“All disease begins in the gut,” a phrase credited to Hippocrates of Kos, a brilliant physician who lived in ancient Greece during the 4th and 5th centuries BC widely recognized as the father of Western medicine [1]. While this statement is not entirely precise, ongoing research into the gastrointestinal tract and its associated immune system, and the increasing evidence regarding the impact of microbiota on our health have spurred scientists to reevaluate Hippocrates’ renowned saying [2].

This article intends to describe the distinctive characteristics of the immune system associated with the gastrointestinal tract. Additionally, we will delve into the captivating realm of gut microbiota, which shares a close connection with the immune system and exerts significant influence on various aspects of our well-being. Lastly, we will explore the intricate relationship between gut microbiota and the immune system, concerning other organs.

The Digestive System

All living beings require nutrients for growth, survival, and reproduction. Among the various evolutionary strategies developed to obtain nutrients from the environment, the vertebrate digestive system stands out as one of the most complex and fascinating. It primarily derives from the endoderm, the innermost of the three primary germ layers that form during the early stages of embryo development. Likely, the endoderm appeared earlier than the other layers, shortly after the advent of multicellularity [3,4].

Comprising the gastrointestinal tract and its accessory organs (salivary glands, liver, gall bladder, and exocrine pancreas), the digestive system serves a paramount purpose. Its primary functions are to ingest and digest food, absorb nutrients (including carbohydrates, fats, proteins, minerals, and vitamins), and expel waste [5]. Serving as the entry point for food, the gastrointestinal tract is in continuous contact with external elements, which are often harmless. However, in certain instances, these elements may carry bacteria, fungi, viruses, toxins, and other potentially harmful components.

The Gut Mucosa

The mucosa, forming the innermost layer of the gastrointestinal tract's wall, covers the entire length of the tract and consists of three components. First, the epithelium, which interfaces with the lumen (the gut’s internal cavity) and carries out digestion, absorption, and secretion. Second, the lamina propria, a layer of connective tissue within the mucosa housing blood vessels, nerves, and lymphatic tissue. Third, the muscularis mucosae, a thin layer of smooth muscle [6]. In the small intestine, the mucosa is structurally organized forming finger-like protruding structures known as villi, a structural adaptation that vastly augments its surface area. Remarkably, the gastrointestinal tract alone boasts a surface of 400 m², approximately 200 times that of skin. This vast surface significantly enhances the absorption process, a primary physiological function of the mucosa [7].

The gastrointestinal tract’s mucosa often serves as the initial point of contact with the multitude of microbes accompanying each food mouthful. As a result, the gut mucosa has evolved an extensive immune system with distinct anatomical and functional characteristics, setting it apart from immune systems in other organs [7]. Notably, it is worth highlighting that the lymphoid tissues associated with mucosal surfaces throughout the body constitute the largest compartment of the immune system. They host more lymphocytes than all other components of the immune system combined and are responsible for producing nearly 70% of the total antibodies. It is estimated that the population of T cells within the epithelial layer of the small intestine alone could account for almost 60% of all T cells present in the entire body [8,9].

Gut-associated lymphoid tissue (GALT)

Immune cells within the gut mucosa can either be located in the structured GALT or dispersed throughout the lamina propria and epithelium.

Lymphoid cells

A diverse array of lymphoid cells not associated with structured lymphoid tissues reside in the lamina propria and epithelium of the gut mucosa.

• B-lymphocytes: B-lymphocytes (or plasma B cells) found in the lamina propria are responsible for producing high levels of specific secretory IgA antibodies. These antibodies are subsequently released into the gut lumen by epithelial cells through transcytosis [10].
• T-lymphocytes: The function of T-lymphocytes is to rapidly respond to pathogens and secret effector cytokines that modulate the immune response. CD4+ naive cells differentiate into regulatory T (Treg) or helper T cells following antigen presentation by dendritic cells or microfold (M) cells [11].
• Intraepithelial Lymphocytes (IELs): The IELs are a subpopulation of T-lymphocytes residing within the epithelial layer of the gut mucosa. Unlike other T-cells, they do not circulate in peripheral blood. IELs, representing the largest subpopulation of T-lymphocytes in the entire body, serve as the first line of defense against pathogens crossing the epithelial barrier [12,13].
• Innate Lymphoid Cells (ILCs): ILCs are capable of secreting a range of effector cytokines that regulate both innate and acquired immunity cells. They reside in the mucosa and can mount swift immune responses to tissue damage induced by pathogens [14].
• Macrophages: Macrophages primarily reside within the lamina propria and muscularis mucosae. However, they can project cytoplasmic extensions known as dendrites through the epithelium to engage pathogens and act as antigen-presenting cells [13].
• Dendritic Cells: Dendritic cells are antigen-presenting cells that produce retinoic acid and TGF-β to induce plasma B cells to produce IgA antibodies. They also contribute to the maturation of Treg and some IELs [13].

