5 Introduction to the Physiology of the Mesentery

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Introduction to the Physiology of the Mesentery

Karl Andersen, Assad Munis, and Eli D. Ehrenpreis

Anatomy

The mesentery is an organ within the abdomen that has multiple purposes, including suspending the intestines and preventing their collapse into the pelvis, acting as a conduit for arteries, veins, nerves, and lymphatics to the intestines, and being a reservoir for adipose tissue and immune cells. The mesentery was traditionally described as a fragmented structure that helped suspend the small intestine, transverse colon, and mesosigmoid, but new research has demonstrated that it is a contiguous structure that extends from the duodenojejunal ﬂexure to the mesorectum. This has facilitated the development of uniform anatomical nomenclature, and provided the foundation to investigate the pathophysiological role that the mesentery plays in different disease processes.

Histologically, the mesentery is derived from the mesoderm germ layer and is composed primarily of two layers of mesothelium: an interposed loose connective tissue layer and adipocytes intermixed in the connective tissue. During embryological development, a network of neurons, blood vessels, and lym phatic channels grow within it and connect the developing gut to the rest of the body. Proper embryological formation of the mesentery ensures correct anatomical placement within the adult body and prevents the development of potentially devastating conditions, such as volvulus and malrotation, that can occur when the gut is not properly anchored to the posterior abdominal wall. These conditions can occur when the mesentery remains suspended at the vascular insertion points of the superior and inferior mesenteric arteries but fail to be attached to the posterior wall, allowing for twisting and occlusion of the arteries. In a normal adult, the root of the mesentery, which is approximately 15 cm in length, is the attachment point to the

K. Andersen  A. Munis  E. D. Ehrenpreis (&) Department of Medicine, Advocate Lutheran General Hospital, 1775 Dempster St, 6 South, Park Ridge, IL 60068, USA e-mail: E2bioconsultants@gmail.com

https://doi.org/10.1007/978-3-030-71963-0_5

36 K. Andersen et al.

posterior abdominal wall. It is here where it ﬂattens and becomes the retroperitoneum. It extends inferiorly and obliquely to the right, and from the duodenojejunal junction to the ileocolic junction on the right, crossing over the aorta and inferior vena cava. Thus, the mesentery maintains the right and left colon in their normal anatomic conﬁgurat ion by attaching to the posterior abdominal wall and overlying the retroperitoneum.

With increasing research directed at the function of the mesenteric organ, new understanding of the important role of the mesentery in health and disease. Functioning portions of the mesentery are outlined in this chapter and summarized in Table 5.1.

Vascular Physiology

Coursing through the mesentery are a series of arteries and veins that carry oxygen-rich blood from the heart to the small and large intestine and nutrient-dense blood back to the liver. The primary artery that supplies blood to the mesenteric circulation is the superior mesenteric artery, which brings blood to the small intestine, ascending colon, and the proximal two-thirds of the transverse colon. Regulation of blood ﬂow through the mesentery is dynamic and determined by a complex set of neurologic, hormonal, and metabolic signals that ensure adequate intestinal blood ﬂow supply. During periods of high metabolic demand, such as the

Table 5.1 Functional Components of the Mesentery

Component Function

Vascular • Complex system of neurologic, hormonal, and metabolic signals that

Immunologic • Visceral adipocytes are being considered as a major contributor in the

Neurologic • Described as the “second brain” due to its complexity and ability to

Mesenteric Adipose

ensure adequate intestinal blood ﬂow supply

• Intrinsic and extrinsic systems are major regulators of blood ﬂow through the mesentery

pathogenesis of pro-inﬂammatory states

• Antigen presenting cells located within the intestines play a pivotal role in maintaining the balance in the gut microbiome

function independently from the rest of the body

• Neurogenic vasoconstriction within the mesentery is mediated mainly by the sympathetic postganglionic cells

• Mesentery serves as major reservoir for the total effective circulating volume and plays a crucial role in maintaining adequate systemic perfusion

• A dynamic endocrine and immunologic component that is involved in multiple disease states including metabolic syndrome, inﬂammatory bowel disease,and coronary artery disease

• Mesenteric adipocytes play big role than previously thought in fat wrapping

• Increase inﬂammation through release of C-reactive protein

5 Introduction to the Physiology of the Mesentery 37

post-prandial state, these signaling networks will respond by causing vasodilation and increasing blood ﬂow through the mesentery to the intestines. Conversely, these networks will shunt blood away from the intestines when other organs have greater metabolic demands, such as during periods of exercise, hypovolemia, shock, and hemorrhage.

