immune system and the gut

How does the gut immune system differentiate between friend and foe with the bacteria it encounters?

The Gut is the Body’s ‘Interface’

Your gut is one of the largest organs of your body. It acts as the interface through which your body communicates with the surroundings.

It encounters countless bacteria daily- both friends and foe. The gut seems to do an unbelievably amazing job at differentiating types of bacteria.

How does the gut achieve this mind-boggling feat? Recent research has brought to light some little-known facts about the gut immune system.

bacteria in gut

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How Does Gut Respond to Commensals (Friends) vs. Pathogens (Foes)?

The gut is home to 10*14 (Yes, 10 followed by 14 zeros!) commensal bacteria. These bacteria live inside the gut in a healthy relationship with the gut cells.

In a crowd of billions of bacteria, how does the gut differentiate between good and bacteria?

It boils down to three key factors.

# 1: Commensals Do Not Breach The Gut Barrier

The first line of gut defense against any bacterial attack is the ‘gut barrier’. Think of it as a physical wall comprising gut cells (enterocytes) and mucous (a jelly-like substance). The gut barrier is highly selective in what it lets through (1).

One way the gut differentiates a friend bacteria from a foe is how these bacteria interact with the gut barrier. Commensals peacefully live on the mucosal layer, occasionally interact with the cells, and never try to cross this physical barrier.

Pathogen bacteria attack the enterocytes and try to destroy them. They try to punch a physical hole so they can gain entry into the inner parts of the gut wall and subsequently into the bloodstream (2).

This act of destroying the integrity of the gut barrier raises alarms for the gut that the latching bacteria is a pathogen.

# 2: T-Cells Respond Differently to Commensals vs. Pathogens

T-cells are a part of your gut immune machinery that do most of the heavy lifting for killing potentially harmful bacteria. Once activated, these T-cells then differentiate into active immune cells that physically or chemically destroy the potential threat.

Any bacteria that encounter the gut cells have certain proteins on their surface called ‘antigens’. Think of antigens as the unique code for these cells. A type of gut cells called ‘antigen-presenting cells (APCs)’ function to engulf these antigens, do the initial information processing, and present them to T-cells. The signal generated from the interaction between APCs and T-cells decides whether the bacteria are commensals or if the bacteria are a potential threat.

Since commensals live inside your gut since birth, your APCs and T-cells learn to recognize them as ‘friends’ and do not ring the alarm buttons. However, if the APCs encounter an unknown bacterial antigen, they rapidly transfer the information to T-cells, who then differentiate into active cells to neutralize the threat (2).

immune system in the gut

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# 3: The Inflammatory Pathways Respond Differently to Commensals vs. Pathogens

Another way the gut responds to an attack from pathogens is to trigger certain inflammatory cascades. Here is what this means.

When a part of your body is injured or infected with bacteria, certain immune cells (including macrophages, neutrophils, and lymphocytes) sense this intrusion. As a result, they release certain chemicals called inflammatory chemicals. Think of it as a way your immune cells signal other immune cells for help and tell them about the location of the damage.

One of the major pathways triggered during the release of inflammatory chemicals is the NF-κB pathway. Once activated, the NF-κB pathway triggers the release of several pro-inflammatory chemicals that function as a signal for other cells and actively target to kill the pathogens as well.

The commensal bacteria suppress the NF-κB pathway. Once the gut immune cells recognize new antigens and physical damage to the gut barrier from pathogens, this instigates the NF-κB (3).


Q1. How does the human immune system tell the difference between healthy cells and pathogens in the body?

Ans. Cells belonging to the body contain specific markers called antigens that mark them as “self.” This tells the immune system not to attack them. When the immune system recognizes a pathogen as non-self, it attacks them with chemical defenses.

Q2. How can I boost my gut immune system?

Here are top five tips to maintain a healthy gut and immune system:

  • Hydrate and drink plenty of fluids.
  • Plan meals containing plenty of probiotics and prebiotics.
  • Limit the intake of caffeine and alcohol.
  • Get seven to eight hours of uninterrupted sleep daily.
  • De-stress, exercise and practice yoga regularly, or find other ways to relax.

Q3. Can I reboot my immune system?

A study showed that a 3-day fast could reboot the immune system and provide many additional benefits (4). These benefits include reduced inflammation, lower blood pressure, and better endurance.

Q4. How does the immune system determine which cells to attack?

To destroy the invaders, the immune system needs to recognize them first. This means the immune system needs to differentiate the non-self from the self. The immune system can make this distinction easily because all the cells have identification molecules on their surface called ‘antigens’.

Q5. How the gut bacteria boost the immune system?

According to the latest studies, gut bacteria interact with the cells of the immune system and the epithelial cells. This action balances the immune responses and protects the body from unwanted inflammation.


1. Vancamelbeke, M., & Vermeire, S. (2017). The intestinal barrier: a fundamental role in health and disease. Expert review of gastroenterology & hepatology, 11(9), 821–834.

2. Sorini, C., Cardoso, R. F., Gagliani, N., & Villablanca, E. J. (2018). Commensal Bacteria-Specific CD4+ T Cell Responses in Health and Disease. Frontiers in immunology, 9, 2667.

3. Magalhaes JG, Tattoli I, Girardin SE. (2007). The intestinal epithelial barrier: how to distinguish between the microbial flora and pathogens. Semin Immunol, 9(2):106-15. doi: 10.1016/j.smim.2006.12.006.

4. Cheng, C. W., Adams, G. B., Perin, L., Wei, M., Zhou, X., Lam, B. S., Da Sacco, S., Mirisola, M., Quinn, D. I., Dorff, T. B., Kopchick, J. J., & Longo, V. D. (2014). Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression. Cell stem cell, 14(6), 810–823.

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