Leaky gut syndrome and the big factor that reinforces it

Leaky gut syndrome, or intestinal permeability, is a condition which has only gained mainstream acceptance over the last decade.  Once restricted to the realm of charlatans, it’s become readily apparent that leaky gut syndrome exists And it may predispose us to a range of health issues such as:

  • Cardiovascular disease
  • Type 2 diabetes
  • Fibromyalgia
  • Functional gastrointestinal disorders (IBS, IBD, SIBO, & Celiac disease)

It’s not entirely clear what the primary driver is, and in most people it probably varies.  We know that inflammation can cause leaky gut but that leaky gut can also cause inflammation.  It’s sort of a chicken and egg thing.

A lot of people have taken to restrictive diets, eliminating things ranging from gluten to FODMAPs to lectins, in the hopes of curing their digestive ills and preventing or reversing leaky gut.  Unfortunately there’s a pretty big driver of leaky gut that functions as sort of a feed forward loop where leaky gut probably promotes it, and it promotes leaky gut.

What I’m talking about is excess adipose tissue. And you don’t have to be obese to experience this amplification. Where you accumulate fat tissue is just as important as how much you have. In fact, it may be more important.

But that doesn’t mean obesity is benign, it’s not. Obese people typically have more of this fat, so they’re typically more affected and have higher levels of intestinal permeability. All fat matters, and we’ll discuss the most important type of fat towards the end.

Leaky gut syndrome

Leaky gut syndrome and obesity

A recent review discusses how leaky gut and obesity feed in to one another. In other words, leaky gut can promote obesity while obesity can promote leaky gut.  According to the review, leaky gut induces a chronic state of inflammation which causes increased inflammation in fat tissue.

As fat tissue becomes more inflamed, the inflammation seeps out in to the bloodstream and eventually makes it back to the gut.  This increases leaky gut and feeds forward back to the fat tissue, developing a vicious cycle.  Understanding this gives you a clear indication as to why you need to address both to resolve leaky gut.

So let’s dig a little deeper into this relationship

Leaky gut causes an inflammatory cascade

Let’s start with leaky gut.  As a consequence of leaky gut, endotoxin from the bacteria that live in our gut, leaks in to the bloodstream.  Lipopolysaccharide(LPS), one of these components found in gram-negative bacteria, is highly inflammatory.  In fact, it’s the most common method to induce systemic inflammation in animal models.

When LPS leaks in to the bloodstream, it causes system-wide inflammation.  But how does it do this?  Cells of the immune system called macrophages keep the peace inside the body. They do this by promoting or inhibiting inflammation and consuming microbes and damaged tissue.  Macrophages exist in 3 states, but we’ll focus on 2 of them: M1 and M2.

In the M1 state, macrophages cause inflammation and gobble up invaders and damaged tissue.  In the M2 state, macrophages resolve inflammation and repair damaged tissue.  Health and the inflammatory state of your body involves a delicate balance between the 2 states. Ideally, they remain in an M2 state for most of the time, and convert to the M1 state when invaded or damaged.

When LPS enters the body via the gut, macrophages stay in the M1 state and chronic inflammation ensues.  Adipose tissue is particularly affected as M1 macrophages accumulate.  But it gets worse. When they remain in an M1 state, damage accumulates and never fixed.  A perpetual loop of inflammation and damage ensues.

Obesity amplifies the signal

Most people view fat as a storage tissue, but it’s actually an endocrine organ due to the hormones and signaling molecules that it secretes.  The fat of obese and lean people differs quite a bit. Obese people have more macrophages and a higher proportion of M1 to M2 macrophages in their fat tissue than lean people.

With a higher proportion of M1 macrophages, the fat tissue of obese people acts essentially like an inflammation factory.  As this inflammation leaves the fat cell it, can circulate back to the gut and cause leaky gut.  When more LPS makes it from the gut to the fat tissue, it amplifies this response and the cycle continues.