GALT structures

Due to its continuous exposure to a diverse range of antigens, lymphoid tissue within the gut mucosa has developed specialized structures that are unique to the human body.

• Peyer’s Patches: Peyer’s patches (PPs) are protruding dome-shaped structures scattered throughout the mucosa, resembling multi-follicular lymphoid tissue. They are separated from intestinal lumen by a specialized follicle-associated epithelium (FAE), which houses various types of immune cells. The FAE is enriched with M cells, pivotal in transporting luminal antigens from viruses and bacteria to the PP parenchyma through transcytosis. This M cell-mediated transcytosis appears to be crucial for an optimal IgA response to luminal antigens. A variety of immune cells reside in the lymphoid follicles underneath the FAE in PPs: T-lymphocytes, B-lymphocytes, IELs, and antigen-presenting cells [15]. The number, density, and immune cell composition of PPs vary along the length of the intestine, adapting to different conditions and microbiota [16].
• Vermiform Appendix: Although long considered a vestigial organ, with appendectomy showing no long-term adverse effects, recent discoveries suggest a potential role of the vermiform appendix in gut immunity. It contains numerous lymphoid structures akin to PPs, hinting at a role in priming the gut immune system. In addition, some studies propose that the vermiform appendix serves as a sanctuary for intestinal bacteria, affording them protection against diarrheal cleaning and peristalsis [17].
• Isolated Lymphoid Follicles: Isolated Lymphoid Follicles (ILFs) consist of individual lymphoid follicles dispersed throughout the intestine. Approximately 30,000 ILFs are estimated to populate the intestine, constituting a vital compartment of the GALT. Their cellular composition, density, and distribution within the gut wall vary between different segments of the intestine [15].

Thus far, we have delved into the distinctive aspects of the gut immune system. Many of these unique features have evolved in response to the complex array of dietary antigens the gastrointestinal tract is exposed to. However, the gut immune system has to interact with another substantial source of antigens: the microbiota.

The Microbiota

Gut microbiota, also known as gut flora or gut microbiome, is defined as the group of microorganisms inhabiting our intestines. It encompasses archaea, viruses, fungi, and bacteria, which account for 99% of the microbiota composition [18]. Remarkably, our intestines harbor as many bacteria as there are cells in our bodies [19]. A growing body of evidence underscores the pivotal role played by gut microbiota in the pathogenesis of various diseases, including inflammatory bowel disease, type 2 diabetes, hypertension, and cancer [20,21].

Functions of Gut Microbiota

Beyond its impact on the development of metabolic disorders and diseases, gut microbiota fulfills crucial roles in maintaining health and homeostasis.

• Metabolic functions: Gut microbiota ferments dietary fiber and endogenous mucus. It generates short-chain fatty acids that serve as a source of energy. Other metabolic functions include the synthesis of vitamin K and the metabolization of drugs and toxins [20]. Recent studies in mice show that specific strains of commensal bacteria contribute to endocrine resistance in prostate cancer by producing androgens [22].
• Trophic functions: Gut microbiota controls epithelial cell proliferation and differentiation. As an example, a subpopulation of T-lymphocytes modulates epithelial stem cell differentiation by secreting cytokines [23]. Gut microbiota participates in the homeostasis and development of the gut immune system [20], as it promotes the development of gut-associated lymphoid tissue like PPs among others [24].
• Protective functions: Commensal bacteria prevent colonization and infection of the host by pathogenic agents, thus creating a barrier effect that protects us [20].

