The term “leaky gut,” its symptoms and causes, are becoming highly ambiguous to my patients and readers alike. So, in this article, I will attempt to clear up some of the confusion. I’ll look at some key points to simplify things a little more and help you perhaps prioritise your understanding around its influence on digestive and mental health. Finally, I’ll look at some of the next steps to take.
The title says it all. I remember walking through an airport and seeing the caption “Do you have leaky gut?” on the front of Women’s Health magazine and smiling as it seemed to have finally crossed into the public vernacular. Of course, this was when we could fly freely as a side note.
Who’s at risk of leaky gut, and what causes it?
As of the beginning of 2022, writing this, there are many different hypotheses around what makes the gut “leaky.” They are as varied as can be. Generally, activities that involve some kind of stress on the body comprise the bulk of the list. We start with endurance exercise, non-steroidal anti-inflammatories drugs and pregnancy.[1]
Yep, pregnancy.
Other potential causes would be antibiotic use via the creation of higher levels of opportunistic bacteria that aggravate the intestinal lining.[2] Dietarily, high-fat diets and other commonly used food additives such as emulsifiers,[3] found in things like coconut milk can have a negative contribution.
Oh, and I forgot to mention psychological stress as well.[4]
It’s easy to see why in many cases, you’re damned if you do and damned if you don’t. However, let’s not get too stuck on these things and spend the time exploring what these stressors do.
The fancy name for leaky gut is intestinal permeability
Whilst it’s possible to do some solid research using the term “leaky gut,” your best bet if you are research or scientifically-minded is to use the term intestinal permeability.
This different definition refers to the notion that the intestinal lining can become more porous or leaky under the influence of various forms of stress. It’s a little clearer in my opinion.
The reason why we care about intestinal permeability so much?
The intestinal barrier is the interface between the environment outside the body and the sensitive environment within the body. Let’s look at the intestinal barrier first.
A functionally intact intestinal barrier allows absorption of nutrients and fluids. Still, at the same time, it prevents harmful substances such as toxins and bacteria from crossing the barrier and reaching the body. If these toxins and bacteria do reach the body they can trigger the immune system.[5]
The barrier itself is made of a few different layers or components. An easy way to think about it is like the earth’s crust. The first layer consists of active parts of the immune and digestive systems. These active parts protect the lining from being colonised by undesirable, organised crime-like, opportunistic bacteria that produce antimicrobial substances.[6]
I’m sure if you’ve read some of the other articles on the site, you would have heard of some of these parts.
They include bile (secreted into the small intestine from the gall bladder), gastric acid (produced in the stomach), pancreatic juice (secreted into the small intestine from the pancreas) and other forms of bacteria that have a probiotic (think positive effect) against these undesirables.[7]
There’s a microclimate that contains water, mucus, and immune cells within the intestinal lining that strengthen the intestinal wall’s physical barrier.
Here we see higher quantities of bacteria-fighting molecules and immune cells, such as secretory IgA (an immune marker in comprehensive stool tests). Secretory IgA circulates and keeps guard so the undesirable forms of bacteria don’t colonise the lining and break down the barriers to the bloodstream.
Consider that this microclimate’s primary purpose is to protect the sensitive epithelial cells within the final layer of the intestinal barrier.
Wait a minute, what are epithelial cells?
Good question and essential when we look at how intestinal permeability forms. Epithelial cells are similar cells bound closely together to form the lining of many body surfaces.[8] You can find epithelial cells in the digestive, respiratory and urinary tracts, your glands, and the brain.
Here’s a sneak peek about where we’re going here.
Epithelial cells that get inflamed or infected can initiate an immune response via increasing inflammatory cells. These inflammatory cells then attract the appropriate immune cells to the problem site. Whilst they are considered the most sensitive part of these linings, epithelial cells also secrete anti-bacterial substances. These substances support the work of the layers we’ve previously discussed.[9]
We’ll come back to this later; let’s deepen our understanding around the lining and its composition, so it’s clearer from where these leaks are coming.
There are three different pathways where molecules can cross from the intestines to the bloodstream.
Two of those pathways are managed by “tight junctions” that regulate what passes through the bloodstream and what doesn’t. These tight junctions are the link between the epithelial cells.[10] Consider them similar to immigration at the airport, where molecules queue to gain permission to access the body.
It’s here that things begin to unravel for those experiencing the stressors we mentioned above.
Currently, there are a few reasons why the tight junctions within the intestinal lining can become more porous. Although it seems more work is needed on the research front to confirm this.
The proposed godfather of leaky gut, or at least the first person to identify the process of the loosening of the tight junctions in a lab, is NIH head, Alessio Fasano. Alessio Fasano states that one of the breakthroughs in intestinal permeability was the discovery of a molecule called Zonulin. A molecule he says is the “only physiologic intestinal modulator described so far.”[11]
After the best efforts of the immune components, an imbalance in gut bacteria on the gut barrier creates a disproportional amount of zonulin.
