al (2009) A core gut microbiome in obese and
lean twins. Nature 457: 480-484
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