“Intelligence is not the ability to store information, but to know where to find it.”
— Albert Einstein
There is increasing evidence for a vibrant and bidirectional exchange of information between the brain, the gut, and other organs, including diffusely organized systems like the immune system. The discussion extends beyond just what we eat to how and when we eat; this emerging discipline of chrononutrition has been touched upon in previous columns. But in some respects, none of this is new. For well over a century, various types of fasting, e.g., short-term fasting, intermittent fasting, and caloric restriction, have been reported to extend the lifespan and enhance tissue regeneration in various species, including humans. Of particular interest is the fact that some fasting regimens have been observed to inhibit tumor growth [1].
When we eat, the intestinal epithelium, the lining of our gut, rapidly acquires information from its immediate environment, which includes, among other things, what we choose to eat. These cells, which include intestinal stem cells (ISCs) and immune system cells, can then dynamically respond and affect changes to local and systemic physiology. These cells, in turn, are partially regulated by their microenvironment, which includes our diet and gut microbiota. But even when we don’t eat, when we are fasting (like every night when we sleep, which gives us the term breakfast where we “break” the fast of the night before) our gut is busy processing the empty space. It is an interconnected Lion King-esque Circle of Life.
And like a circle, where does it begin and where does it end? And what of those betwixt and between times, say when we have not eaten for a while and we begin to gnaw anew, like when we break a fast? Is it a different space than the everyday meal breaks? Using a murine model, this week’s study examined how the body responds to such a post-fast meal.
- The study used a mouse intestinal model.
- It has been previously shown that acute 24-hour fasting directly improves intestinal stem cell (ISC) function.
- It has also been previously shown that long-term, 40% reduced energy intake indirectly augments ISC function by suppressing certain functions and other cells (Paneth cell niche mTORC1 signaling).
- This study focused on what happens after fasting or the post-fast refeeding response.
- The mice were subjected to the following dietary conditions:
- Ad libitum: free access to food anytimeFasted: deprived of food for 24 hours
- Refed: free access to food following a 24-hour fast
- The refed group was subdivided into access for one day or three days.
- The researchers found that refeeding post-fast augmented intestinal stem cell-mediated regeneration after injury but also increased tumorigenicity.
- Tumorigenicity refers to the capacity or ability to form or induce tumors; it describes how likely something is to cause the development of tumors.
The Caveat:
This murine study demonstrated that intestinal cells continually acquire information and respond to their environment. When no food is present, particularly for a prolonged time, such as during a 24-hour fast, the system is not asleep and unresponsive. In fact, a unique series of cellular programs is executed.
After we break a prolonged fast, such as the 24 hours used in this study (again, this was a mouse study, so this is hypothetical extrapolation and inference but a reasonable hypothesis), the intestinal cells respond to what we eat with “a unique cellular program distinct from both fasting and ad libitum feeding.”
This unique program enhances particular characteristics of intestinal stem cells, such as:
- Self-Renewal: ISCs can divide and produce more stem cells, ensuring a continuous supply of cells that can maintain the stem cell population over our lifetime. This self-renewal is critical for the long-term maintenance of the intestinal epithelium, one of the body’s most rapidly renewing tissues.
- Multipotency: ISCs are multipotent, meaning they can differentiate into the multiple cell types that comprise the intestinal lining, including absorptive enterocytes, goblet cells (mucus-secreting), Paneth cells (immune function), and enteroendocrine cells (hormone-secreting). This diversity of cell types is essential for the proper function of the intestinal epithelium, including nutrient absorption, barrier function, and immune defense.
- Quiescence: Sometimes ISCs exist in a quiescent (inactive) state, dividing only occasionally. These cells serve as a reserve pool that can be activated in response to injury or other physiological needs, providing additional protection and regenerative capacity.
- High Proliferative Capacity: ISCs can increase in number rapidly, especially in response to damage or stress. This rapid proliferation is necessary to replace the intestinal lining, which undergoes constant turnover every few days.
- Niche Dependence: ISCs are regulated by their microenvironment, known as the stem cell niche. This niche provides signals that maintain and control the balance between self-renewal (more stem cells) and differentiation (more different and specialized cells). The niche ensures ISCs function correctly and respond appropriately to our body’s needs.
- Response to Signals: Signaling pathways transmit information that promotes ISC proliferation and maintenance of the stem cell state or regulates the differentiation of ISCs into specific cell lineages within the intestinal epithelium.
- Plasticity: ISCs exhibit plasticity, meaning they can adapt and change their behavior in response to injury, environmental changes, or other information. This plasticity allows the intestinal epithelium to regenerate effectively after injury, with ISCs capable of re-entering the cell cycle and producing the necessary differentiated cells to restore the tissue.
Collectively, these properties are known as stemness attributes. This study reinforced the evidence that highlights how our gut constantly collects information, responds to it, and distributes it to the brain and other organ systems. Even when we think it is doing nothing, like when we’re fasting, our guts are reacting to that information with a particular sequence. It is a system so finely tuned that it even knows the difference between a regular meal (ad libitum) and when we haven’t eaten something for a while (post-fast refeeding). We are all equipped with a powerful AI; appetite intelligence!
[1] (Nencioni, 2018)
The Study:
Additional resources:
