The Connection Between Your Gut and Immunity

The gastrointestinal system not only plays a crucial role in nutrient digestion and absorption but is also pivotal in maintaining immune homeostasis. The gut encounters numerous antigens daily through diet, requiring a sophisticated immune mechanism to differentiate between harmful and harmless substances.

This is supported by a robust intestinal barrier and a complex immune system within the gut, which can malfunction, leading to disorders like celiac disease, inflammatory bowel diseases, and allergies. The diet significantly impacts this system, with bioactive food components such as plant metabolites and probiotics enhancing the gut's immune functions and promoting health.

The gut microbiota is integral to this immune regulation, interacting dynamically with the host's immune system to maintain intestinal homeostasis and prevent inflammation. These microbes metabolize nutrients, synthesize vitamins, and produce metabolic products that facilitate communication between gut epithelial and immune cells.

An imbalance in these microbial communities, or dysbiosis, can lead to increased intestinal permeability, inflammation, and a higher risk of chronic diseases like type 2 diabetes, cardiovascular disease, and various autoimmune conditions.

Dietary choices significantly influence the gut microbiome's composition and, by extension, overall health. Nutrients, including vitamins, can alter the microbial community, enhancing microbial diversity and the production of beneficial compounds like short-chain fatty acids.

These changes can positively affect the gut barrier and immune responses, offering potential therapeutic strategies for managing and preventing chronic conditions. Future research into these diet-microbiome interactions will be vital for developing dietary guidelines and interventions to improve public health.

Schematic representation of the interplay between nutrients,

gut microbiota and immune system

The gut-associated lymphoid tissue (GALT) occupies a large area of the gut; it is scattered within the intestinal epithelium and is organized into lymphoid follicles in the lamina propria called Peyer’s patches. GALT consists mainly of B and T cells, macrophages, and dendritic cells (DCs). Enterocytes (Paneth cells, goblet cells, microfold (M) cells) are responsible for the active transport or passive diffusion of antigens from food during digestion and microbial components. M cells, located in Peyer’s patches, take up luminal antigens by transcytosis and present them to underlying DCs in the lamina propria, which in turn interact with B and T cells either in Peyer’s patches or in mesenteric lymph nodes. DCs secrete cytokines and induce differentiation of T helper cell precursors (Th0) into effector Th cells (Th1, Th2, Th17) or Tregs. Antigen impingement on intestinal epithelial cells and subsequent activation of DCs induces differentiation of B cells into IgA-secreting plasma cells. In parallel, nutrients modulate the gut microbiota by promoting or inhibiting its growth and affecting its ability to derive energy from dietary chemicals. Microbiota-derived metabolites (short-chain fatty acids, capsular polysaccharide A, lipopolysaccharides) stimulate and modulate DCs and macrophages to create an antigen presentation environment that favors the differentiation of Th0 cells into Th3 Tregs that inhibit T- and B-cell inflammatory responses triggered by food, commensal, and environmental antigens.

Source: Tourkochristou, Evanthia et al. “The Influence of Nutritional Factors on Immunological Outcomes.” Frontiers in immunology vol. 12 665968. 31 May. 2021, doi:10.3389/fimmu.2021.665968 This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).

Probiotic effects on the gut

(a) Indirect probiotic effects on the intestinal barrier. By cross-feeding, generated metabolites from one bacterial strain may be utilized by another strain resulting in the generation of various other metabolites consequently affecting the gut barrier (1). The damaging effect of pathogen-generated toxins may be attenuated through toxin binding (2) and an inhibition of toxin production (3). A direct interaction of pathogenic bacteria with the host’s intestinal epithelial cells may be prevented by both, a formation of biofilms (4) and a competition for binding sites (5). The growth of intestinal pathogens may be inhibited by different mechanisms mediated by probiotics: Either through specific probiotic metabolites (6), the production of anti-microbial compounds (7) or a competition for nutrients/localization (8).

