The Mesentery and Inflammation

Description:

The volume summarizes the most recent advances in our understanding of the mesentery and explains the how these are important in inflammation.  It comprises a series of state of the art chapters by leading authorities in each area.  It explains how recent advances in our understanding of the mesenteric organ, have advanced the diagnosis and treatment abdominal and systemic conditions including cancer, inflammatory bowel disease and endocrine conditions such as diabetes, and circulatory disorders such as atherosclerosis.

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Preface

Recent advances demonstrated the mesentery is the organ in and on which all abdominal digestive organs develop and remain connected to throughout life. These also show that the mesentery and contiguous organs collectively form a discrete anatomical domain (the mesenteric domain of the abdomen). Genitourinary organs and the musculoskeletal frame comprise a separate domain called the Non-Mesenteric Domain of the abdomen. This description of abdominal organisation is called the Mesenteric Model of Abdominal Anatomy. It is quickly replacing the conventional description of abdominal anatomy which, despite numerous inaccuracies, prevailed as the standard model of abdominal anatomy for the past 150 years. It is now recognised that the Mesenteric Model is a more accurate foundation on which to base the scientific and clinical exploration of the abdomen. It thus provides a new foundation on which to study fundamental biological responses such as inflammation. In keeping with this, the following book explores inflammation in light of the new, mesenteric-based model of abdominal anatomy.
Mounting evidence points to a role for the mesentery in regulating inflammation. Just how this occurs merits explanation here, as it explains why we selected particular topics to explore the role of the mesentery in inflammation.

Each second a substantial volume of blood passes through the mesenteric domain. This is the sum of blood flow to the liver, spleen, pancreas and the entirety of the intestine. Thus, at any one moment, a major proportion of the total circulating blood volume is passing through the mesenteric domain. Products of organs of the mesenteric domain are rapidly distributed throughout the body, via the circulation.

C Reactive Protein (CRP) is an acute phase reactant that drives key cell and tissue level events in inflammation. It is produced in the liver and mesentery (i.e., it is a product of the mesenteric domain). After leaving the mesenteric domain, CRP is rapidly distributed to sites of inflammation to exert key regulatory functions.
Shortly after its leaving the mesenteric domain, a major proportion of the actual blood volume that left rapidly returns to transit through the mesenteric domain again, completing its circulation. In this manner, products from sites of inflammation are delivered back to the mesentery and liver, where they regulate subsequent CRP production. CRP is only one of the numerous mediators released by the mesentery and mesenteric organs.

Thus, the new understanding of the anatomical organisation of the abdomen logically leads to the identification of the mesentery, and mesenteric domain, as being centrally important in the orchestration and regulation of inflammation.

It follows that events occurring in and on the mesentery (and in the mesenteric domain) become important as these could have systemic and local effects that include the initiation and maintenance of inflammation. Bacterial, viral and fungal translocations are examples of such events. Whilst translocation occurs at a local anatomical level between the intestine and adjoining mesentery, it leads to systemic effects triggered by mediators launched from the mesenteric domain (i.e., CRP). It is thus important that we have a clear understanding of translocation in normality and in disease. In line with this, Devkota and Ha summarise current knowledge of translocation, in their state-of-the-art chapter. From that chapter, it is clear that a remarkable gradient is normally maintained between intestinal and mesenteric nodal microbiome. However, that breaks down to produce specific translocation phenotypes in different diseases. Dunne and Kiernan explore this further demonstrating that such phenotypes provide the basis for new diagnostic tests to differentiate between diseases that have long challenged pathologists. In turn, Devine explores translocation of other pathogen types to mesenteric nodes, and translocation from sites other than the intestine. Devine also describes how the mesenteric interstitium provides an immunological safe house for pathogens (including HIC, and SARSCoV-2) to evade immunological clearance and from which these viruses can re-emerge after periods of apparent latency. Given the physiological and anatomical centrality of the mesentery, this must be addressed if such pathogens are to be definitively cleared from the body.

Within the mesentery, events such as translocation are played out on an histological framework. This structural scaffold includes the mesenteric interstitium, lymph nodes and lymphatic channels. It is thus essential that we understand the nature of these. Theise and colleagues elegantly describe the mesenteric component of the interstitium and in so doing raise intriguing possibilities regarding disease spread and dissemination. Li and colleagues describe the lymphatic component of the mesentery in detail. They explore the molecular events involved in setting up that histological infrastructure, and how derangements in these are associated with in tandem development of mesenteric inflammation and systemic metabolic disorders.

Next there are the cellular players acting on the histological platform provided by the interstitium and lymphatic framework. Many of these are immunologic (i.e., dendritic cells, natural killer cells etc), immuno-metabolic (i.e., adipocytes, preadipocytes) and still others contribute structurally (i.e., fibrocytes, fibroblasts). Siegmund and Weidinger explore the immunological components of the mesentery and the signalling functions subserved by these. Molecular mechanisms underpin mesenteric cellular events. The bridge between cellular and molecular events is explored by Siegmund and Weidinger, and further by Mao and Rieder. The latter use mesenteric-intestinal interactions in Crohn’s disease as a model to identify intracellular events and targets for pharmacological approaches to disease management.

Characterisation of the molecular landscape, and interactions in that landscape, brings one back to the ideal of being able to regulate mesenteric (and hence systemic) events in inflammation, by non-operative means. This is explored by Argikar and Argikar in a state-of-the-art summary of knowledge on the pharmacology of the mesentery. At present, the only means of altering mesenteric inputs in inflammation and disease is by surgical means. The surgical alteration of mesenteric inputs in inflammation is comprehensively explained and discussed by Holubar and colleagues.

In summary, the book provides the basis for intriguing questions related to the involvement of the mesentery in inflammation. The new foundation means that new questions can now be considered scientifically and clinically legitimate in the exploration of inflammation, and the involvement of the mesentery in this. This book is the platform on which to base that exploration.

Limerick, Ireland J. Calvin Coffey

Table of contents :

Preface
Contents
Introduction to “The Mesentery in Inflammation´´
1 Introduction: Inflammation and the Mesentery
2 Overview of Chapters
3 The Mesentery
4 Inflammation of the Mesentery
5 The Mesenteric Interstitium
6 The Mesenteric Lymphatic Framework
7 General Immunology of the Mesentery
8 Bacterial Translocation
9 The Effects of Mesenteric Inflammation on Adjoining Intestine
10 Targeting the Mesentery
11 Conclusion
References
The Development and Anatomy of the Mesentery
1 Introduction
2 The Mesentery Redefined
3 The Mesenteric Model of Abdominal Anatomy
4 Histology of the Mesentery
5 Vasculature of the Mesentery
6 The Mesentery and the Immune System
7 Implications for Our Understanding of Abdominal Inflammation
8 Implications for Treatment
9 Implications for Medical Practice in General
10 Conclusion
References
The Interstitium of the Mesentery: Contents and Inter-organ Connections
1 Introduction
2 Categories of Interstitial Spaces
3 Interstitial Spaces of the Mesentery
3.1 Continuity of Interstitial Spaces Within the Mesentery
3.2 Continuity Between the Mesenteric Interstitium and Extra-Mesenteric Tissues
4 Resident Cells of the Interstitium
4.1 Interstitial Lining Cells and Other Stromal Cells
4.2 Macrophages
4.3 Mast Cells
4.4 Cell Derived Exosomes
5 The Matrix of the Interstitium
5.1 Extracellular Matrix
5.2 Fluid Contents of the Interstitium
6 The Mesenteric Interstitium in Disease
7 Conclusion
References
Mesenteric Organ Lymphatics in Abdominal Inflammation
1 Introduction
2 Anatomy of the Mesenteric Lymphatic Vasculature
3 Developmental Origins of Mesenteric LECs
4 Mesenteric Lymphatic Molecular Regulation
5 Function of Mesenteric Lymphatics
6 Mesenteric Lymphatics and Abdominal Inflammation
6.1 Obesity
6.2 Inflammatory Bowel Disease
6.3 Intestinal Infection
7 Translational Perspectives
References
The Immunological Importance of the Mesentery
1 Phenotypic Findings and Functional Implications
1.1 Adipocyte Hyperplasia: Immune Nutrition?
1.2 Only Adipocyte Hyperplasia?
2 Adipokines
2.1 Leptin
2.2 Adiponectin
3 Adipocytes as Cells of the Innate Immune System
4 Immune Cell Infiltration and Function
4.1 Macrophages
4.2 T and B Cells
4.3 Intestinal Barrier
5 Working Model
6 Conclusion
References
Bacterial Translocation to the Mesentery
1 Concept of Bacterial Translocation and Methods of Detection
1.1 Historical Context
1.2 Detection Methods
2 Translocation of the Gut Microbiome in Chronic Inflammation
2.1 The Leaky Gut Hypothesis
2.2 Bacterial Translocation Patterns in Distinct Chronic Inflammatory Diseases
2.3 Microbial Influence on Mesenteric Adipose Immune and Metabolic Function
2.4 Bacterial Translocation and Creeping Fat
2.5 Management Strategies for Creeping Fat
3 Translational Perspectives
References
Mesenteric Microbiology and Inflammatory Bowel Disease: Improved Understanding Due to Accelerating Innovation and Sophisticati…
1 The Mesentery and Microbiology
2 Inflammatory Bowel Disease and Microbial Species
3 Crohn´s Disease and the Microbiology of Mesenteric Fat
4 IBD and Mesenteric Microbiomes
5 IBD and Mesenteric Metagenomes
6 Conclusion
References
Mesenteric Adenopathy and Adenitis
1 Introduction
2 The Mesentery
3 Mesenteric Adenitis
4 Viral Pathogens Associated with Mesenteric Adenitis
5 Major Viral Pathogens That Lead to Mesenteric Adenopathy/Adenitis
5.1 SARS-CoV-2
5.2 Human Immunodeficiency Virus (HIV) and the Mesentery
6 Viral Infection of Organs of the Mesenteric Domain
7 Non-viral Pathogens Associated with Mesenteric Adenopathy and Adenitis
8 Mechanisms by Which Viruses and Other Pathogens Access Mesenteric Lymph Nodes
9 Mesenteric Adenopathy and Adenitis in Abdominal Disease in General
10 Future Directions
10.1 Clinical Investigation of the Mesentery
10.2 Vibriota and the Mesentery
10.3 New Modalities of Disease Spread That Utilise the Mesentery
11 Conclusions
References
The Effects of Mesenteric Inflammation on Intestinal Fibrosis
1 Introduction
2 Mesenteric Alternation in Crohn´s Disease
2.1 Cellular Signature and Microbial Signature of Mesentery in Crohn´s Disease
2.2 Secreted Factors from Mesentery in Crohn´s Disease
2.2.1 Cytokines
2.2.2 Adipokines
Leptin
Adiponectin
Resistin
Free Fatty Acids
3 Link Between Mesenteric Inflammation and Intestinal Fibrosis: Clinical, Imaging, and Histology Evidence
4 Mechanism of Mesentery-Induced Intestinal Fibrosis in Crohn´s Disease
5 Mechanism of Intestinal Fibrosis Induced Mesenteric Alternations in Crohn´s Disease
6 Translational Perspectives
6.1 Potential Novel Targets for Anti-Fibrotic Treatment in Crohn´s Disease in Relation to the Mesentery
6.2 Barriers and Solutions of Developing Anti-Fibrotic Agents in Crohn´s Disease
References
Drug Metabolizing Enzymes and Transporters of the Mesentery
1 Introduction
2 Drug Metabolizing Enzymes and Transporters
3 Drug Metabolizing Enzymes of the Mesentery
4 Transporters of the Mesentery
5 Regulation of Drug Metabolizing Enzymes and Transporters and Their Association with the Diseases of the Mesentery
6 Potential Impact of Mesentery in ADME and Toxicology
7 Conclusions
References
Targeting the Mesentery with Surgery
1 Introduction
2 The Role of the Mesentery in Inflammation
3 The Traditional Surgical Approach to the Mesentery
3.1 Colorectal Cancer
3.2 Inflammatory Bowel Disease
3.2.1 Ulcerative Colitis
3.2.2 Medically Refractory Colitis
3.2.3 Ulcerative Colitis Associated Neoplasia
3.3 Crohn´s Disease
3.3.1 Ileocolic Crohn´s
3.3.2 Strictureplasty for Small Bowel Crohn´s
3.4 Sigmoid Diverticulitis
4 Progressive Surgical Approach to the Mesentery
4.1 Pouchitis and Peri-Pouch Fat
4.2 Ileocolic Crohn´s: Extended Mesenteric Excision
4.3 Ileocolic Crohn´s: Kono-S Anastomosis
5 Future Directions
6 Conclusions
References
Future Directions in Investigating “The Mesentery in Inflammation´´
1 Introduction
2 The Development and Anatomy of the Thorax
3 The Interstitial Continuum
4 Mesenteric Lymphangiogenesis, Obesity, and Inflammation
5 The Mesenteric Component of the Immune System
6 Bacterial Translocation and Translocation Phenotypes
7 Viruses, Parasites, Bacteria, and the Mesentery
8 Mesenteric-Based Radiological and Endoscopic Indices of Disease Activity
9 Pharmacology of the Mesentery
10 Surgical Interruption of Mesenteric Events
11 Conclusion
References