Bugs as Drugs

Therapeutic Microbes for Prevention and Treatment of Disease

Robert A. Britton, Patrice D. Cani, Robert A. Britton, Patrice D. Cani

• Publisher: ASM Press
• Year: 2018
• Print ISBN: 9781555819699
• eBook ISBN: 9781683673026
• Edition: 1
• Topic: Medicine
• Subtopic: Medical Microbiology & Parasitology

Examining the enormous potential of microbiome manipulation to improve health

Associations between the composition of the intestinal microbiome and many human diseases, including inflammatory bowel disease, cardiovascular disease, metabolic disorders, and cancer, have been elegantly described in the past decade. Now, whole-genome sequencing, bioinformatics, and precision gene-editing techniques are being combined with centuries-old therapies, such as fecal microbiota transplantation, to translate current research into new diagnostics and therapeutics to treat complex diseases. Bugs as Drugs provides a much-needed overview of microbes in therapies and will serve as an excellent resource for scientists and clinicians as they carry out research and clinical studies on investigating the roles the microbiota plays in health and disease.

In Bugs as Drugs, editors Robert A. Britton and Patrice D. Cani have assembled a fascinating collection of reviews that chart the history, current efforts, and future prospects of using microorganisms to fight disease and improve health. Sections cover traditional uses of probiotics, next-generation microbial therapeutics, controlling infectious diseases, and indirect strategies for manipulating the host microbiome. Topics presented include:

• How well-established probiotics support and improve host health by improving the composition of the intestinal microbiota of the host and by modulating the host immune response.
• The use of gene editing and recombinant DNA techniques to create tailored probiotics and to characterize next-generation beneficial microbes. For example, engineering that improves the anti-inflammatory profile of probiotics can reduce the number of colonic polyps formed, and lactobacilli can be transformed into targeted delivery systems carrying therapeutic proteins or bioengineered bacteriophage.
• The association of specific microbiota composition with colorectal cancer, liver diseases, osteoporosis, and inflammatory bowel disease. The gut microbiota has been proposed to serve as an organ involved in regulation of inflammation, immune function, and energy homeostasis.
• Fecal microbiota transplantation as a promising treatment for numerous diseases beyond C. difficile infection. Practical considerations for using fecal microbiota transplantation are provided, while it is acknowledged that more high-quality evidence is needed to ascertain the importance of strain specificity in positive treatment outcomes.

Because systems biology approaches and synthetic engineering of microbes are now high-throughput and cost-effective, a much wider range of therapeutic possibilities can be explored and vetted.

If you are looking for online access to the latest clinical microbiology content, please visit www.wiley.com/learn/clinmicronow.

B. NEXT-GENERATION BACTERIOTHERAPY: OPPORTUNITIES IN CHRONIC DISEASES

4 Microbial Interactions and Interventions in Colorectal Cancer

TERENCE VAN RAAY1 and EMMA ALLEN-VERCOE1

INTRODUCTION

Colorectal cancer (CRC), the most common form of gastrointestinal (GI) tract cancer, is globally the third leading cause of cancer and is associated with significant mortality (1). Approximately 90% of CRC cases are sporadic, caused by somatic mutations leading to the progression of invasive carcinomas (2). There are numerous risk factors associated with the development of CRC, and the disease is more common in industrialized countries than it is in the developing world (1). Poor diet (in particular, a diet that is low in fiber and high in fat) appears to be a major influencing factor for disease development and progression, and recently it has been recognized that gut microbes may act as the interface between dietary factors and tumor development (reviewed in reference 3). This chapter will review the pathways that lead to CRC, what is currently known about microbial involvement in these processes, and how these may be manipulated therapeutically.

THE HOST SIDE: PHYSIOLOGY AND DEVELOPMENT IN COLORECTAL CANCER

In order to understand the pathogenesis of CRC and how this is affected by the microbiota, it is important to first understand something of the normal biology of the colon, as well as what is understood about how CRC can arise through mutations and aberrant signaling pathways. The salient points are thus reviewed below, and Fig. 1 is provided as a guide to the physiology and anatomy of the colon to orientate the reader.

FIGURE 1 (A) Schematic of the anatomy of the human colon, indicating right/proximal and left/distal regions and their designations. (B) Depiction of the overlap between development, innervation, vascularization, and tumorigenesis of the human colon. Abbreviations: superscript c, chick; superscript m, mouse; superscript z, zebrafish; PMF, parasympathetic motor fibers; SMF, sympathetic motor fibers; SF, sensory fibers.

COLONIC CRYPT

Makeup of the Colon Epithelium

There are numerous reviews on intestinal crypt stem cells (4–6), and so we mention only the more salient points here. The basic unit of the colon consists of a crypt and the luminal surface. During homeostasis, the colonic crypt contains 14 to 16 multipotent stem cells marked by the transmembrane protein LGR5 (Leu-rich repeat-containing G protein-coupled receptor 5) that are capable of generating all of the differentiated cell types lining the lumen (7, 8). A major difference between the small intestine crypt and the colonic crypt is the absence of Paneth cells in the latter, which intercalate with the LGR5+ cells in the small intestine. The LGR5+ stem cells generate rapidly proliferating transit-amplifying (TA) cells that occupy the approximate top two-thirds of the crypt. These TA cells will differentiate into primarily four differentiated cell types: goblet cells (mucosecreting cells), enteroendocrine cells (hormone-producing cells), absorptive enterocytes, and tuft cells (prostanoid-secreting cells) (4). The majority of these cells are renewed approximately once per week, a rate that provides a sense of the regenerative capacity of the stem cells.

Colonic Crypt Signaling Pathways

There are several signaling pathways that are involved in the proliferation and differentiation of the colonic crypt stem cells (9), but the major players are the Wnt signaling pathway, which maintains the stem cells in the base of the crypt, the Notch-Delta signaling pathway, which aids in specifying progenitors of either the secretory or absorptive fates (10, 11), and the bone morphogenic protein (BMP) signaling pathway, which is involved in differentiation and antagonism of Wnt signaling. For the purposes of this review, the Wnt signaling pathway seems to be the most critical with respect to homeostasis of the intestinal crypt stem cells and its malignant transformation (12). Under normal conditions, the essential signaling pathway involves a Wnt ligand activating the frizzled and LRP5/6 receptors, which in turn activates the scaffolding protein dishevelled, which inhibits the β-catenin destruction complex (Fig. 2A). The main components of this destruction complex consist of the scaffolding proteins adenomatous polyposis coli (APC) and axin and the kinases casein kinase 1 (CK1) and glycogen synthase 3β (GSK3β). In the absence of a Wnt ligand, this destruction complex is charged with seeking out and destroying cytoplasmic β-catenin. Upon its inhibition, β-catenin will accumulate in the nucleus, where it will inte...

Table of contents

• Contents
• Contributors
• About the Editors
• Preface
• A. TRADITIONAL PROBIOTIC APPROACHES
• B. NEXT-GENERATION BACTERIOTHERAPY: OPPORTUNITIES IN CHRONIC DISEASES
• C. CONTROL OF INFECTIOUS DISEASE BY MICROBES
• D. NEXT-GENERATION MICROBIAL THERAPEUTICS: TOOLS AND REGULATION
• E. INDIRECT STRATEGIES TO TARGET MICROBIOME FUNCTION FOR HEALTH