Abstract
The scope of Toxicology of the Gastrointestinal Tract, Second Edition, subsequently referred to as “text,” is set forth in the Preface and it is to focus on the adverse effects of drugs and other xenobiotics on the structure and function of the gastrointestinal (GI) tract. In addition, the editor recognizes the critical role that the digestive system plays in responses to toxicities and the normal physiological functions of the entire organism. These non-gastrointestinal (GI) effects cannot be ignored whether or not a toxicity investigation is directed on the GI tract. Considering this latter focus, the book signals a prophetic tone by stating that it wishes to lay the foundation to investigate toxicity beyond the target organ toxicity of the GI tract. To be sure, it is becoming increasingly important to recognize and understand the interaction of the GI tract with other organs, and indeed, the organism as a whole.
Beyond target organ toxicity of the GI tract and organ-to-organ interaction among the GI tract and other organs in the body, the text addresses obvious, and perhaps not-so-obvious, other organ interactions associated with the GI tract. For example, the toxicity of xenobiotics with direct effects on the GI tract may also demonstrate adverse responses in remote organs. Those satellite connections with the GI tract are unfolding daily. Other important issues, addressed as chapters, serve as modular units to be arrayed with the target organ toxicity information to serve the toxicologist as an informed starting point for a complete hazard assessment for the GI tract and its influence on other organs and physiologic systems.
The text is composed of 461 pages that are distributed among 15 chapters and an index. Each of the 15 chapters is authored by one or more contributors, of which there are 17. Each chapter is structured to include a Contents section, usually an outline form of the chapter, so the reader can see and know the content within the chapter.
The first 2 chapters, The Gastrointestinal (GI) Tract as a Barrier and as an Absorptive and Metabolic Organ and Methods for the Analysis of Gastrointestinal Function, collectively contribute to slightly more than 10% of the book, lay the foundation for the structure and function of the GI tract. Chapter 4, Gastrointestinal Tract Development and Its Importance in Toxicology, seems to be out of place because it contributes to the foundational material that a toxicologist would need to go beyond GI tract anatomy and physiology and get to toxicological issues. Chapter 3, Safety Pharmacology of the GI Tract, which is a logical flow from chapters 1, 2, and 4, is the portal for the toxicologist to transition from a general understanding of the GI tract to the toxicologically important issues of health hazards associated with drugs and other xenobiotics. To that aim, the most important mode for drugs and other xenobiotics in humans is addressed in Chapter 5, Gastrointestinal Tract as a Major Route of Pharmaceutical Administration.
Two of the remaining 10 chapters address toxicological topics associated with the GI tracts of canines and minipigs. These 2 chapters constitute a little more than 25% of the book. These 2 chapters are comprehensive and important. There is no similar chapter for rodents which may be important for understanding rodent testing results for some xenobiotics. Chapter 12, Normal and Abnormal Intestinal Absorption by Humans, is a 41-page chapter that will assist a toxicologist in making human health risk assessments by providing interpretive value to GI studies conducted in animals.
The remaining 8 chapters are topic-driven which are relevant to many toxicity and hazard determinations. These topics include absorption of macromolecules, alteration of GI function caused by xenobiotics, classes of compounds that cause GI toxicity, and effects of nanoparticles on the GI tract. Of special note are 2 chapters that address the connection between the gut microbiome and the GI tract. Although the gut microbiome of each test animal species is different, the text serves the toxicologist well for an introduction and a starting point for specialized literature searching and laboratory investigations involving the GI tract and its microbiome partners.
Historically, the GI tract was viewed as an alimentary canal with chambers created by multiple sphincters and dependent upon innervation from the host for its peristaltic movement. That understanding of the GI tract is woefully incomplete today, especially in light of advances that have been made that are centered around the microbiome, specifically the intestinal microbiome. Today we know that the GI tract, in its partnership with the gut microbiome, communicates with and influences the behavior of the central nervous system (CNS) and the immune systems, as well as other remote locations and physiologic systems in the body. As an example, Alessio Fasano, MD (Chair, Pediatric Gastroenterology and Nutrition, MassGeneral Hospital for Children) gave a powerful Plenary Lecture at the 40th Annual Meeting of the American College of Toxicology (ACT) on November 18, 2019, entitled “The Healing Power of Nutrition: How Diet Can Reshape the Gut Microbiome and Influence the Balance between Health and Disease.” 1 In his talk, Dr Fasano discussed the truly complex nature of the GI tract and the GI microbiome nexus with the host’s immune and CNS systems using some material from ACT’s own publication, International Journal of Toxicology. 2 He also revealed the importance of the >100 trillion microorganisms and their influence on the GI tract’s ultimate ability to cope with various clinical states. There is an apparent relationship of the composite GI function with multiple diseases and adverse effects in humans through chronic inflammation connections.
To be sure, drug discovery is at a precipice of a vast unknown course for selecting GI tract drug candidates and even a greater unknown role to which the drugs will affect the composite network of GI tract, gut microbiome, and disease states. Certainly, the dynamic duo of GI tract and gut microbiome is going to be in the sights of drug developers for a wide variety of therapies to cure a seemingly endless list of health maladies that seem to find a relationship with the GI tract. This will mandate the calls for toxicological expertise to assess the direct hazards to the GI tract for new therapeutic agents. It doesn’t stop there. Toxicologists will also be required to assess the adverse impacts directly on the gut microbiome, the gut microbiome’s effects on satellite organs, which, in turn, may not be related to the targeted disease. It seems as if the more we discover and know, the more complex the toxicological issues and the health risk assessments become.
Recently, there has been a spate of reference texts for diseases, especially cancer, focused on the GI tract. However, there are only a limited number of suitable texts on the GI tract to guide the toxicologist through the labyrinth of potential GI tract toxicities. Fortunately, Toxicology of the Gastrointestinal Tract, Second Edition serves as an excellent portal for hazard determination and risk assessment when the GI tract is the toxicity target but that can only happen if the text is on the toxicologist’s bookshelf.