Uncongugated Bilirubin As A Cause Of Leaky Gut

[Lurker]

https://www.wellnessresources.com/news/friendly-flora-inhibits-bilirubin-induced-digestive-damage

I hadn’t heard of this hypothesis for leaky gut before. I had read something about too much bile acid as a cause of colon cancer but this is a much more specific idea. The unconjugated seems like it could be a problem with phase two liver detox or other removal mechanisms.

Also interesting is their suggested probiotic solution which fits a lot of the protective microbiome narrative. L. plantarum comes from fermented foods. It is gram positive (no endotoxin) but lactic acid forming.

Please discuss...

Edit: sorry for the typo. I can’t edit the title.

 

[lvysaur]

The article link doesn't work, but I found a copy:
Friendly Flora Inhibits Bilirubin-Induced Digestive Damage
Here's a paste in case it's deleted later

Your body recycles all of its red blood cells over a six week period. During this process heme is released from your red blood cells in your spleen and converted to unconjugated bilirubin. For a variety of reasons (which I will explain shortly) a person can wind up with too much of this compound in their digestive tract, which promotes highly inflammatory damage to the lining of your digestive tract. This has become known as the “leaky gut,” wherein toxic compounds in your digestive tract leak back into your circulation and cause multiple health problems. In a new study a strain of friendly flora,1 called Lactobacillus plantarum, was shown to offset the digestive damage of unconjugated bilirubin.

Yes, I know, it sounds like a lot to understand—and it is. First, it requires more explanation so you will understand how the issue relates to your health. For any of you with digestive problems, it's worth taking the time to understand, as it may help you to improve your digestive health.

Unconjugated bilirubin (also called indirect bilirubin) is a fat-soluble compound that your body would like to make water-soluble. It is attached to albumin in your blood and carried to your liver where it is conjugated to (bound to) glucuronic acid. At this point, the bilirubin is now water-soluble (also called conjugated or direct bilirubin) and what is not recycled is sent into bile for excretion into your digestive tract.

Jaundice is a condition of too much unconjugated bilirubin in the blood, causing the yellow appearance in the whites of eyes and possibly skin. This can be a significant problem in a newborn baby if it persists for any length of time. This fat-soluble substance can readily cross the immature blood-brain barrier and damage evolving brain structure during a critical two weeks of metabolic development. In others words, leptin and thyroid brain circuitry can be injured for life, to a greater of lesser degree, by this problem. Individuals with anxiety were often jaundiced following birth, reflecting damage to core brain structure. Much more serious brain damage can occur than these functional issues. In some cases, liver health is compromised—especially in premature babies—leading to a perpetually higher level of unconjugated bilirubin (Gilbert’s syndrome). While this is likely to result in an adult with chemical sensitivity, inflammatory digestive issues (including leaky gut), and energy/metabolic problems are not as serious in the first few weeks of life, as the blood-brain barrier is better able to defend against the unconjugated bilirubin entering the brain.

In addition to these readily definable medical issues with unconjugated bilirubin there are also less obvious issues with unconjugated bilirubin that pose rather significant challenges to digestive health. One key sign of a problem is that your stool color is pale, yellow, or lighter as opposed to darker brown. Your intestinal bacteria act on conjugated bilirubin by changing it into various compounds that end up darker brown. Lighter color stools indicate a lack of friendly flora as well as the likelihood that the clearance process of conjugated bilirubin isn’t working properly. This means that there is a significant likelihood that conjugated bilirubin is simply turning back into unconjugated bilirubin and piling up in your digestive tract in excess. Too much unconjugated bilirubin is caustic on contact, thus having the potential to injure the lining of your digestive tract. In the current study, researchers meticulously showed how unconjugated bilirubin in the digestive tract damaged multiple tight protein junctions and blocked repair of the injured areas—which obviously leads to leaky gut. They also showed that friendly flora can prevent such damage.

In addition to lighter color stools, indigestion is another sign you could be having a problem. The burning or pain across your abdominal region is contributed to by the unconjugated bilirubin. This isn’t the only reason for indigestion, but it is one. Of course, simply being deficient in friendly flora from the excess consumption of sugar, alcohol use, and/or antibiotics use are other common factors that set the stage for this problem.

There is also the issue of poor liver function, or your red blood cells may be breaking down too fast by inflammatory stress. One of the first signs of unconjugated bilirubin in your blood is when the whites of your eyes look a bit yellowish. Such issues are common in overweight people, and in people whose hemoglobin and red blood cell scores are on the lower edge of the normal range. Of course, someone with anemia because their red blood cells are being broken down too fast (hemolytic anemia) would be the classic example of this. However, many people without blatant anemia experience this problem to some degree simply from wear and tear. This health issue can turn into a nasty catch 22, as the leaky gut problem allows toxins back into the blood which then damages red blood cells and increases the load of unconjugated bilirubin that further perpetuates the leaky gut. While all this may sound rather complex, it is happening to many people who have ongoing digestive stress of one type or another.