The major regulators of blood ﬂow through the mesentery and gut are divided into intrinsic and extrinsic systems. The intrinsic system is further divided into the metabolic pathway, which involves adjusting blood ﬂow during periods of digestion and hypoxia, and the myogenic pathway, which involves vasoconstriction and vasodilation via smooth muscle cells to maintain a constant blood ﬂow. The extrinsic system is compo sed of neurohumoral, autonomic, and cardiovascular signals that augment the blood ﬂow through the mesentery. The neurohumoral control is a mixture of systemic hormones, such as catecholamines, angiotensin II, and vasopressin, and local gastrointestinal hormones, such as gastrin and secretin, all of which bind to their respective receptors and augment blood ﬂow during different physiological conditions. The autonomic control is divided into the sympathetic and parasympathetic branches, with the sympathetic branch having the greater effect on blood ﬂow. Cardiovascular signals, such as cardiac output and effective circulating volume, also play a pivotal role in regulating mesenteric blood ﬂow.

Immunologic Physiology

The digestive system is the largest interface between the outside world and the internal body. The immune system is responsible for p atrolling pathogens that attempt to traverse the mucosal barrier. The immune system lining the gut is also responsible for recognizing beneﬁcial micro- and macronutrients and separating them from potentially harmful antigens. The failure to differentiate between harmful and beneﬁcial antigens, or commensal bacteria from pathogenic bacteria, can result in an inappropriate inﬂammatory state with subsequent development of multiple medical conditions, including Crohn’s disease and Celiac disease. Maintenance of a functioning intestinal immune system relies largely upon a network of lymph nodes and immune cells, including ﬁbrocytes, lymphocytes, macrophages, dendritic cells, and neutrophils. The role of visceral adipocytes, which have a large concentration in the mesentery, is currently being investigated as a major contributor to the pathogenesis of pro-inﬂammatory states.

The process of differentiating harmless from harmful molecules begins with antigen presenting cells (APCs). These cells are located within the lamina propria of the intestines or within lymphoid follicles within the submucosa of the gut (Peyer’s patches). The antigen-laden APCs in the lamina propria will travel through lymphatic channels to mesenteric lymph nodes and present directly to naive CD4+ T cells. Similarly, APCs in Peyer’s patches will present to naive CD4+ T cells within the submucosa, or will travel through lymphatic channels to mesenteric lymph nodes. The naive CD4+ T cells will then differentiate into type 1 helper T-cells

38 K. Andersen et al.

(Th1) that generate local and systemic inﬂammation, or into type 3 helper T- cells (Th3) and regulatory T cells (Tregs) that will lead to systemic immunity, IgA secretion, and local tolerance. The development of inﬂammatory diseases of the gut, such as those seen in inﬂammatory bowel disease, are not fully understood but likely involve a combination of genetic susceptibility, dysbiosis of the gut, sustained innate immunity, and defective regulation. The relationship of the mesenteric function to gastrointestinal immune regulation is currently being explored and it remains to be seen what relationship exists amongst these entities.

Neuronal Physiology

The enteric nervous system is frequently described as the “second brain” of humans due to its size and ability to function independently from the rest of the body. It connects to the rest of the body through the parasympathetic and sympathetic branches of the autonomic nervous system. The primary parasympathetic innervation for the small intestine, right colon, and the ﬁrst half of the transverse colon comes from the vagus nerve. The sympathetic innervation to these segments of the gut comes from the greater, lesser, and least splanchnic nerves, which originate from thoracic segments T5-T12. The parasympathetic innervation to the remaining transverse colon, the descending colon, and the sigmoid colon is derived from the lumbar splanchnic nerves, which come from lumbar segments L1-L3. Sympathetic innervation to the second half of the colon comes from sacral splanchnic nerves that originate from segments S2-S4.

Within the mesentery, sympathetic postganglionic cells accomplish neurogenic vasoconstriction of vessels. In animal studies, there is little evidence that the parasympathetic nervous system plays a role in vasodilation. The primary neurotransmitter responsible for vasoconstriction from the sympathetic nerves is noradrenaline, with ATP and neuropeptide Y as co-transmitters. Immunohistochemical staining of human mesenteric and submucosal vessels have demonstrated that a subset of neurons are positive for substance P (SP). Additionally, SP might be the primary vasodilatory neuropeptide responsible for sensory nerve-mediated effector function based on animal studies that revealed SP could cause edema and plasma extravasation.

Innervation of the mesenteric veins and arteries is quite unique compared to the rest of the body. Typically, arteries require more innervation to efﬁciently allow the body to adjust vascular tone to maintain an adequate blood pressure. In the mesentery, however, the mesenteric veins need greater innervation because the mesentery serves as a major reservoir of the total circulating volume and requires a meticulous control to allow for volume to ﬂow into the effective circulatory system when the blood pressure needs to be adjusted. Innervation of the large mesenteric lymphatic vessels originates from noradrenergic NPY-positive nerve ﬁbers that arise from periarterial plexuses of the mesentery, but the extent to which that the innervation affects lymphatic ﬂow is yet to be determined.

5 Introduction to the Physiology of the Mesentery 39

Currently, the mesenteric nervous system is being investigated for its role in acute decompensated heart failure. During a heart failure exacerbation, there is an elevated sympathetic tone that causes the inappropriate movement of ﬂuid out of the mesentery into the effective circulatory system, accelerating the decompensation. Medications that reduce sympathetic tone are now being utilized to hold more blood in the splanchnic circulation to decrease the rate of decompensation.

Role of Mesenteric Adipose

One of the major mesenteric contributions to the pathogenesis of inﬂammation is through the interaction of the gut with mesenteric adipocytes. Adipose tissue is no longer considered to be a passive repository of stored fuel or a thermoregulatory layer, but rather a dynamic endocrine and immunologic component that is involved in multiple disease states including metabolic syndrome, inﬂammatory bowe l disease, and coronary artery disease. It is thought to contribute to systemic and local disease through the expression of cytokines, i.e. adipokines. It is important to note, however, that not all adipose tissue has the same pro-inﬂammatory contribution. Subcutaneous adipose has been shown to be the least associated with provoking inﬂammation. Vi sceral fat, which is the most abundant in the mesentery, has a greater association with generating inﬂammation through the release of adipose-speciﬁc cytokines such as leptin and resistin. Adipose cells also secrete common cytokines such as tumor necrosis factor alpha (TNF-a), interleukin 6, and interleukin 8.

In regards to Crohn’s disease, it has been demonstrated that adipocytes are signiﬁcant producers of TNF-a, which is strongly associated with its pathogenesis. Mesenteric adipocytes have also been shown to have the ability to dedifferentiate into preadipocytes. Preadipocytes have the capacity to differentiate into macrophages and help sustain a proinﬂammatory state. Another example of the role that mesenteric adipocytes play in Crohn’s disease is the phenomenon known as fat wrapping. This phenomenon is known to occur when greater than 50% of a segment of the large or small intestine is enveloped in mesenteric fat. Interestingly, fat wrapping is commonly used as a landmark by surgeons to identify more diseased sections of the gut. It is felt that these regions of the intestine is where majority of luminal narrowing and stricture formation occur as a consequence of muscularis propria hyperplasia and intestinal ﬁbrosis.

Mesenteric adipose also contributes to systemic inﬂammation and frequently precedes many common medical conditions including metaboli c syndrome, diabetes, and coronary artery disease. A recent study demonstrated that adipocytes from subcutaneous, mesenteric, omental, or periaortic tissue have different cytokine proﬁles. Mesenteric adipocytes having the greatest inﬂammatory proﬁle and can contribute to metabolic dysfunction that precedes coronary artery disease. Adipose cells were found to increase inﬂammation through the release of C reactive protein (CRP), a non-speciﬁc marker of inﬂammation that has been positively correlated with the pathogenesis and severity of Crohn’s disease and coronary artery disease.

