The Mesentery’s Pivotal Role in the Brain-Gut-Liver Axis

Abstract

Background:

Prior to 2012, the mesentery was perceived as a fragmented structure, lacking distinct functional and anatomical characteristics, and was merely considered part of other digestive organs. Dr. J. Calvin Coffey's in 2012 in his study redefined the mesentery as a distinct organ with a clearly defined anatomical and histological structure, although its specific function remains under investigation. The continuous structure and unique tissue properties of the mesentery classify it as the 78th independent organ in the human body. Insights into mesenteric adipose tissue have enhanced our understanding of normal metabolic processes and disease etiology, impacting health significantly. Experimental and clinical research highlights the vital roles of visceral adipose tissue, influencing neighboring organ function. The interaction within the brain-gut-liver axis is illuminated by the newfound functions of mesenteric adipose tissue, emphasizing its independent organ status.

Objective:

This study aims to evaluate the latest findings on the structure and function of the mesentery, focusing on visceral-mesenteric adipose tissue, and assess its role as a new organ in the brain-gut-liver axis.

Methods:

A comprehensive analysis of clinical and experimental studies on the mesentery's structure and function was conducted, focusing on recent discoveries regarding mesenteric adipose tissue and its role in the brain-gut-liver axis.

Results and Discussion:

Recent research has revealed the mesentery's unique functions, particularly in mesenteric adipose tissue. Mesenteric adipose tissue plays a crucial role in metabolic functions and influences disease onset. It acts as a vital link in the brain-gut-liver axis, directly influencing hepatic metabolism and disorders such as metabolic syndrome.

Conclusion:

Scientific evidence confirms the mesentery's anatomical and functional specificities, solidifying its status as the 78th independent organ in the human body. It serves as a crucial link in the brain-mesentery-small intestine-liver axis, impacting health and disease. Ongoing research holds promise for advancing our understanding of pathophysiological mechanisms and treatment approaches for metabolic syndrome and other chronic diseases.

1. BACKGROUND

The positioning of abdominal organs has traditionally been described with a central connection to the abdominal cavity walls via segmented portions of the mesentery, integral to individual organs (such as the mesocolon, mesoduodenum). This peritoneal model of human anatomy encompassed various forms of the mesentery without distinct shared anatomical and functional characteristics. However, recent research presents an alternative model, conceiving the mesentery as a distinct organ with anatomical continuity from the duodenojejunal flexure to the distal portion of the mesorectum. As a singular organ, the mesentery interconnects all other abdominal organs (mesenteric model) (Figure 1) (1-3).

Figure 1. Small and large intestines and associated mesentery. https://www.thelancet.com/journals/langas/article/PIIS2468-1253%2816%2930026-7/fulltext.

Based on these studies, the abdominal space can be divided into visceral-mesenteric and somatic-musculoskeletal compartments (4). Research has revealed vital functions of the mesentery as a distinct organ, including mechanical support of the intestines, immunological and anti-inflammatory functions, neurophysiological roles, and coordination in all metabolic processes (2).

The mesentery plays a particularly important role in the prevention and development of metabolic syndrome, insulin resistance, and systemic inflammatory response syndrome (SIRS) (2). Within the mesentery's structure, visceral adipose tissue holds significant importance, serving as a crucial endocrine organ. While visceral fat is present in other organ locations, notable distinctions exist between mesenteric adipose tissue and others, including vascularization, cellular composition, adipocyte appearance, distribution, and density (4). Beyond adipocytes, this tissue harbors phagocytes, lymphocytes, immunocytes, dendritic cells, and other stromal cells, producing numerous biologically active substances, notably adipokines (5).

Mesenteric fat tissue exhibits heightened hormonal activity, secreting over 50 cytokines and other signaling molecules. These substances play fundamental roles in maintaining homeostasis and coordinating innate and acquired immunity (6-10). Key adipokines include adiponectin, leptin, resistin, omentin, chemerin, visfatin, and ghrelin. Leptin, the first discovered adipocyte hormone in 1994, along with ghrelin as neurohormones, regulate appetite and energy balance via the hypothalamus. Imbalances in their secretion can induce oxidative stress and insulin resistance (9, 10). Macrophages and adipocytes communicate, influencing the character of immune responses. Production of pro-inflammatory factors like TNF, IL-6, and others can lead to low-grade chronic infection. To maintain normal metabolic processes, mesenteric fat tissue produces anti-inflammatory factors such as adiponectin. Dysregulation of the endocrine and immune functions of mesenteric fat tissue ultimately leads to insulin resistance, liver steatosis, and various cardiovascular and autoimmune diseases (10, 11).

