Fasting, Autophagy and Gut Health: new science about intestinal stem cells

by Mike Mutzel




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Fasting & Gut Health: New Links with Autophagy

New research highlights a critical interplay between autophagy and gut health, specifically with regard to supporting the integrity of the gut barrier and preventing pathogens from inflicting damage. As you may know by now, autophagy is your cells’ recycling and reuptake process. This spring-cleaning-like process is amplified during times of stress, say during fasting or exercise and heat exposure, leading to the recycling of damaged proteins and defective mitochondria.

In our snack-every-two-hours world, the signals to initiate autophagy are muted, and this may be partly why gut health issues are so rampant. Before we dive into new details about how autophagy impacts the gut barrier, through controlling inflammation and regulating intestinal stem cell release, let’s review the switches regulating the autophagy process.

The Activators and Inhibitors of Autophagy

In the post-meal window, the enzyme mTOR increases to help your body utilize the nutrients you ate for growth and survival. With energy on board, there’s no reason to “spring clean” or scrounge up nutrients from aberrant parts of your cell. As such, nature has designed mTOR to put the brakes on autophagy.

But let’s say you eat dinner at 6:30 or 7:00 PM, go to bed at a reasonable hour and then wake up around 6:00 AM to exercise. Your muscle cells start demanding more energy in the form of ATP and mTOR’s counterpart AMPK (activated protein kinase) to both increase mTOR and kick-start the process of autophagy. Spring cleaning time!


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How Autophagy Impacts Gut Health

Genetic studies reveal that deficiency in autophagy genes compromise the gut barrier’s defense against infections by altering a key cell type within the intestinal wall (epithelium) called the Paneth cell. Because these cells release antimicrobial peptides and support intestinal stem cells, they are critical to the health and maintenance of the gut lining. As such, defects or under-functioning autophagy compromises the intestines’ ability to repair damage and recover from inflammation.

To grossly oversimplify the process, an autophagy deficiency weakens the intestines’ ability to regenerate in the following manner: imbalanced Paneth cell function, loss of antimicrobial peptides, loss of stem cell release, compromised gut barrier, inflammation and leaky gut.

Autophagy and Intestinal Stem Cells

It sounds gross, but there is just a single epithelial cell layer separating you from vomit, poop and loads of bacteria. These gut (epithelial) cells depend on continual replenishment by intestinal stem cells (ISC). Not only do defects in autophagy compromise the Paneth cell’s ability to support these ISCs, but these cells rely upon mitochondria to generate ATP. Since autophagy is essential to the maintenance of healthy mitochondria, this may be another link between autophagy imbalances and poor gut health, scientists say.

How Autophagy Enhances Gut-Barrier Function

Your single epithelial gut layer is able to simultaneously prevent vomit and poop from entering your body while allowing nutrients to be absorbed by way of tight junction proteins. If your gut cells are the bricks, tight junctions are the mortar holding adjacent cells together. A lot of people have imbalanced bricks (epithelial cells) and screwed-up mortar (tight junction proteins) caused by consuming processed foods, certain medications, alcohol and more. But new science suggests that autophagy compromises these tight junctions, further harming the mortar and increasing the porousness of your gut lining to allow inflammatory food components, bacteria, and viruses to reach the tissues below it.

Last but, but certainly not least, vitamin D deficiency is also linked with imbalances in autophagy and Paneth cell functioning.




Elisabeth G. Foerster, Tapas Mukherjee, Liliane Cabral-Fernandes, Juliana D.B. Rocha, Stephen E. Girardin & Dana J. Philpott (2021): How autophagy controls the intestinal epithelial barrier, Autophagy,

  1. There is lot of talk about how bad it is for gut to be constantly working with eating frequently every 2-3 hours, but what about eating 1-3 giant meals a day in short feeding window? Isn’t that even unhealthier?

    I personally did 16:8 with 2-3 meals a day, problem with that was that it ruined my gut health and after every meal I felt so exhausted with gut discomfort and inflammation and created bunch of digestive issues.
    It seems like some people have just gut that is better at handling small frequent meals than large infrequent meals.

    Now I am trying to space my meals more and have longer feeding window and my gut does feel much better and I am less bloated and feel more energy.
    I think time restricted feeding and 1-3 meals a day are great if you are trying to lose weight, but once you are fit and try to keep up active lifestyle it can become very harmful as was in my case because I was only losing weight and strength beyond where it was healthy, yet I spent whole day overeaten with bad digestion from large meals I had to eat in too short feeding window just to not lose 1kg a day.

    I would prefer to have just 1-3 meals a day but it seems impossible to get enough calories for me to survive without overwhelming my gut and digestion with too large portions in too short feeding window.
    Only way for me to do that is to not move whole day.

    Do you have any advice or suggestions for people like me who are very active and have fast metabolism and are already very fit but want to get benefits of autophagy but cannot squeeze all calories needed to maintain healthy bodyweight into less than 10-12h feeding window without creating gut and digestion issues?

    • Since you’re training a lot, may not need to worry so much about fasting-induced increases in autophagy–exercise is an autophagy enhancer as well.

      Might tweak window when volume decreases.

      My 2 cents,


      • Thank you for your reply, Mike.

        Could we then say that autophagy is about being periodically in energy deficit? So it really does not matter in principle whether we induce such energy deficit by limiting input (caloric restriction or fasting) or increasing output of energy (more exercise or energy expenditure)?

        Are there any differences between the two? Would one be healthier by eating less or less often or by exercising more (within healthy reason of course which will depend on the individual) or it would be same as long as energy deficit is same?

  2. How Autophagy Impacts Gut Health

    But the previous paragraph states: …” As such, defects or under-functioning autophagy compromises the intestines’ ability to repair damage and recover from inflammation.”

    How Autophagy Enhances Gut-Barrier Function

    “… But new science suggests that autophagy compromises these tight junctions, further harming the mortar and increasing the porousness of your gut lining to allow inflammatory food components, bacteria, and viruses to reach the tissues below it.”


    MY QUESTION: Does autophagy help or harm tight junctions?

    Thank you

    • Hi there,

      Based on the available data at present, autophagy helps support the function of tight junctions and thus gut barrier health.


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