40 K. Andersen et al.

The liver primarily releases C-reactive protein, but many studies have shown that obesity, especially visceral obesity, is linked to a rise in CRP production as well. A proposed mechanism for great er CRP release is that that visceral adipocytes produce larger amounts of inﬂammatory adipokines that cause the liver to release greater amounts of CRP. Another hypothesis is that with increasing obesity there is more macrophage and monocyte invasion of the adipose tissue, and that these same macrophages and monocytes help sustain a proinﬂammatory state. Furthermore, another link has been proposed that connects the role of adipose tissue and systemic inﬂammation. There appears to be an inverse relationship between adiponectin , an immunomodulatory adipokine, and obesity. The Coronary Artery Risk Development in Young Adults (CARDIA) study demonstrated that increased amounts of central obesity correlated with lower levels of adiponectin. Since adiponectin increases insulin sensitivity, low levels of adiponectin will result in more insulin resistance and the subsequent development of metabolic disorders. Nonetheless, as the role of mesenteric adipose tissue in local and systemic diseases is further scrutinized, it is expected that more effective therapeutic regimens will come to fruition to alleviate the burden of mesenteric adipose- generated inﬂammatory conditions.

Emergence of the Human Gut Microbiota as an Influencer in Health and Disease

Miranda G. Kiernan, Suzanne S. Dunne, and Colum P. Dunne

The Gut Microbiome

Gut microbiome proﬁles were determined initially through identiﬁcati on of microbial communities associated with faecal matter, luminal contents and mucosal tissue. Early studies utilised culture methods, which provided limited information. Reports from studies investigating luminal contents and faeces concluded that non-sporing, Gram-positive anaerobes dominate throughout the length of the intestine. Bacteroides were found to be ubiquitous, mainly Bacteroides fragilis, with biﬁdobacteria, streptococci and lactobacilli also present in relatively high numbers. Luminal contents, taken from various locations along the small and large intestine, and faecal matter, displayed differing microbial proﬁles. This variation was thought initially to be inﬂuenced by location along the intestine. The duodenum and the jejunum contained low numbers of bacteria, suggesting that colonisation of the proximal small intestine by bacteria may be transient. Of the bacteria present in the proximal small intestine, Bacteroides and biﬁdobacteria were the most abundant while enterobacteria, lactobacilli, and streptococci were detected in lower numbers. In contrast, whilst the large intestine was colonised by low numbers of enterobacteria and staphylococci, it also contained enterococci, clostrid ia, Veil- lonella, Streptococcus salivarius and Bacteroides melaninogenicus. The microbial proﬁle of the terminal ileum had more in common with that of the large intestine than the small intestine.

Studies investigating mucosal tissue microbiota promptly followed, providing an arguably more accurate representation of the human gut microbiota. Healthy duodenal mucosa was sterile in general, whilst the jejunum and ileum were sterile in some healthy individuals. In contrast, studies evaluating colonic mucosa consis-

M. G. Kiernan  S. S. Dunne  C. P. Dunne (&) School of Medicine and Centre for Interventions in Infection, Inﬂammation and Immunity, University of Limerick, Castleroy, Limerick V94 T9PX, Ireland e-mail: Column.dunne@ul.ie

https://doi.org/10.1007/978-3-030-71963-0_6

44 M. G. Kiernan et al.

tently demonstra ted bacterial colonisation. Gorbach et al. [14] cultured streptococci and lactobacilli from small intestinal mucosa, while others found E. coli, Enter- obacter and Klebsiella in ileal mucos a only. The most frequent and abundant bacteria in the large intestinal mucosa were streptococci, enterococci, and Bac- teroides. However, more recent studies have conﬁrmed differences in the micro- biota detected in patients’ faecal matter compared with their intestinal mucosa. Most importantly, while studies using culture methods provided us with preliminary information relating to the gut microbiota, it is estimated that up to 80% of intestinal bacteria cannot be cultured.