Moreover, mesentery plays a crucial role in local immune responses, particularly in maintaining homeostasis in adjacent organs (small and large intestines, liver) through migration of its immune cells (T and B cells) and entire segments of fat tissue (creeping fat) (12-14). In inflammatory bowel disease (IBD), particularly in Crohn's disease, the mesentery actively participates in pathogenesis and complication development. Besides inflammation regulation, it plays a significant role in the fibrinolysis and coagulation processes (14-16).

Determining the quantity and distribution of visceral fat holds significant clinical importance as it can indicate the onset of insulin resistance and consequent diseases (7, 16). Preventive measures such as lifestyle modifications and nutritional interventions can prevent or delay the onset of chronic non-communicable diseases. Methods for determining the quantity and distribution of visceral fat tissue, especially mesenteric locations, include anthropometric measurement, ultrasonography, CT and MRI imaging, Dual-energy X-ray absorptiometry (DXA), and bioelectrical impedance analysis. Each method has its advantages and limitations, with anthropometric measurement combined with bioelectrical impedance being easily applicable in practice (Figure 2) (17).

Figure 2. Visceral fat volume measured by CT.

Due to its specific structure, the mesentery presents with specific diseases. Mesenteric and omental fat tissue comprise the most significant and voluminous portion of total visceral fat tissue. Mesenteric lipodystrophy and mesenteric panniculitis (sclerosing mesenteritis) represent specific autoimmune diseases of this organ (2). The disease course varies from asymptomatic to aggressive forms with complications necessitating surgical interventions (14, 15). Other mesentery diseases are rare, except for vascular thromboembolic incidents in mesenteric blood vessels leading to ischemic changes and intestinal compromise, significantly endangering life (2).

Because of its metabolic and immunological activity, the mesentery, as an independent organ, actively participates in the vital complex system of coordinating digestion, overall metabolism, and maintaining human health (18). This system has previously been described as the brain-gut-liver axis. By uncovering numerous important functions of the mesentery and mesenteric fat tissue, as well as the anatomical position of this organ, there is sufficient evidence to establish it as a crucial component in this axis.

The coordination and harmonization of organ functions within the brain-mesentery-intestine-liver axis play a pivotal role in maintaining overall health and homeostasis in the human body. This complex network involves intricate communication and interaction between the central nervous system (CNS), mesentery, intestines, and liver (19, 20).

The brain acts as a command center, receiving and processing sensory information and coordinating appropriate responses to maintain optimal organ function. The brain communicates with the mesentery via adipokines and other signaling molecular pathways, as well as with various nerves and hormonal pathways and the liver. The mesentery serves as a bridge, transmitting signals between the brain and intestines, facilitating nutrient absorption, immune responses, and interactions with microorganisms (21).

The intestines, with their extensive surface area and diverse microbial community, play a crucial role in digestion, nutrient absorption, and immune system modulation. The enteric nervous system, often referred to as the "second brain," coordinates and regulates intestinal motility, secretion, and barrier function. It communicates bidirectionally with the brain and mesentery, creating a feedback loop essential for maintaining gut-brain axis homeostasis (22).

The liver, a vital metabolic organ, receives nutrient-rich blood from the intestines via mesenteric circulation. It performs numerous functions, including detoxification, nutrient metabolism, and synthesis of essential molecules. The liver primarily communicates with mesenteric adipose tissue and subsequently with the brain and intestines via neuroendocrine signals, regulating metabolic processes and influencing systemic homeostasis. Portal circulation is a crucial segment of overall immune and metabolic status regulation, directly linking the mesentery and liver (portal theory) (23).

Understanding the complex relationships and harmonization within the brain-mesentery-intestine-liver axis is essential for comprehending the pathogenesis and management of various disorders. Disorders within this axis are associated with conditions such as inflammatory bowel disease, functional dyspepsia, irritable bowel syndrome, and metabolic syndrome (23).

A thorough understanding of this axis promises the development of new therapeutic strategies and interventions aimed at promoting health, preventing, and treating dysfunctional organ functions within this critical physiological network (2).

2. OBJECTIVE

This study aims to comprehensively evaluate and summarize the latest findings on the structure and function of the mesentery, with a specific focus on visceral-mesenteric adipose tissue. Additionally, it seeks to assess the mesentery's role as a new organ in the brain-gut-liver axis and evaluate the clinical significance of its newly discovered functions in the communication network between the brain and the gut, serving as the crucial fourth link in this axis (brain-mesentery-gut-liver).

3. MATERIAL AND METHODS

Our analysis involved a thorough examination of clinical and experimental studies on the structure and function of the mesentery within current scientific literature, stored and indexed in biomedical databases. We specifically concentrated on mesenteric adipose tissue function, delving into recent discoveries regarding the mesentery's role as a new organ within the brain-gut-liver axis. Our approach included a narrative review of select literature.

4. RESULTS AND DISCUSSION

Due to the necessity for a better understanding of the structure of the human body, a categorization into tissues, organs, and systems has been conducted. Until recently, the mesentery was only perceived as a constituent part of the organs within the abdominal cavity. Based on advancements in understanding the structure of abdominal organs and a more detailed insight into embryology, anatomical and histological structure, and the function of the mesentery in the scientific and clinical fields of biomedicine, a re-categorization of the organ system of the digestive tract has been proposed (1 ,2). The mesentery, as a distinct organ, presents a significant challenge for clinicians and researchers to substantiate the benefits of such an approach in everyday practice (1, 2). This challenge may manifest in surgical approaches to gastrointestinal tract diseases, in diagnosing disorders in the structure of the mesentery itself, particularly in the structure and quantity of mesenteric adipose tissue and its distribution. Study results indicate that the quantity and distribution of mesenteric adipose tissue can be verified through various methods, with CT abdominal analysis and bioelectrical impedance being the most commonly applied in practice, showing good correlation. A positive correlation has been demonstrated between the amount of mesenteric fat tissue and the occurrence of insulin resistance and metabolic syndrome, as well as an increased risk for cardiovascular diseases (17).

Specific diseases of the mesentery confirm the justification for applying the mesenteric model in clinical practice. Mesenteric sclerosis and mesenteric panniculitis are primary diseases of this organ. Systemic diseases can also affect the mesentery in the form of secondary mesenteropathies. Metastases of tumors of the digestive tract are common, and diagnosis is important for accurately assessing the extent of the disease and treatment strategy. Mesenteric adipose tissue plays a significant role in the etiopathogenesis of IBD, especially Crohn's disease (2).

The role of the mesentery in homeostasis and systemic diseases has been particularly evaluated in numerous experimental and clinical studies. Research has demonstrated that mesenteric adipose tissue plays a leading role in metabolic homeostasis. Structural and functional disorders in adipose tissue, in terms of quantity, size, and secretory activity of adipocytes, lead to far-reaching consequences for the entire organism. The occurrence of chronic low-grade inflammation and disorders in the secretion of hormones, adipokines, and other inflammatory and immune parameters lead to the development of insulin resistance, diabetes, and cardiovascular diseases. The occurrence of autoimmune diseases and early atherosclerosis with coagulation disorders has also been described (2, 8, 9).

Overall homeostasis depends on the regular communication of the mesentery with its signaling mechanisms towards the brain, small intestine, and liver. Bidirectional connections of adipocytes with specific centers in the brain, predominantly the hypothalamic region, have been proven. Numerous connections with the small intestine have been elucidated in many clinical and experimental studies, as there exists a direct morphological connection and the possibility of migration of adipose tissue into the intestine. Dysfunction in the mucosal barrier of the small intestine and its microbiota are associated with the function of mesenteric adipose tissue.

The manifold connections with the liver due to the presence of portal circulation give the mesentery a particularly important role, as it can be the primary factor in the development of insulin resistance and metabolic syndrome. A prerequisite for maintaining normal homeostasis is undoubtedly appropriate nutrition and emotional stability.

New knowledge about the structure and function of the mesentery revealed its specific role in the brain-gut-liver axis (Figure 3).

Figure 3. Schematic representation of the brain-mesentery-gut-liver axis.

5. CONCLUSION

Scientific evidence confirms the mesentery's anatomical and functional specificities, solidifying its status as the 78th independent organ in the human body. It serves as a crucial link in the brain-mesentery-small intestine-liver axis, impacting health and disease. Ongoing research holds promise for advancing our understanding of pathophysiological mechanisms and treatment approaches for metabolic syndrome and other chronic diseases.

Author’s contribution:

The all authors were involved in all steps of preparation this article. Final proofreading was made by the first author.

Conflict of interest:

None declared.

Financial support and sponsorship:

Nil.