The maintenance of macrophages in the M1 state by LPS is partially due to a protein called CD38.  CD38 is an inflammatory protein used to differentiate between M1 and M2 macrophages.  When activated, it promotes the conversion to M1 macrophages. Blocking CD38 prevents the LPS-induced conversion of macrophages to the M1 state.

CD38 also has another effect: it’s a marker of the generation of new fat cells.  But one of the most important effects of CD38 has to do with what it consumes: NAD+.  NAD+ is one part of the metabolic arm of the circadian clock, and as we age our NAD+ levels decline. CD38 appears to be the primary driver of age-related NAD+ decline and blocking it prevents this effect and the metabolic dysfunction that comes with it.

This is at least partially due to macrophage circadian disruption.

Circadian disruption amplifies the signal even more

LPS disrupts the circadian rhythms of macrophages.  This forces them in to a pro-inflammatory state due to excessive oxidative stress.  As mentioned, health and the inflammatory state are determined by a delicate balance between macrophages being primarily in an M2 state and entering an M1 state at the proper time.

Circadian disruption in macrophages skews them towards an M1 state chronically.  This will amplify the signal even further.  Evidence in mice indicates that circadian disruption via night shift potentiates the high fat diet induced accumulation of fat tissue, the skewing of macrophages to the M1 state, and the infiltration of these macrophages to the fat tissue.

But we’re not done.  Circadian disruption causes mice to become more prone to leaky gut by altering their microbiome.  There’s an enrichment in bacteria that decrease gut integrity and a loss of bacteria that help maintain it. As a result the mice are more susceptible to leaky gut syndrome.  A study in humans found the same effect in people working night shift. They’re more prone to alcohol induced leaky gut than people who work the day shift.

It’s clear that getting a handle on leaky gut involves a lot more than just avoiding dairy and gluten.  In fact, it goes well beyond diet in general, and being obese will simply amplify the signal and cause you to enter a vicious cycle that never resolves.  That’s not to say that one needs to be overweight or obese to experience this, but it dramatically increases their chances and magnitude of the problem.

Mesenteric fat: amplifier of leaky gut

While total fat mass is important, the location of the fat also plays a crucial role. We typically break fat in to 2 categories: subcutaneous fat(SAT) and visceral fat(VAT). SAT, while unsightly, presents fewer metabolic issues than VAT. SAT is found just under the skin.

VAT, on the other hand, is underneath our muscle and surrounds our organs. It is predominantly found in the abdomen, and mesenteric fat is a subcategory of VAT. Mesenteric fat surrounds our organs of digestion, in fact, it directly borders them.

Image source

Under normal circumstances, the mesenteric fat acts as a second barrier against bacteria that may pass through the intestine. Under these conditions, the mesenteric fat increases inflammatory cytokines to draw immune cells to the area. These immune cells help clean up the mess.

But under chronic overfeeding, the mesenteric fat tissue expands. It also remains enriched with macrophages that are primed to the M1 state. So chronic leaky gut increases mesenteric fat and increased mesenteric fat reinforces leaky gut.


Efforts to correct leaky gut syndrome often fail, and part of the problem is that correcting leaky gut requires a lot more than a handful of supplements and a restrictive diet.  When push comes to shove, our behavior likely plays a much larger role in how well our gut functions, including how “leaky” it is.

Part of this is due to physiological changes that occur in the fat cell that help amplify the inflammatory signal. And part of it is driven by the fact that many of the behaviors that drive obesity are horrible for your gut.  This includes inactivity, eating too much, poor sleep, circadian disruption, and eating late at night.

Fortunately, correcting these behaviors not only helps support a healthy gut, they also tend to reverse obesity.  Thus, modifying behavior and reducing overweight and obesity may yield the greatest benefit in reversing and preventing leaky gut syndrome.

But don’t think that because you’re not overweight you’re in the clear. Mesenteric fat is ultimately the worst type of fat to have given its proximity to the gut. So even if you’re lean, high levels of mesenteric fat are still problematic.

Reducing this depot via the above lifestyle factors goes a long way in improving this condition.


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