This disproportional amount of zonulin leads to tight junctions losing their integrity. Imagine immigration had one desk manned and one desk unmanned, and you had the choice to go through either one.
If this loss of integrity continues via a continued response to high levels of zonulin, the adaptive immune response, the more focused one, gets more active, creating an inflammatory process. This process inflames the tight junctions even further in a self-perpetuating cycle.
Wow, I held my breath typing that and almost passed out!
Whilst it is primarily the bacterial overgrowths that cause an increase in Zonulin, it has also been found in high levels in people living with Celiac disease. This higher level suggests that gluten is also a significant trigger.
It’s thought that gluten is misinterpreted by the zonulin system as a harmful antigen, thus leading to inflammation. This misinterpretation further suggests that zonulin production is primarily a defensive response.[12] A response, though, that depending on the source you refer to can cause a host of consequences around chronic disease origin.
Intestinal permeability or leaky gut doesn’t just cause digestive problems. Its effects can be vast.
Don’t get me wrong. Leaky gut has substantial research around its contribution to irritable bowel syndrome (IBS)[13] and inflammatory bowel diseases such as Crohn’s disease.[14]
Conditions with limited research (meaning that we might be wrong but aren’t sure yet) associated with leaky gut, include the following:
Asthma, autism, Parkinson’s disease, multiple sclerosis, eczema, psoriasis, depression, chronic fatigue syndrome, non-alcoholic fatty liver disease (NAFLD), obesity, metabolic syndrome, and rheumatoid arthritis, to name a few.[15]
An important note on this list is that we are yet to understand the deeper mechanisms behind how intestinal permeability causes these conditions on a deeper level.
There are theories, though.
Gram-negative bacteria that colonise the intestinal lining creating the zonulin response we discussed above have a particular habit of releasing endotoxins called “lipopolysaccharides.” Commonly known as LPS.
These LPS molecules, due to their proximity to the more porous tight junctions we touched on before, get into the bloodstream, causing chronic low-grade inflammation, referred to as metabolic endotoxemia.[16]
As this form of inflammation continues to rage over time, it causes broader systemic inflammation across the body. Hence the list above is mainly conditions associated with high levels of inflammation.
What do we need in the future to learn more about this?
One of the critical things we need to see in the research, or at least at the time of writing this, is that the correction of intestinal permeability helps with the prognosis of the non-gastrointestinal based conditions we’ve listed above.
From an anecdotal point of view, clearing gram-negative bacteria and rebuilding the digestive and immune systems afterwards have led to good outcomes for my patients. Which is a good start in my mind.
You didn’t expect me to write an article and not include the brain-gut connection, did you?
No, neither did !.
So, this particular connection often stuns patients. I remember I was just as amazed when I first heard it postulated by Dr Datis Kharrazian almost a decade ago. But if the theories above are true, it explains how this type of inflammation is attributed to many neuropsychiatric conditions.[17]
Leaky gut leads to a leaky brain, specifically, a leaky blood-brain barrier. This leaky blood-brain barrier was first found in mice studies in 2014 when researchers concluded that the gut microbiota influenced the blood-brain barrier and its permeability.[18]
A further discovery launched the concept further when researchers realised that small bacterial molecules, such as the LPS molecules we discussed earlier, leave the intestinal barrier and travel to other body sites, including the brain, causing more inflammation.[19]
If you are a regular reader of articles on philipwatkins.health, then you’ll be used to me telling you that this subject deserves its own article and deep dive.
I’ll be doing so, but to express the importance of a leaky brain, the scope of mental health conditions such as depression and neurodegenerative disorders like multiple sclerosis and Alzheimer’s disease is the tip of the iceberg it seems.[20]
So what is intestinal permeability, and why do you need to know about it to solve your digestive and mental health problems?
Well, suppose the theories we’ve discussed in this article are accurate. In that case, we may just be looking at the origin story of a large proportion of the chronic illnesses that modern society is living with. Not just the mental and digestive oriented diseases that we focus on for our readers.
Furthermore, whilst we haven’t explored the solutions much here, natural medicine has the tools and testing facilities to gain a quantitative and personalised intervention. An intervention that offers some light at the end of the tunnel for those living with anxiety, depression, IBS and other digestive conditions that still seem somewhat mysterious in their origin.
Hope this helps. x
References
[1] Camilleri M. Leaky gut: mechanisms, measurement and clinical implications in humans. Gut. 2019;68(8):1516-1526. doi:10.1136/gutjnl-2019-318427
[2] Feng Y, Huang Y, Wang Y, Wang P, Song H, Wang F. Antibiotics induced intestinal tight junction barrier dysfunction is associated with microbiota dysbiosis, activated NLRP3 inflammasome and autophagy. PLoS One. 2019;14(6):e0218384. Published 2019 Jun 18. doi:10.1371/journal.pone.0218384
[3] Pereira MT, Malik M, Nostro JA, Mahler GJ, Musselman LP. Effect of dietary additives on intestinal permeability in both Drosophila and a human cell co-culture. Dis Model Mech. 2018;11(12):dmm034520. Published 2018 Nov 28. doi:10.1242/dmm.034520
[4] Ilchmann-Diounou H, Menard S. Psychological Stress, Intestinal Barrier Dysfunctions, and Autoimmune Disorders: An Overview. Front Immunol. 2020;11:1823. Published 2020 Aug 25. doi:10.3389/fimmu.2020.01823
[5] Schoultz I, Keita ÅV. The Intestinal Barrier and Current Techniques for the Assessment of Gut Permeability. Cells. 2020;9(8):1909. Published 2020 Aug 17. doi:10.3390/cells9081909
[6] Camilleri M. Leaky gut: mechanisms, measurement and clinical implications in humans. Gut. 2019;68(8):1516-1526. doi:10.1136/gutjnl-2019-318427
[7] Camilleri M. Leaky gut: mechanisms, measurement and clinical implications in humans. Gut. 2019;68(8):1516-1526. doi:10.1136/gutjnl-2019-318427
[8] Ganz T. Epithelia: not just physical barriers. Proc Natl Acad Sci U S A. 2002;99(6):3357-3358. doi:10.1073/pnas.072073199
[9] Ganz T. Epithelia: not just physical barriers. Proc Natl Acad Sci U S A. 2002;99(6):3357-3358. doi:10.1073/pnas.072073199
[10] Anderson JM, Van Itallie CM. Physiology and function of the tight junction. Cold Spring Harb Perspect Biol. 2009;1(2):a002584. doi:10.1101/cshperspect.a002584
[11] Fasano A. All disease begins in the (leaky) gut: role of zonulin-mediated gut permeability in the pathogenesis of some chronic inflammatory diseases. F1000Res. 2020;9:F1000 Faculty Rev-69. Published 2020 Jan 31. doi:10.12688/f1000research.20510.1
[12] Fasano A. All disease begins in the (leaky) gut: role of zonulin-mediated gut permeability in the pathogenesis of some chronic inflammatory diseases. F1000Res. 2020;9:F1000 Faculty Rev-69. Published 2020 Jan 31. doi:10.12688/f1000research.20510.1
[13] Camilleri M, Lasch K, Zhou W. Irritable bowel syndrome: methods, mechanisms, and pathophysiology. The confluence of increased permeability, inflammation, and pain in irritable bowel syndrome. Am J Physiol Gastrointest Liver Physiol. 2012;303(7):G775-G785. doi:10.1152/ajpgi.00155.2012
[14] Teshima CW, Dieleman LA, Meddings JB. Abnormal intestinal permeability in Crohn’s disease pathogenesis. Ann N Y Acad Sci. 2012;1258:159-165. doi:10.1111/j.1749-6632.2012.06612.x
[15] Camilleri M. Leaky gut: mechanisms, measurement and clinical implications in humans. Gut. 2019;68(8):1516-1526. doi:10.1136/gutjnl-2019-318427
[16] Mohammad S, Thiemermann C. Role of Metabolic Endotoxemia in Systemic Inflammation and Potential Interventions. Front Immunol. 2021;11:594150. Published 2021 Jan 11. doi:10.3389/fimmu.2020.594150
[17] Fourrier C, Singhal G, Baune BT. Neuroinflammation and cognition across psychiatric conditions. CNS Spectr. 2019;24(1):4-15. doi:10.1017/S1092852918001499
[18] Braniste V, Al-Asmakh M, Kowal C, et al. The gut microbiota influences blood-brain barrier permeability in mice [published correction appears in Sci Transl Med. 2014 Dec 10;6(266):266er7. Guan, Ng Lai [corrected to Ng, Lai Guan]]. Sci Transl Med. 2014;6(263):263ra158. doi:10.1126/scitranslmed.3009759
[19] Obrenovich MEM. Leaky Gut, Leaky Brain?. Microorganisms. 2018;6(4):107. Published 2018 Oct 18. doi:10.3390/microorganisms6040107
[20] Obrenovich, M., Rai, H., Mana, T. S., Shola, D., McCloskey, B., Sass, C., & Levison, B. (2017). Dietary co-metabolism within the microbiota-gut-brain-endocrine metabolic interactome. BAO Microbiol, 2, 22.