If you have a history of high bilirubin following birth, then this topic may be of special importance. Your body may be sensitized to higher levels of digestive unconjugated bilirubin, similar to having an old injury that flares up later in life. One sign of this would be sensitivity to alcohol, as unconjugated bilirubin highly reacts with alcohol. In other words, alcohol intake should be minimized in individuals with this problem as the “benefits” of moderate alcohol intake is most likely a joke.

It is quite interesting that friendly flora can help break this problematic cycle, and will promote a more competent digestive lining while helping to guard against higher levels of unconjugated bilirubin in your digestive tract.
Referenced Studies

1. ^ Friendly Flora Protects Digestive Lining from Unconjugated Bilirubin British Journal of Nutrition Yukun Zhoua, Huanlong Qina, Ming Zhanga, Tongyi Shena, Hongqi Chena, Yanlei Maa, Zhaoxin Chua, Peng Zhanga and Zhihua Liua.

 

[lvysaur]

Referenced Studies

1. ^ Friendly Flora Protects Digestive Lining from Unconjugated Bilirubin British Journal of Nutrition Yukun Zhoua, Huanlong Qina, Ming Zhanga, Tongyi Shena, Hongqi Chena, Yanlei Maa, Zhaoxin Chua, Peng Zhanga and Zhihua Liua.

I can't find this referenced study but it was on the wellnessresources website:

Friendly Flora Protects Digestive Lining from Unconjugated Bilirubin
Study Abstract
Although a large number of in vitro and in vivo tests have confirmed that taking probiotics can improve the intestinal barrier, few studies have focused on the relationship between probiotics and the intestinal epithelial barrier in hyperbilirubinaemia. To investigate the effects of and mechanisms associated with probiotic bacteria (Lactobacillus plantarum; LP) and unconjugated bilirubin (UCB) on the intestinal epithelial barrier, we measured the viability, apoptotic ratio and protein kinase C (PKC) activity of Caco-2 cells. We also determined the distribution and expression of tight junction proteins such as occludin, zonula occludens (ZO)-1, claudin-1, claudin-4, junctional adhesion molecule (JAM)-1 and F-actin using confocal laser scanning microscopy, immunohistochemistry, Western blotting and real-time quantitative PCR. The present study demonstrated that high concentrations of UCB caused obvious cytotoxicity and decreased the transepithelial electrical resistance (TER) of the Caco-2 cell monolayer. Low concentrations of UCB inhibited the expression of tight junction proteins and PKC but could induce UDP-glucuronosyltransferases 1 family-polypeptide A1 (UGT1A1) expression. UCB alone caused decreased PKC activity, serine phosphorylated occludin and ZO-1 levels. After treatment with LP, the effects of UCB on TER and apoptosis were mitigated; LP also prevented aberrant expression and rearrangement of tight junction proteins. Moreover, PKC activity and serine phosphorylated tight junction protein levels were partially restored after treatment with LP, LP exerted a protective effect against UCB damage to Caco-2 monolayer cells, and it restored the structure and distribution of tight junction proteins by activating the PKC pathway. In addition, UGT1A1 expression induced by UCB in Caco-2 cells could ameliorate the cytotoxicity of UCB.
Study Information
Yukun Zhoua, Huanlong Qina, Ming Zhanga, Tongyi Shena, Hongqi Chena, Yanlei Maa, Zhaoxin Chua, Peng Zhanga and Zhihua Liua.
Lactobacillus plantarum inhibits intestinal epithelial barrier dysfunction induced by unconjugated bilirubin
British Journal of Nutrition
2010 August
Shanghai Jiaotong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai 200233, China

 

[gaze]

@lvysaur

great post! Thanks. I was born with a blood condition which causes more rapid hemolysis. So I’ve always had an enlarged spleen + high billirubin. I do think a lot of my digestive issues are caused from the billirubin and high iron recycling in the blood

 

[Inaut]

@lvysaur

great post! Thanks. I was born with a blood condition which causes more rapid hemolysis. So I’ve always had an enlarged spleen + high billirubin. I do think a lot of my digestive issues are caused from the billirubin and high iron recycling in the blood

Have to agree @Ivysaur . Excellent post. I need to take time to read this over. Thanks for sharing

 

[lvysaur]

Have to agree

I do think a lot of my digestive issues are caused from the billirubin and high iron recycling in the blood

Thanks, and no problem, I'm just getting into the topic myself. I've always had high bilirubin at random times (aka Gilbert's syndrome). I'll share this post I made in a different thread:

Yellow Eyes, Elevated Bilirubin Aka Gilbert's Syndrome

However, since I've developed COVID I've had many more blood tests. And I've noticed that when my bilirubin gets low, my neutrophils get high, and I feel worse.

