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Exploring GALT

By Heather Davis, MS, RDN, LDN

Going on cell count alone, some say we may be more microbe than human. The total number of human cells in the body is around 36 trillion, whereas the human gut contains approximately 40 trillion microbes in its diverse microbiota.1,2 The gastrointestinal tract also contains the greatest number and diversity of immune cells and compartments in the body. An impressive 70% to 80% of the body’s total immune cells reside in the gut.2 Intestinal immune compartments can be generally classified in the following ways:

  1. The intestine-draining mesenteric lymph nodes (MLN); 
  2. the gut-associated lymphoid tissues (GALT); and 
  3. the intestinal lamina propria and epithelium.2 

There’s a lot going on in the gut, and it’s constantly exposed to contradictory signals. As it encounters a variety of antigens, it must be able to quickly and effectively differentiate between nonpathogenic resident bacteria and invasive pathogens. It must do this while also juggling important tasks of digestion and nutrient absorption, electrolyte exchange, and hormone metabolism.3

GALT plays a significant role in intestinal homeostasis, infection, and inflammatory disease, but it is hard to study in humans. This is due to difficulty in obtaining human intestinal tissue and a lack of protocols allowing the isolation and analysis of human GALT.2 This is why many studies on the subject have used mouse models. What do we know about how GALT works in humans? How might it influence conditions dietitians work with regularly, such as inflammatory bowel disease (IBD), celiac disease, and even cancer? How can nutrition influence the function of GALT?

What Is GALT, Exactly? 
The mucosa-associated lymphoid tissues (MALT) are collections of organized lymphoid tissues within the mucosa, which are associated with local immune responses at those mucosal surfaces. The three major regions of MALT are the bronchus-associated lymphoid tissue (BALT), nasal-associated lymphoid tissue (NALT), and GALT.4

To the naked eye, many areas of GALT resemble tiny lymph nodes. These organized lymphoid tissues can be found throughout the intestinal tract and include both multifollicular lymphoid tissues, such as Peyer's patches of the small intestine, and the many isolated lymphoid follicles (ILF) distributed along the length of the small and large intestines. The tonsils and appendix are also part of GALT.2

GALT is chronically activated by the intestinal microbiota throughout life. It also supports the development of different types of B cells, including varieties that recognize T-cell-independent carbohydrate antigens and others that reside in the spleen and can protect the lungs.3

In intestinal infections, young T cells from the blood must arrive at certain GALT and other immune sites in the gut, where they prepare to respond to antigens. Antigen-carrying dendritic cells from the intestinal mucosa are carried to the MLNs, where naïve T cells first encounter specific antigens in the gut, triggering their activation. After activation, T cells become effector cells capable of causing an immune response and combating infection.3

GALT in Chronic Disease 
In celiac disease, gluten-derived peptides will activate GALT and usher in a cascade of inflammatory havoc.5

In instances of acute intestinal inflammation, immune cell activation and cytokine production help restore intestinal homeostasis and immune balance. However, when acute intestinal inflammatory responses become chronic, the risk for IBD goes up, along with the risk for colorectal cancer (CRC).6

Dysfunction of the mucosal barrier of the intestines contributes to the development of IBD, which includes Crohn’s disease (CD) and ulcerative colitis (UC). Both CD and UC involve a chronic immune response against the intestinal microbiota with dysfunctional lymphocyte responses.2 A major component of GALT, there are an estimated 30,000 ILF in the human intestine.2 Increased numbers of lymphocytes can be found in the ILF of CD patients, but researchers don’t know the direction of causality.2 Is it the case that increased numbers of these lymphocytes are the body’s attempt to counteract inflammation in CD, or do they play a pathogenic role? It’s possibly both.

The numbers and size of visible GALT are also known to increase in UC-affected tissues. The inflamed colon of patients with UC is awash in cells and molecules associated with GALT. UC is also often preceded by appendix inflammation and removal of the appendix is correlated with a lower risk of the development of UC and less severe symptoms after disease onset. Some researchers suggest that abnormal B- and T-cell responses in GALT may contribute to the generation and continuation of pathogenic immune responses in UC. However, more research is needed to confirm these suspicions.2

People with IBD are also more likely to develop CRC. The reason for this may have to do with intestinal immune cells, including GALT, dysregulation. In intestinal immune cells, the cytoplasmic polyadenylation element binding proteins (CPEBs) control important cytokines that maintain the immune system’s equilibrium and protect against infection. CPEB4 is required for the development of GALT and is crucial for intestinal homeostasis, including mucosal barrier function.6