As we have explored thus far, we coexist in a symbiotic relationship with hundreds of bacterial species and other microorganisms. They fulfill indispensable roles that enable our bodies to carry out fundamental physiological functions. Indeed, our existence would not be possible without them. Consequently, a pressing question emerges: How does the immune system distinguish potentially harmful microorganisms from those that confer benefits? How does it discern which microorganisms must be eliminated and which ones must be preserved?

Keeping the balance: Homeostasis of gut microbiota and immune system

The human intestine resembles an ecosystem that must preserve its equilibrium to persist. The mechanisms to uphold gut microbiota homeostasis and the immune system can be categorized into four main groups.

• Minimize bacteria-epithelial cell contact: Globet cells are a subgroup of epithelial cells that specialize in secreting a mucus layer that covers and protects the gut mucosa. This mucus layer acts as a physical barrier, making it challenging for bacteria and other microorganisms to reach the epithelium [25].
• Antimicrobial proteins: The majority of epithelial cell lineages possess the capability to produce proteins with antimicrobial activity. These proteins can eliminate bacteria through different mechanisms, including enzymatic attacks on bacterial cell walls, disruption of the bacterial inner membrane, or deprivation of essential metals like iron [25].
• IgA: Secreted IgA prevents bacterial interaction with the intestinal epithelial layer and limits the passage of symbiotic bacteria through the epithelium. Dendritic cells sample beneficial bacteria and trigger the activation of plasma B cells to produce IgA antibodies [25].
• Treg cells: A subpopulation of Treg cells repress immune response by secreting IL-10 after dendritic cells present dietary or commensal bacteria antigens. Conversely, other Treg cells activate the immune response upon presentation of pathogenic antigens. Alterations in Treg cells affect gut homeostasis and favor the onset of diseases like inflammatory bowel disease [26]. Recent research has unveiled that specific subpopulations of antigen-presenting cells may induce either suppression or activation of immune response by Treg cells, shedding light on the intricate process of immune homeostasis within the gut [27].

Beyond the gut: The intestinal neuro-immune axis

The intricate network of neurons that innervates the digestive system coordinates essential physiological functions, including mucus secretion and peristalsis. Enteric neurons interact with both epithelial cells and immune cells to preserve gut and neuronal homeostasis. In a manner akin to the immune modulation carried out by the microbiome, the gut microbiota influences neuronal development and homeostasis [28]. A noteworthy example of this precise and fragile balance between the nervous system and gut microbiota lies in how the microbiome stimulates the formation of cerebral cavernous malformations in a mouse model of stroke [29].

We are what we eat: Effect of the diet on the gut immune system

In addition to microbiota and pathogenic agents, the gut immune system is directly exposed to dietary antigens. Imbalanced diets, such as those high in fats or deficient in vitamins or unsaturated fatty acids, disrupt the immune system’s equilibrium with gut microbiota by perturbing the mechanisms outlined above [30].

The Gut Immune System in Health Optimization Medicine and Practice (HOMe/HOPe)

For optimal health, it is absolutely essential to address the intricate balance and interplay of entire gastrointestinal tract (from mouth to anus). The second module of the Essential Certification in HOMe/HOPe is focused on the Gut Immune System. In it, clinicians learn how to detect and correct imbalances in five different categories: Maldigestion, Inflammation, Metabolic Imbalance, Dysbiosis, and Infection.

Detection will require a comprehensive stool analysis and clinicians are taught how to use correction strategies such as the use of lifestyle and dietary changes + bioidenticals, probiotics, prebiotics, postbiotics, digestive enzymes, phytoceuticals, fungiceuticals, and more.

Check out the Gut Immune System module in the HOMe/HOPe Essential Course here.

Conclusion

While not all diseases originate in the gut, as Hippocrates posited over 2000 years ago, our contemporary understanding emphasizes the profound influence that an imbalanced gut immune system and microbiota can wield over our health.

Consequently, it is imperative to delve into the implications these factors hold for the development of specific diseases, as such investigations may unveil novel avenues for treatment and healthcare provision.

In addition, optimizing gut function using novel detection and correction strategies like those found in HOMe/HOPe may be able to prevent, mitigate, or potentially even reverse pathogenesis.

The goal, however, with HOMe/HOPe, is not to treat any disease or condition but instead to optimize health. And in this case, optimizing gut health has many beneficial side effects, all of which make not only the gut more resilient, but the whole body.

Written by Ferran Riaño-Canalias, PhD

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