The advent of culture-independent methods, speciﬁcally next generation sequencing, has advanced a far more accurate understanding of the human gut microbiome. Inter-individual variation and geographical factors are now recognised as confounders in the search for a deﬁnitive microbial signature of healthy individuals. Others inﬂuencers include general hygiene, sanitation, the prevalence of breast-feeding, use of antibiotics and vaccines, and ethnicity. Despite these challenges, consensus is developing regarding what a normal healthy gut microbiota proﬁle may be. As more countries adopt westernised lifestyle and diet, both Firmicutes and Bacteroidetes phyla have begun to dominate the microbiome (approximately 50% and 40%, respectively). The remaining 10% comprise other phyla, including mainly Proteobacteria (includes bacteria from Enterobacteriaceae, Pseudomonadaceae, Burkholderiaceae and Desulfobacteraceae) and Actinobacteria (includes bacterial from Streptomycetaceae, Corynebacterineae and Micrococcaceae).

Bacterial Translocation to Blood and the Mesentery

Bacterial translocation is the movement of viable or non-viable microbes and their metabolites from the intestinal tract to extra-intestinal sites such as the mesentery, bloodstream, mesenteric lymph nodes (MLNs), or other organs such as the liver, spleen and kidneys. Translocation has been described in the context of various types of cancers, sepsis, acute pancreatitis, liver cirrhosis and inﬂammatory bowel disease.

In IBD speciﬁcally, increased intestinal permeability has been described well. For example, increased permeability due to loss of E-cadherin expression allows bacteria or their byproducts translocate to the mesentery, MLNs, Peyer’s patches and the bloodstream. MLNs harvested from patients with IBD have been examined for the presence of translocated bacteria. As early as 1994, Sedman et al. found MLNs from patients with Crohn’s disease to be free of bacteria but successfully cultured Citrobacter spp from nodes of patients with ulcerative colitis. Since then, others have successfully cultured bacteria from MLNs of pati ents with IBD, including E. coli, C. freundii and coagulase negative staphylococci.

6 Emergence of the Human Gut Microbiota … 45

Despite advances in molecular technology, few studies have characterised the microbial ecology of blood and MLNs using culture independent techniques. Notably, Vrakas et al. (2017) found that patients with IBD had increased concentrations of bacterial DNA in their blood, particularly during active disease, when compared to healthy controls. O’Brien et al. (2014) investigated bacterial translocation to MLNs in patients with IBD. This study focussed primarily on patients with Crohn’s disease where E. coli was the most common organism found. While using considerably different approaches, both of these studies described a dysbiosis in blood and MLNs from patients with IBD compared to controls. However, it is difﬁcult to evaluate from these studies as to whether translocation is actually increased in IBD patients as their control subjects were, in some cases, undergoing surgery for alternative or additional pathologies. Furthermore, it is estimated that bacterial translocation occurs normally in 5–10% of healthy individuals.

Irrespective, bacterial translocation to blood in patients with Crohn’s disease is associated with increased serologic levels of Th1-derived pro-inﬂammatory cytokines, such as IL-21, TNFa and IFNc. Translocation to MLNs elicits an adaptive immune response. Bacteria have also been detected in the mesenteric fat of patients with Crohn’s disease. Previous studies have demonstrated that adipocytes, when cultured with bacteria or their products, such as lipopolysaccharide (LPS), increase expression of IL-6, TNFa, IL-1b, IL-8, RANTES, CCL11 (also known as Eotaxin-1), MCP-1, adiponectin, resistin, visfatin and leptin at protein and mRNA levels. In patients with Crohn’s disease, CRP mRNA and protein levels are increased in mesenteric adipocytes stimulated with E. coli or LPS. Given the potential consequences of bacterial translocation to the mesentery, MLNs, or blood in patients with IBD, the mesenteric nodal microbiome appears to be of critical importance.

The Microbiome of Mesenteric Fat

Although numerous studies have demonstrated that bacteria can be isolated from mesenteric fat, no study has determined deﬁnitive bacterial proﬁles of the mesentery fat component in disease states. Zulian et al. (2013) speciﬁcally investigated and con ﬁrmed the presence of Enterococcus faecalis in mesenteric and omental fat in both Crohn’s disease and ulcerative colitis. Numbers of E. faecalis were signiﬁcantly increased in fat deposits in Crohn’s disease, but not ulcerative colitis. Peyrin-Biroulet et al. (2012) reported that the rate of bacterial translocation to mesenteric fat is similar to that of the MLNs. They demonstrated this is also higher for patients with Crohn’s disease than healthy individuals and those with ulcerative colitis.