New study indicates “leaky gut” precedes inflammation in the gut

A new study published last week found that in the dextran sodium sulfate(DSS)-induced model of colitis, the gut becomes leaky prior to the inflammatory process.  Furthermore, introduction of probiotics either improved or worsened the situation depending on when they were introduced.  While there’s quite a bit to take from this study, it’s important to identify what they were researching and how we can apply that model to our individual circumstances.  So let’s dig in.

Study Background

First and foremost, how was this study carried out and why was it done this way?  The study was designed as a gut-on-a-chip model.  These models are very useful in identifying things like the order of events that lead to pathology when the mechanisms involved are numerous and impossible to tease out in human or animal models.  In other words, we can’t determine the order of sequence in the DSS-induced mouse model of colitis so we need a model where we can have more control over the conditions and monitor pathology as it unfolds.

The DSS-induced colitis model is a very useful mouse model of colitis that’s very similar to what we see in human colitis.  However, we have to be careful with what we’re applying this data to.  The DSS-induced colitis model is useful for colitis, but not for things like IBS and SIBO.  It’s ok for looking at the general inflammatory process in the gut, but there are many ways to get to gut inflammation without DSS-induced colitis, so I’d stick to this being a decent model for colitis.

The Findings

The findings of the study were very interesting.  Even though leaky gut and inflammation are associated with one another, it’s useful to determine which came first.  So in this chicken and egg scenario, the researchers found that leaky gut preceded intestinal inflammation in the DSS-induced colitis model.  When DSS was applied to the model, there was an increase in intestinal permeability with no immediate change in inflammation.

Once the intestinal barrier was breached, immune cells on the systemic side of the gut called peripheral blood mononuclear cells(PBMCs) were able to interact with bacterial components in the gut to cause inflammation.  This model used non-pathogenic E. coli and lipopolysaccharide(LPS) to achieve this result.  So, what we can take from this is that in order to get to colitis in the DSS model, you need a loss of intestinal permeability, the presence of PBMCs, and their interaction with some bacterial components that cause inflammation.  Losing any of these factors did not lead to inflammation.

But they didn’t stop there.  The researchers wanted to look at the effect of beneficial bacterial strains in this model.  So they took a commonly used probiotic, VSL #3, and introduced it prior to and after treatment with DSS.  They found that adding VSL #3 prior to DSS protected against leaky gut but introducing it after DSS actually caused greater inflammation.  This jibes with the data that probiotics can be problematic in people with active colitis.

These results were very interesting, but what can you really take from them?  I got a million questions so let’s go through the practical significance of this study.

Takeaways from the study

Probably one of the biggest things I took from this study is further reinforcement on the idea that many gut issues are mediated by lifestyle.  A previous study I discussed showed that inducing hyperglycemia in mice causes leaky gut and, in humans, systemic circulation of microbial products from the gut correlates to glycemic control as determined by HgA1c.

Certainly bad news for Type 2 diabetics, but if this mouse model is indicative of what we see in human colitis, this can be a problem for healthy people under the proper conditions as well.  A study in humans found that alcohol caused greater intestinal permeability in the lower gut of night workers than those working during the day.

And you don’t need to work the night shift to experience circadian disruption.  In his book the Circadian Code, Dr. Satchin Panda states that most of us are under something termed “social jet lag”, where our circadian rhythms are disrupted simply because we stay up too late, eat too late, or get exposed to lights at the wrong hours of the day.  Intestinal permeability follows a circadian rhythm, so eating at the wrong time is no bueno too.  There’s an entire review on the topic you can read here.

Poor sleep on its own can get you there as well.  Surely circadian disruption can cause poor sleep, but just 2 nights of poor sleep can cause poor glucose tolerance the following morning.  And since we’re dealing with blood glucose control, physical inactivity is another huge variable to look at here.  I can easily push my post-meal blood glucose out of a healthy range if I choose the proper foods under sedentary conditions.  Glycemic control is a highly dynamic process, and knowing it can cause intestinal permeability and gut inflammation has certainly changed my behavior.

Spore-based probiotics-Yea or nay

This has to be the most frequently asked question I received after posting this study to Facebook so I feel I should address it.  Does the data here showing probiotics to be detrimental during an inflammatory flare hold for spore-based probiotics.  In a word, yes.

I know that studies have shown the spore-based probiotics to be useful for inhibiting inflammation, but we really don’t know how they do this.  The strains in VSL #3 also inhibit inflammation, but when introduced in to a leaky gut, they promoted inflammation.

Many of you may posit that the spore-basd probiotics work by preventing leaky gut, but the one study published regarding this topic didn’t show that they prevented leaky gut.  It showed that Megasporebiotic reduced bacterial endotoxin burden in the blood and reduced triglycerides in “responders”.

Bacterial endotoxin is known to hop a ride on chylomicrons and get absorbed along with fat from a meal.  This effect has nothing to do with leaky gut, and in the Megaspore study endotoxin levels were measured after a high fat meal, so it’s likely this played a major role in the postmeal serum endotoxin increase.  This is more pronounced in obese men than lean men, but it only led to endotoxemia in the obese men.

Based on the subject characteristics in the Megaspore study, if the subjects were men they were obese(Bodyfat=25.2% in the probiotic group), but the write-up didn’t indicate gender in the study group.  That’s not to say that these results aren’t impressive, decreasing serum endotoxin and triglyceride levels in obese people is tremendous.  But whether it has anything to do with leaky gut or applies to lean individuals is not a leap I’d be willing to take.

As far as I can tell, “responders” can simply be obese or Type 2 diabetic people who make more chylomicrons with a high fat meal.  I look forward to the new data they have coming out to potentially shed some light on the mechanism behind Megaspore, as I’ve heard many swear by it.

All that being said, this model pertains to colitis and so my recommendation would be specific to those individuals.  If I had colitis, I wouldn’t take any form of probiotic if there is evidence of leaky gut, certainly not during a flare.

Conclusion

So what would I do based off this study?

  • If you are Type 2 diabetic, fix it
  • If you are overweight or obese, fix that too
  • If you eat late at night, stop
  • If you follow a keto diet, don’t deviate

It seems apparent to me that if the DSS-induce colitis mouse model is a good representation of human colitis, human colitis may follow the same pattern where leaky gut precedes inflammation.  As such, things that promote leaky gut such as hyperglycemia would be things I would strive avoid.

None of these things in the above list are difficult to do from a conceptual standpoint, most of the issues come with people being compliant.  But if you keep in mind that anything that leads to hyperglycemia coupled with poor insulin signaling can lead to leaky gut based on the recent data, eliminating these issues should be where you start.  Taking probiotics is waaaaaaaay further down the road.

This has been a focal point of my Circadian Retraining Program, and the primary endpoint I’ve been trying to influence personally is glycemic control based on HgA1c.  It’s not difficult at all, but to me, putting in a little work on the exercise, diet, and light exposure front is worth it to me to be able to drink coffee, enjoy craft beer, and eat foods I used to avoid without worrying about negative consequences.

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