Inflammation may be caused by various stressors (such as an infection) but can also be a stressor itself. Stress-induced expression of CPEB4 in intestinal immune cells enables these cells to return to homeostasis and prevent acute inflammation from becoming chronic. When CPEB4 regulation falls out of balance, it becomes more difficult for intestinal cells to find their way back to homeostasis. If CPEB4 is over- or underexpressed, this can lead to chronic inflammation and disturbance of GALT. For example, CPEB4 is constantly overexpressed by inflammatory cells in patients with IBD and CRC, which encourages the formation of tumors.2

How Nutrition Impacts GALT 
Research looking at the impact of various diets on immune health is not new. Adequate nutrition, including meeting macro- and micronutrient needs, is crucial for immune function. Improper fueling to support activity levels and other types of undernutrition notoriously impair the immune system.7 Other types of dietary approaches that may activate a prolonged stress response in the body, including eating patterns promoting dysbiosis and intestinal inflammation, poor blood sugar regulation, and extended fasting, can have negative immune effects as well.8

Parenteral nutrition can also cause significant changes in the gut microbiota and induce a proinflammatory reaction in the intestines, resulting in impaired gut barrier and GALT function. Intestinal atrophy is a known risk in these settings, and one reason dietitians understand the need to limit these feeding methods when able.9

In mouse studies and regardless of water supply, 24 hours of fasting also led to gut atrophy, with notable GALT lymphocyte losses.10

Diet impacts the types and amounts of certain microbes in the gut, which may further alter the function of GALT. Carbohydrates may act both directly and indirectly (via products of microbial metabolism) to stimulate immune responses within the gut itself and systemically. The immunogenic properties of dietary carbohydrates are a very interesting ongoing area of study.11

Dietitians can use this evidence-based knowledge to help support and educate patients and clients about the far-reaching role of nutrition in immune health while appreciating that there’s still plenty we don’t yet know about the complex genetic and environmental factors influencing GALT in humans.

— Heather Davis, MS, RDN, LDN, is editor of Today’s Dietitian.

References 

  1. Hatton IA, Galbraith ED, Merleau NSC, Miettinen TP, Smith BM, Shander JA. The human cell count and size distribution. Proc Natl Acad. 2023;120(3):e2303077120. 
  2. Mörbe UM, Jørgensen PB, Fenton TM, et al. Human gut-associated lymphoid tissues (GALT); diversity, structure, and function. Mucosal Immunol. 2021;14(4):793-802. 
  3. Surd AO, Răducu C, Răducu E, Ihuț A, Munteanu C. Lamina propria and GALT: their relationship with different gastrointestinal diseases, including cancer. Gastrointest Disord. 2024;6(4):947-963. 
  4. Elmore SA. Enhanced histopathology of mucosa-associated lymphoid tissue. Toxicol Pathol. 2006;34(5):687-696. 
  5. Patt YS, Lahat A, David P, Patt C, Eyade R, Sharif K. Unraveling the immunopathological landscape of celiac disease: a comprehensive review. Int J Mol Sci. 2023;24(20):15482. 
  6. Sibilio A, Suñer C, Fernández-Alfara M. Immune translational control by CPEB4 regulates intestinal inflammation resolution and colorectal cancer development. iScience. 2022;25(2):103790. 
  7. Bourke CD, Jones KDJ, Prendergast AJ. Current understanding of innate immune cell dysfunction in childhood undernutrition. Front Immunol. 2019;10:1728. 
  8. Hassanpour H. Interaction of allostatic load with immune, inflammatory, and coagulation systems. Immunoregulation. 2023;5(2):91-100. 
  9. Covello C, Becherucci G, Di Vincenzo F, et al. Parenteral nutrition, inflammatory bowel disease, and gut barrier: an intricate plot. Nutrients. 2024;16(14):2288. 
  10. Higashizono K, Fukatsu K, Watkins A, et al. Influences of short-term fasting and carbohydrate supplementation on gut immunity and mucosal morphology in mice. JPEN J Parenter Enteral Nutr. 2019;43(4):516-524. 
  11. Qi X, Tester RF. Gut associated lymphoid tissue: carbohydrate interactions within the intestine. Bioact Carbohydr Diet Fibre. 2020;21:100210.