 

[rob]

However, since I've developed COVID I've had many more blood tests. And I've noticed that when my bilirubin gets low, my neutrophils get high, and I feel worse.

I have similiar relationship between neutrophils and unconjugated bilirubin (UCB).

I have Crohn's in my colon and Gilbert's syndrome. When my Crohn's is in remission, as is the case now, my UCB is consistently high and my neutrophils are on the low side – the opposite is true in flare.

UCB levels are actually inversely correlated with IBD activity in many studies. This has been related to UCB's potent anti-oxidant activity, which, unlike glutathione, is lipophilic and therefore can inhibit membrane-bound enzymes (e.g. NADPH oxidase) directly.

There's also evidence that UCB, via beta glucuronidase, inhibits protease activity in the colon: Unconjugated bilirubin ameliorates the inflammation and digestive protease increase in TNBS-induced colitis.

In addition, UCB modulates immune function as an AhR ligand. The following paper evidences its effect on the Th17 lineage: Bilirubin suppresses Th17 immunity in colitis by upregulating CD39.

 

[lvysaur]

There's also evidence that UCB, via beta glucuronidase, inhibits protease activity in the colon: Unconjugated bilirubin ameliorates the inflammation and digestive protease increase in TNBS-induced colitis.

So this protease activity could be either from the animal itself, or from gut bacteria, right? They never say either way.

Because increased protease would be a good thing, if it came from the intestine's own secretions. If it came from gut bacteria then obviously it's bad. So it's not certain if bilirubin is limiting your protein digestibility, or if it's handicapping bacteria.

 

[gaze]

Thanks, and no problem, I'm just getting into the topic myself. I've always had high bilirubin at random times (aka Gilbert's syndrome). I'll share this post I made in a different thread:

Yellow Eyes, Elevated Bilirubin Aka Gilbert's Syndrome

However, since I've developed COVID I've had many more blood tests. And I've noticed that when my bilirubin gets low, my neutrophils get high, and I feel worse.

interesting. How low does it get? Did you get better or do you have long haul Covid?

 

[lvysaur]

interesting. How low does it get? Did you get better or do you have long haul Covid?

The lowest reading I've gotten for bilirubin is at the high end of normal (1.3 maybe?). The highest reading ever was 2.6 I think (forgot the units but i can post labs later)

My neutrophils have ranged from 2x the lymphocyte level to 4.5x the level. My lymphocytes are always at 1.8 roughly, won't budge.

I didn't get better, but amoxicillin made the symptoms disappear for a month, then they came back. Yes, long haul since March

One thing worth noting is that aspirin lowers the bilirubin without the other symptoms. Low bilirubin always gives me higher blood sugar and higher neutrophils (I'm not diabetic). If I take aspirin I get low bilirubin with normal levels of these.

 

[rob]

So this protease activity could be either from the animal itself, or from gut bacteria, right? They never say either way.

Because increased protease would be a good thing, if it came from the intestine's own secretions. If it came from gut bacteria then obviously it's bad. So it's not certain if bilirubin is limiting your protein digestibility, or if it's handicapping bacteria.

IBD patients have been shown to have considerable elevations in host, not microbial, proteases (see: Fecal Serine Protease Profiling in Inflammatory Bowel Diseases).

Regardless of source, significant proteolysis in the colonic lumen is not a good thing having been evidenced to increase intestinal permeability (see figure 1 in: Regulation of intestinal permeability: The role of proteases).

It is beleived that unconjugated bilirubin (UCB), via the hydrolysis of bilirubin glucuronides by beta glucuronidase, could help alleviate this issue as a potent colonic protease inhibitor (see: https://www.dldjournalonline.com/article/S1590-8658(15)00188-7/abstract).

That said, as elluded to in my previous post, UCB works by multiple mechanisms to theoretically alleviate inflammation.

Notable is the well documented pathway of AhR ligand binding, ectonucleotidase (CD39/CD37) activation and purinergic signalling whereby intracellular ATP is metabolised to adenosine, which acts as a potent immunosuppressant. Issues with this pathway in general (CD39/CD37 polymorphisms, decreased AhR expression etc) are potentially significant to a number of pathologies, especially the colon where there's a interesting interplay between HIF stabilization as per the oxygen gradient and purinergic signalling (if interested, see: https://www.jimmunol.org/content/200/3/897). On this theme, zinc deficiency is known to severely impair ectoenzymes, resulting in an increased extracullular ATP/ADP:adenosine ratio.