How the Gut Modulates the Development of Inflammation

By Wayne Persky

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Recent studies reveal enlightening insights into the interaction between gut health and systemic inflammatory conditions. Researchers at the Centro Nacional de Investigaciones Cardiovasculares (CNIC) in Madrid, Spain have discovered how disruptions to the intestinal barrier allow gut bacteria to trigger epigenetic changes in immune stem cells, resulting in both enhanced infection resistance and exacerbation of inflammatory diseases (Robles-Vera, et al., 2025).1 These findings significantly improve our understanding of the gut-immune system axis and its implications for health.​

The researchers found that:

1. Damage to the intestinal barrier allows Enterococcus faecalis (a common gut bacterium), to translocate to the bone marrow.
2. There, the bacteria interact with the receptor protein Mincle (Clec4e) in cells known as hematopoietic progenitors (immature blood cells that can differentiate into various types of mature blood cells like red blood cells, platelets, and white blood cells), inducing epigenetic modifications in the way immune cells are trained.
3. Trained immunity enables macrophages and other innate immune cells to respond more robustly to future infections, marking a significant shift from the traditional view that only adaptive immunity possesses memory.

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Mincle (also known as Clec4e or Clecsf9), is a type of receptor protein found on the surface of immune cells such as macrophages and dendritic cells, for example. It's a C-type lectin receptor, meaning that it binds to carbohydrates. Mincle is an innate immune receptor on myeloid cells (immature white blood cells that originate in the bone marrow). It senses molecular patterns associated with pathogens, and molecular patterns associated with damage, (molecules associated with pathogens or damaged cells). Mincle's activation triggers the release of cytokines and other immune molecules that help mediate the immune response. 

But they also found that:

While trained immunity enhances protection against bacterial, viral, and fungal infections, it also exacerbates inflammatory conditions such as:
​

• Colitis (as shown in animal models with heightened gut permeability).
• Cardiovascular diseases, such as atherosclerosis.
• Neurodegenerative diseases, linked to systemic inflammation.
• ​The inflammatory response is dependent on Mincle, as mice lacking this receptor showed reduced inflammation and pathology.

It's well-known that:

Poor diet, chronic stress, alcohol consumption, and certain medications can weaken the gut barrier, promoting bacterial translocation and systemic inflammation.

And other research shows that:

A healthy diet can maintain a healthy gut microbiota, reducing inflammation and mitigating chronic disease risks.

The implications of this discovery suggest that:

Blocking Mincle could be a promising strategy to prevent or reduce inflammation in diseases associated with gut permeability, such as colitis and cardiovascular conditions. The discovery that innate immunity can be trained redefines its role in health and disease. This finding opens avenues for novel treatments that utilize trained immunity, and underscores the far-reaching influence of gut health on systemic diseases, emphasizing the importance of a holistic approach to managing chronic conditions.

In the meantime, our best strategy for maintaining gut health primarily depends on maintaining gut barrier integrity, and this can be achieved by:

• Totally avoiding the foods, supplements, and medications that cause us to react
  
• Avoiding excessive alcohol or processed foods that contain undesirable ingredients.
  
• Managing stress.

Conclusions:

This research highlights the delicate balance of the gut-immune axis. While trained immunity provides robust protection against infections, it comes at the cost of heightened inflammatory responses. Understanding this duality could lead to innovative treatments for inflammatory diseases, with lifestyle modifications playing a critical role in prevention. These findings emphasize the importance of gut health as a cornerstone of systemic well-being.

Reference:

1. Robles-Vera, I., Jarit-Cabanillas, A., Brandi, P., Martínez-López, M.,Martínez-Cano, S., Rodrigo-Tapias, M., . . . Sancho, D. (2025). Microbiota translocation following intestinal barrier disruption promotes Mincle-mediated training of myeloid progenitors in the bone marrow. Cell Immunity, Retrieved from https://www.cell.com/immunity/fulltext/S1074-7613(24)00577-6