From birth to old age, the gut microbiota play a significant role in our immune system’s maturation, function and regulation. Trillions of bacteria, viruses, fungi, and parasites co-evolve in relationship with our immune system participating in defensive responses to potential antigens.^3,12

Probiotics can influence the gut microbiota, affecting their composition, structure and metabolites. They also share many of the same functions as our microbiota, with their ability to affect immune function.^8,11,12

Probiotics are defined by The Food and Agriculture Organization/World Health Organization (FAO/WHO) Working Committee on Probiotics as “live microorganisms which when administered in adequate amounts confer health benefits on the host.” ¹⁰

Preclinical and clinical trials show activation and modulation of multiple immune and inflammatory mechanisms by probiotic bacteria, enhancing the function of the mucosal and systemic immune systems.^4,8           

The intestinal mucosal immune system          

The gut has evolved a complex and effective mucosal immune system that provides structural, chemical and immunologic barriers to antigens in the lumen.

Gut microbiota and probiotics closely interact with the gut mucosa and its associated immune structures and functions, known as the intestinal mucosal immune system (IMIS).

The IMIS consists of 3 primary parts:^1,8,11,16

1. Intestinal epithelial barrier
2. Lamina propria
3. Gut-associated lymphoid tissue (GALT)

The complex interplay between these three zones, our gut microbiota and supplemental probiotics generates immune effects locally and systemically.

Intestinal epithelium: the gatekeeper             

The complex environment within the gut presents our body’s immune system with continuous challenges. The space of the lumen is functionally outside the body. A fine line of intestinal epithelial cells (IECs) separating us from potential antigens, supplied by:^1,12

• Food and other ingested substances
• Commensal microbiota
• Pathogenic microbiota
• Environmental xenobiotics

The IECs and associated tight junctions, covered with mucous, are the interface between the outside and inside of our bodies. This fine line of cells is a sensory interface, a site of communication between the contents of the lumen and lamina propria/GALT.⁸

The maintenance of epithelial integrity is essential for health. Damage increases permeability and allows excessive bacteria, bacterial fragments, and products to pass from the lumen to adjacent tissue.^5,15

Intestinal barrier dysfunction can trigger systemic inflammation and tissue damage. Inflammatory chronic diseases are associated with barrier impairment, including allergy, autoimmune diseases, inflammatory bowel diseases, irritable bowel syndrome, neurodegenerative diseases, and metabolic diseases.^4,5  

Key actions of probiotics suggested by preclinical and clinical studies

The lumen ^1,6,8,9,10

• Competitive exclusion of pathogenic microbes through the occupation of adhesion sites on the mucosa and competing for nutritional sources.

• Direct antibacterial and anti-viral effects through secretion of organic acids, hydrogen peroxide and bacteriocins.

• Release of substantial quantities of short-chain fatty acids, inducing significant anti-inflammatory activity, strengthening epithelial tight junctions, and regulating Paneth cells. 

The epithelium^{1,5,6,9,10,15}

• Internalisation and transport of probiotic antigenic fragments triggering a complex sequence of signals, primarily stimulating innate immune cells in the lamina propria and GALT

• Stimulation of Paneth cell production, enhancing the secretion of a variety of antimicrobial peptides such as lysozyme and defensins.

• Enhancement of mucosal layer integrity through stimulating the synthesis and function of tight junction proteins,  enhancing the function of mucous-producing goblet cells, and suppressing apoptosis of IECs.
  
  

Lamina propria & GALT ^{1,5,6,8,9,10,15}

• Antigenic fragments of probiotic bacteria are internalised by and pass through IECs and M cells on the surface of Peyer’s patches. This antigenic material is then processed and presented to components of the innate and acquired immune systems in the lamina propria and GALT, triggering complex signalling pathways resulting in:

• Stimulation of innate immune cell function, including phagocytosis and natural killer cell activity.

• Dendritic cells, macrophages and monocytes acting as antigen-presenting cells, signalling to the acquired immune system.

• Inhibition of pro-inflammatory pathways, most notably the nuclear factor kappa-B pathway, resulting in the reduced expression of inflammatory cytokines and suppression of inflammation.

• Upregulation of immunoglobulin A (IgA) synthesis and distribution. Through “immune exclusion”, IgA blocks pathogenic bacteria and toxins and aids dendritic cells in sampling the contents of the lumen.

• Activation of regulatory T cells, initiating further immune effects promoting intestinal immune tolerance, triggering the release of anti-inflammatory cytokine interleukin-10.

• Inhibiting mast cell degranulation, balancing TH1/TH2 cytokine production that supports the production of IgG instead of IgE.

Probiotics and systemic immunity

Preclinical and clinical studies suggest that probiotics influence immunity systemically.

As discussed, oral supplementation of probiotics stimulates the production of IgA synthesis and distribution in the intestinal mucosal immune system. This effect is also observed distally in the bronchus and mammary glands.⁸

Researchers postulate that cytokines and T cells drain from the GALT into the blood. From the blood, they move into the liver and spleen and ultimately regulate systemic immune responses.¹⁵      

Restoring resilience with probiotics    

The hallmark of a healthy microbiome and associated immune processes is resilience. In response to disruption, such as antibiotic therapy or pathogenic bacteria, it should have the capacity to recover.⁴

Multiple and ongoing stressors, such as a western-style diet, can erode our microbiome and IMIS resilience – resulting in dysbiosis, intestinal barrier dysfunction, and systemic effects.⁴ Probiotic supplementation is emerging as a key therapy for treating intestinal and systemic immune dysfunction and its health effects, helping to rebuild health and resilience.

REFERENCES

1. Ashaolu, T.J. (2020). Immune boosting functional foods and their mechanisms: A critical evaluation of probiotics and prebiotics. Biomedicine & Pharmacotherapy, 130, p.110625. doi:10.1016/j.biopha.2020.110625.

2. Azad, MdAK, Sarker, M, Li, T & Yin, J 2018, ‘Probiotic Species in the Modulation of Gut Microbiota: An Overview’, BioMed Research International, vol. 2018, pp. 1–8.

3. Bosco, N & Noti, M 2021, ‘The aging gut microbiome and its impact on host immunity’, Genes & Immunity.

4. Cristofori, F, Dargenio, VN, Dargenio, C, Miniello, VL, Barone, M & Francavilla, R 2021, ‘Anti-Inflammatory and Immunomodulatory Effects of Probiotics in Gut Inflammation: A Door to the Body’, Frontiers in Immunology, vol. 12.

5. Di Tommaso, N, Gasbarrini, A & Ponziani, FR 2021, ‘Intestinal Barrier in Human Health and Disease’, International Journal of Environmental Research and Public Health, vol. 18, no. 23, p. 12836.

6. Eslami, M, Bahar, A, Keikha, M, Karbalaei, M, Kobyliak, NM & Yousefi, B 2020, ‘Probiotics function and modulation of the immune system in allergic diseases’, Allergologia et Immunopathologia, vol. 48, no. 6, pp. 771–788.

7. Kwoji, ID, Aiyegoro, OA, Okpeku, M & Adeleke, MA 2021, ‘Multi-Strain Probiotics: Synergy among Isolates Enhances Biological Activities’, Biology, vol. 10, no. 4, p. 322.

8. Maldonado Galdeano, C, Cazorla, S, Lemme Dumit, J, Vélez, E & Perdigón, G 2019, ‘Beneficial Effects of Probiotic Consumption on the Immune System’, Annals of Nutrition and Metabolism, vol. 74, no. 2, pp. 115–124.

9. Quigley, EMM 2019, ‘Prebiotics and Probiotics in Digestive Health’, Clinical Gastroenterology and Hepatology, vol. 17, no. 2, pp. 333–344.

10. Sanders, M.E., Merenstein, D.J., Reid, G., Gibson, G.R. and Rastall, R.A. (2019). Probiotics and prebiotics in intestinal health and disease: from biology to the clinic. Nature Reviews Gastroenterology & Hepatology, [online] 16. doi:10.1038/s41575-019-0173-3.

11. Shi, N, Li, N, Duan, X & Niu, H 2017, ‘Interaction between the gut microbiome and mucosal immune system’, Military Medical Research, vol. 4, no. 1.

12. Wang, X, Zhang, P & Zhang, X 2021, ‘Probiotics Regulate Gut Microbiota: An Effective Method to Improve Immunity’, Molecules, vol. 26, no. 19, p. 6076.

13. Wu, D, Lewis, ED, Pae, M & Meydani, SN 2019, ‘Nutritional Modulation of Immune Function: Analysis of Evidence, Mechanisms, and Clinical Relevance’, Frontiers in Immunology, vol. 9.

14. Yadav, MK, Kumari, I, Singh, B, Sharma, KK & Tiwari, SK 2022, ‘Probiotics, prebiotics and synbiotics: Safe options for next-generation therapeutics’, Applied Microbiology and Biotechnology, vol. 106, no. 2, pp. 505–521.

15. Yousefi, B, Eslami, M, Ghasemian, A, Kokhaei, P, Salek Farrokhi, A & Darabi, N 2018, ‘Probiotics importance and their immunomodulatory properties’, Journal of Cellular Physiology, vol. 234, no. 6, pp. 8008–8018.

16. Zhang, C, Wang, H & Chen, T 2019, ‘Interactions between Intestinal Microflora/Probiotics and the Immune System’, BioMed Research International, vol. 2019.