(b) Direct effects of probiotics on the host. The intestinal barrier may be strengthened by the generation of short-chain fatty acids such as butyrate, propionate and acetate through a metabolization of prebiotics (1) as well as through direct interactions of probiotics with epithelial cells (2) consequently improving tight junctions (TJ) and mucin (MUC) production and inducing anti-inflammatory effects. A potential contact of pathogens with the intestinal barrier may be inhibited by the generation of antimicrobial peptides (AMPs) (3) and the secretion of IgA (4). Additionally, probiotics may directly affect different intestinal immune cells (e.g., dendritic cells (DC), or T-cells) and consequently the intestinal inflammatory response (5).

Source: Zimmermann, Christian, and Anika E Wagner. “Impact of Food-Derived Bioactive Compounds on Intestinal Immunity.” Biomolecules vol. 11,12 1901. 18 Dec. 2021, doi:10.3390/biom11121901 This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

Microbiota-immune crosstalk and disease

The immune system–gut microbiota crosstalk is of sublime importance in understanding the role of dysbiosis-driven diseases in humans. Gut dysbiosis induces immune dysregulation and subsequently increases the risk of developing diseases, including inflammatory bowel disease (IBD), diabetes, obesity, cardiovascular diseases (CVDs), infectious diseases, and autoimmune diseases.

Source: Yoo, Ji Youn et al. “Gut Microbiota and Immune System Interactions.” Microorganisms vol. 8,10 1587. 15 Oct. 2020, doi:10.3390/microorganisms8101587 This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).

Interaction between diet, microbiota, and immune response at mucosal sites.

(A) To keep a healthy state, the local microbiota and mucosal immune system are in homeostasis at mucosal sites. The microbiota educates and promotes the maturation of the immune system by induction of pro-inflammatory and anti-inflammatory immune cells, e.g., Th17 (SFB), T regulatory cells (Clostridia spp.), and Th1 (Bacteroides fragilis). Moreover, the immune system surveys microbial activities (e.g., antigen sampling at the mucosal barrier) and responds in a controlled fashion by producing, e.g., antimicrobial peptides, sIgA to prevent tissue damage. The integrity of the mucosal barrier is sustained by bacteria-produced metabolites (e.g., SCFA) such as butyrate resulting in high expression of tight-junction proteins and mucus production, thereby restricting interaction of microbes to the lumen and luminal epitheliums. The diet is involved in all processes, serving the microbiome with fermentable fibers and the immune system and epithelium with essential nutrients, e.g., vitamins and minerals. (B) During pathological conditions, such as inflammatory bowel disease and asthma, the homeostasis at the mucosal barrier is disrupted. A westernized diet, i.e., high in SFA, high ω-6/ω-3 ratio, high sucrose and iron (oral iron supplements), and low in fiber promotes inflammation and growth of pathogenic/pathobiont (disease causing) bacteria in the gut. The microbiota, which is rich in non-beneficial bacteria, favorably induces the maturation of pro-inflammatory immune cells, leading to uncontrolled inflammation resulting in tissue damage of the mucosal compartment. The damaged mucosa and shifted immune response fail to control the microbiota, which exaggerates the pathophysiological state. Under certain conditions, bacteria-derived LPS enters the systemic circulation and further stimulates the immune system toward a pro-inflammatory state. Abbreviations: LPS, lipopolysaccharide; SCFAs, short-chain fatty acids; SFAs, saturated fatty acids; SFB, segmented filamentous bacteria; sIgA, secretory immunoglobulin A; ω-6/ω-3, omega-6/omega-3 fatty acid ratio; Th, T helper.

Source: Statovci, Donjete et al. “The Impact of Western Diet and Nutrients on the Microbiota and Immune Response at Mucosal Interfaces.” Frontiers in immunology vol. 8 838. 28 Jul. 2017, doi:10.3389/fimmu.2017.00838 This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).

The effects of vitamins on host health

(a) Microbiome dependent effects of vitamin. For example, vitamins such as B vitamins are crucial for microbial interactions, metabolism and signaling. Vitamin C, E and B2 act as local antioxidants that impact the luminal redox balance. Some vitamins when provided in large doses or when delivered to the large intestine have been shown to beneficially modulate the gut microbiome by increasing the abundance of presumed commensals (vitamin A, beta-carotene, B2, D, E), increasing or maintaining microbial diversity (vitamins A, B2, B3, C, K) and richness (vitamin D), increasing short-chain production (vitamin C), or increasing the abundance of short-chain producers (vitamin B2, E). These changes will further beneficially modulate the gut immune response, or barrier and neuroendocrine function, thus, influencing host health. (B) Microbiome independent effects of vitamin. Vitamins such as vitamin C and D directly improve functioning of the gut immune and barrier function via systemic effects. Such changes can further modulate the gut microbiome.

Source: Pham, Van T et al. “Vitamins, the gut microbiome and gastrointestinal health in humans.” Nutrition research (New York, N.Y.) vol. 95 (2021): 35-53. doi:10.1016/j.nutres.2021.09.001 This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Proposed effects of plant bioactives on the gut immune system

Mɸ: macrophage, TJ: tight junction, MOs: microorganisms, MUC2: mucin 2, T_reg: regulatory T-cell, Ig: immune globulin, Th17: T helper 17 cell, HBD-2: human β-defensin-2.

Source: Zimmermann C, Wagner AE. Impact of Food-Derived Bioactive Compounds on Intestinal Immunity. Biomolecules. 2021 Dec 18;11(12):1901. doi: 10.3390/biom11121901. PMID: 34944544; PMCID: PMC8699755.This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

Sustainable Mediterranean Diet

Source: Serra-Majem, Lluís et al. “Updating the Mediterranean Diet Pyramid towards Sustainability: Focus on Environmental Concerns.” International journal of environmental research and public health vol. 17,23 8758. 25 Nov. 2020, doi:10.3390/ijerph17238758 This article is an open access article distributed under the terms and conditions

Optimal Takeaways

• The gut's role extends beyond digestion to include critical immune functions.
• Dysregulation of gut immune responses can lead to serious health issues.
• The gut microbiota plays a central role in maintaining immune and epithelial homeostasis.
• Dietary components profoundly influence the composition and function of the gut microbiota.
• Optimizing diet can potentially regulate gut health and prevent or mitigate chronic diseases.

References

Pham, Van T et al. “Vitamins, the gut microbiome and gastrointestinal health in humans.” Nutrition research (New York, N.Y.) vol. 95 (2021): 35-53. doi:10.1016/j.nutres.2021.09.001

Serra-Majem, Lluís et al. “Updating the Mediterranean Diet Pyramid towards Sustainability: Focus on Environmental Concerns.” International journal of environmental research and public health vol. 17,23 8758. 25 Nov. 2020, doi:10.3390/ijerph17238758

Statovci, Donjete et al. “The Impact of Western Diet and Nutrients on the Microbiota and Immune Response at Mucosal Interfaces.” Frontiers in immunology vol. 8 838. 28 Jul. 2017, doi:10.3389/fimmu.2017.00838

Tourkochristou, Evanthia et al. “The Influence of Nutritional Factors on Immunological Outcomes.” Frontiers in immunology vol. 12 665968. 31 May. 2021, doi:10.3389/fimmu.2021.665968

Yoo, Ji Youn et al. “Gut Microbiota and Immune System Interactions.” Microorganisms vol. 8,10 1587. 15 Oct. 2020, doi:10.3390/microorganisms8101587

Zimmermann, Christian, and Anika E Wagner. “Impact of Food-Derived Bioactive Compounds on Intestinal Immunity.” Biomolecules vol. 11,12 1901. 18 Dec. 2021, doi:10.3390/biom11121901

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