From fighting tumors to improving longevity: How gut microbes build a robust immune system

The educational content in this post, elaborated in collaboration with Bromatech, was independently developed and approved by the GMFH publishing team and editorial board.

A delicate balance: how gut microbes train our immune system

The immune system’s primary roles are to identify and act upon abnormal cells that may develop into cancer cells and respond to disease-causing microorganisms. Human microbiota establishes a complex ecosystem from birth that interacts intricately with our immune system. Early colonization of mucosal surfaces by commensal microbes is fundamental for the maturation of immune responses that maintain immune tolerance to foods and own tissues and eliminate pathogens and other noxious insults. Moreover, recent research highlights microbiota’s significant influence on cancer therapies, aging-related immune decline, drug metabolism, and disease prevention. Understanding these interactions opens new avenues for optimizing therapeutic strategies and enhancing overall health^1,2.

The balance between immune cells and gut microbes is central to regulating inflammatory and anti-inflammatory responses, establishing an essential immune balance for health. When this process goes wrong in early life, previously harmless gut microbiota can activate specific immune cells that cause inflammatory conditions with tissue damage, such as those observed in inflammatory bowel disease.

Harnessing microbial metabolism to fight tumors

The ways the immune system interacts with the microbial communities living in our gut are not so simple. Toll-like receptors are essential components of the innate immune response and recognize particular characteristics or components of pathogens while maintaining tolerance to commensal organisms. Additionally, microbiota-derived metabolites, such as short-chain fatty acids (SCFAs) like butyrate and propionate, play a role in supporting the immune system and helping fight harmful bacteria. These small compounds enhance the function of regulatory T cells, which control the immune response to self and foreign particles and help prevent autoimmune diseases^1-3.

In contrast to commensals, pathogenic microbes trigger stronger inflammatory responses by activating toll-like receptors and other related receptors, leading to immune dysregulation. The equilibrium between commensal and pathogenic species is therefore essential for maintaining immune balance and preventing disease².

Beyond balancing the immune system, the microbiota may play a role in improving the response to cancer therapies^4,5, including immunotherapy¹ and chemotherapy^6-9. Microbial metabolites such as SCFAs, Trimethylamine N-Oxide (TMAO), and tryptophan derivatives influence anti-tumor immune responses. SCFAs, for example, may enhance the activity of cytotoxic T cells within the tumor microenvironment, bolstering anti-tumor immunity. Conversely, metabolites like TMAO, generated in the liver after intestinal bacteria metabolize choline from foods, may foster immunosuppressive environments that facilitate tumor progression. Tryptophan metabolites, such as indole-3-lactate (ILA), indole-3-acrylic acid and indole-3-propionate (IPA), produced by the gut microbiota, promote the differentiation of anti-inflammatory macrophages and Treg cells involved in immune homeostasis, through the activation of the aryl hydrocarbon receptor (AhR)¹⁰.

Recent findings identified the enrichment of indole-3-acetic acid, a tryptophan metabolite produced by the gut microbiome, as a predictor of chemotherapy response in pancreatic adenocarcinoma¹¹. Additionally, the microbiota can modulate host immune responses during chemotherapy^6,7, suggesting potential strategies to optimize therapeutic efficacy and mitigate adverse effects through microbiota-targeted interventions. These findings need to be replicated in humans and suggest tryptophan metabolites emerge as a potential therapeutic approach to enhance the efficacy of chemotherapy in some cancers. While fecal microbiota transfers are the most studied microbiome-based intervention for enhancing responses to current cancer treatments, developing reliable microbiome-based treatments is challenging and it is likely that they will not change clinical practice in the very near future.

Could the secrets to better health lie in the microbiome?

Aging is associated with immunosenescence¹², characterized by changes in both innate and adaptive immune responses¹. This decline in immune function increases susceptibility to infections, malignancies, and other age-related diseases. Adaptive immune cells, particularly T cells, lose effectiveness, diminishing the body’s capacity to respond to infections and abnormal cells. Innate immune cells also undergo functional changes with age, potentially impairing wound healing and inflammatory control.

Unfriendly gut bacteria have been associated with early aging. These age-related changes can impact immune normal function, exacerbating the decline in immune efficacy as we age. Research suggests that a reduced microbial diversity secondary to aging may increase inflammation and weaken immune responses, further contributing to immunosenescence. It is also true that the microbiome may predict how well you age, with the gut microbiome remaining static as we age considered a marker of poor health and survival¹³.

Microbiota also plays a significant role in the prevention of diseases, acting as a form of preemptive therapy. Maintaining a balanced microbial community helps prevent colonization by pathogenic organisms, reduce inflammation, and enhance barrier functions of mucosal surfaces. Probiotics and prebiotics play an important role in regulating the functioning of the immune system response via gut microorganisms, which in turn influence the immune system. For instance, specific probiotic strains have been shown to support gut function during antibiotic use, reduce the risk of respiratory tract infections, and improve the effectiveness of seasonal influenza vaccination ^14,15. Additionally, a diet mostly based on unprocessed plant-based foods seems the best recipe to reduce the risk of obesity, diabetes, and cardiovascular diseases, while a Western-type diet is the worst in terms of increasing our vulnerability to chronic diseases¹⁶.

References

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