Is intestinal permeability part of a regulated response to bacterial infection?

Many times here I have come across the idea that processes usually considered negative are actually perfect regulatory loops, i.e., processes that respond in a controlled way to the surrounding environment. They are not random malfunctions or mistakes of nature. They are long-tested regulatory processes.

Today we will look at intestinal permeability and the endocannabinoid system (eCB). Nowadays, no one doubts intestinal permeability anymore; that is a great success. I remember how about 20 years ago it was a topic that all professionals in the field laughed at, and only a few individuals (e.g., Dr. Natasha Campbell-McBride) tried to convince them to take a closer look, that it is very important. It took a long time, but eventually they did look into it, and intestinal permeability really began to be thoroughly studied.

This is also evidenced by the study that will be discussed today. But as usual, I will again try to bring a few of my own thoughts into this issue. It simply seems strange to me that nature would design a system to make the intestine permeable purely out of malice. Just to harm us. That does not make sense to me. So let’s take a look.

Intestinal permeability is controlled by the endocannabinoid receptor CB1 through the expression of proteins that bind intestinal epithelial cells together (Occludin, ZO-1). When you activate CB1 (e.g., using HU-210), the intestine becomes more permeable and allows endotoxins (lipopolysaccharides, LPS) from the intestine, i.e., remnants of bacterial membranes, to enter the bloodstream. I can’t help it, but this does not seem like a defect to me. It is an integrated part of a system. What system? Perhaps a system for detecting bacterial infection?

The body is used to bacteria. There are plenty of them everywhere — in the intestines, on the skin, on mucous membranes, in the oral cavity, etc. They perform useful work there. But sometimes a species overgrows in a place where it should not be. How does the body find out?

When a bacterial infection occurs, dead bacteria leave behind traces in the form of lipopolysaccharide molecules (LPS, endotoxin). These are detected by TLR-4 receptors and trigger an immune response. A common response is the activation of lipolysis in adipose tissue.

But how is it ensured that this system does not respond to false signals, to normal concentrations of bacteria, for example after a meal? Every meal increases the level of LPS in the blood; that is normal. However, if we are eating, the detection system needs to be switched off. How is that done?

I think insulin does it — it suppresses lipolysis and along with it suppresses signaling via AEA molecules. If insulin stops working, we have a problem.

So we arrive at the conclusion that during a bacterial infection, free fatty acids are released from lipid droplets in fat cells, along with glycerol and also signaling molecules indicating inflammatory lipolysis, specifically anandamide (AEA). Because such an amount of FFAs cannot be burned, free fatty acids in the blood plasma increase, which activates PPARα in the liver, as we saw in the previous post. These free fatty acids must be re-esterified into triglycerides and exported from the liver in the form of VLDL lipoprotein particles, and activation of PPARα does this well. However, it is also necessary that together with PPARα, the enzyme PC is activated, fat beta-oxidation must function, and the level of acetyl-CoA must increase.

Here I will allow myself to formulate a small hypothesis. I think that the release of VLDL particles is precisely the goal of this program. Lipoprotein particles have an immune function—they intercept chemical communication between bacteria. In this way, they prevent bacteria from coordinating whether there are enough of them to attack or whether they should remain inactive. The environment thus appears much less populated by their fighters, and they do not dare to initiate an attack. Quite a clever strategy.

As we can see, activation of PPARα not only increases the production of VLDL particles, through which free fatty acids are removed from the blood, but also reduces the levels of AEA signaling molecules.

Therefore, if for some reason the export of triglycerides from the liver in the form of VLDL particles does not function, AEA will not be removed either. This means that the AEA signal can then activate something other than hepatic PPARα, for example endocannabinoid CB1 receptors in the colon. As we have already seen, this allows more LPS into the bloodstream.

I think this system is primarily designed to amplify the immune effect described above during bacterial infection. In this way, the liver is more easily “persuaded” to perform the required activity, to express PPARα. It is simply a positive feedback loop enhancing the effect in defense against bacterial infection. That is how it seems to me; it makes sense to me.

So far it all looks elegant and cleverly designed by nature. But what happens when the liver refuses to produce triglycerides and VLDL? Then the levels of free fatty acids and the amount of AEA signaling molecules in the blood increase, leading to activation of fat storage and differentiation of new fat cells (HU). In addition, increased intestinal permeability is also activated, apparently to support storage even more effectively. That is probably not what we want, even though easy fat storage improves blood markers.

What can we do about it?

If we suppress the function of CB1 receptors (Ob-SR), we see that mice do not gain weight as quickly. But this is not only due to appetite suppression. Controlling appetite via CB1 receptors is only temporary and does not have a lasting effect.

The main effect is the suppression of intestinal permeability. The third group (Ob-PF, pair fed) received the same amount of food as Ob-SR, but the percentage of fat remained at the level of the control group (Ob-CT). Thus, weight gain is caused by increased intestinal permeability.

Let us repeat what the cause was. It was insufficient activation of processes associated with PPARα activation. It may involve post-translational modification of enzymes, e.g., missing S-sulfhydration of the PC enzyme and sirtuins, or conversely excessive acetylation of enzymes. We know that sometimes the process of fat storage can be stopped by higher activation of PPARα, see for example in this study using fenofibrate (FBR).

I would stick with already identified options. Higher PC activity can be supported by higher levels of acetyl-CoA molecules, i.e., by vinegar and MCT oil.