Small intestinal bacterial overgrowth(SIBO) is commonly found in people with IBS. The small intestine houses a miniscule number of bacteria when compared to the colon. When bacteria overgrow in the small intestine, it can cause symptoms of IBS. This includes:
- Weight loss
- Hormonal imbalance
- Mood/anxiety disorders
Ironically, the small intestine gets exposed to a higher amount of bile than the colon. Bile gets secreted in to the duodenum where it aids in the digestion and absorption of fats. By the time bile reaches the colon, 95% of the bile acids are reabsorbed and sent back to the liver for recycling.
Maybe not so ironically, bile has many effects that prevent SIBO. In this blog, we’ll cover the primary ways that optimizing bile can prevent and reverse SIBO.
1)Bile acids are directly antimicrobial(1)
The primary role of bile in the gut is the emulsification of fats/lipids. You see emulsification every day when you wash your hands with soap.
Emulsifiers such as soap and bile are ampiphatic. This means they have one side that loves water and one side that loves lipids. During emulsification, detergents such as bile separate large fat globules in to tiny emulsion droplets.
With soap, the goal is to break them up so they are taken away with water you rinse with. With bile, the goal is to break them up so fat digesting enzymes can access them better and break up the globule.
The antimicrobial effect of bile is due to this detergent-like effect on cell membranes. All cell membranes consist of a lipid bi-layer and bile can disturb this bi-layer. When this bi-layer gets disturbed, bad things happen. Fortunately your cells have bile acid transporters that prevent damage to them.
The bacteria inhabiting your small intestine aren’t so lucky. In the same way that washing your hands washes bacteria away, bile keeps bacterial counts in the small intestine low.
2)Bile causes the secretion of antimicrobial peptides in the ileum(1)
The ileum is the part of the small intestine located closest to the colon. Since the colon contains the highest concentration of bacteria in the gut, there needs to be a way to prevent bacteria from moving from the colon to the ileum.
When bile acids enter the ileum, they bind to a receptor known as the farnesoid X receptor(FXR). FXR does a few things and is a primary player in the recycling of bile acids. One of the other roles FXR plays is in the secretion of antimicrobial peptides.
FXR is expressed throughout the gut, but primarily in the ileum. This allows most bile acids to flow through the entire small intestine before reabsorption.
When bile acids bind to FXR in the ileum, antimicrobial proteins get secreted to prevent bacterial growth. Unlike the direct effect of bile acids, this is not selective.
This means that when bile acids bind to FXR, it prevents all bacteria from growing. This includes commensals. This is an important distinction because commensals are far more likely to overgrow in the ileum than pathogens.
3)Bile seals up a “leaky gut”
Bile acids also induce the expression of tight junction proteins through binding to the G-coupled protein receptor(TGR5)(2). FXR may also contribute to this effect either directly and/or indirectly(3).
Additionally, some bacteria in the gut convert primary bile acids in to secondary bile acids. The secondary bile acids activate the pregnane X receptor(PXR). This happens everywhere, but mostly in the colon since most commensal bacteria live there.
This metabolite increases tight junction protein synthesis. In layman’s terms, it seals up a leaky gut.
Alkaline phosphatase is an enzyme secreted by the liver, gut, bone, and a few other organs. Recent research has identified intestinal alkaline phosphatase(IAP) as a major player in regulating the gut(8). Coupled with PXR, it may be one of the biggest factors in gut health.
Lipopolysaccharide(LPS) is a component of the cell wall of gram-negative bacteria. The immune system recognizes it and causes inflammation in the gut. This happens when LPS binds to something called the toll-like receptor 4(TLR4). Alkaline phosphatase changes LPS, making it unrecognizable to the immune system. And since it’s located right next to TLR-4, it’s a powerful modulator of inflammation.
Another way IAP promotes gut health is by regulating pH and the growth of commensal bacteria. To keep this blog under 5000 words, I’ll dig deeper in to how this works in a future blog. A little teaser…IAP can protect against antibiotic-induced pathogen overgrowth.
5)Bile decreases motility in the small intestine(9)
People with SIBO have altered motility. Motility refers to the rhythmic muscular contractions that cause peristalsis. These contractions move the contents of the gut towards and out of the anus.
The importance of proper motility in SIBO can’t be overstated. People with altered motility can have opposing symptoms in SIBO. People with fast motility will present with diarrhea. People with slow motility present with constipation.
In the small intestine, bile acids bind to TGR5 and reduce motility. This gives digestive enzymes more time to digest and absorb your food. This also reduces the amount of undigested food in your feces and reduces diarrhea.
Bile acids have opposing effects on motility in the colon via the same receptor. When bile acids bind to TGR5 in the colon, motility increases. Therefore, this effect can prevent constipation.
One could also make the case that this could contribute to diarrhea. However, binding to TGR5 also regulates electrolyte and water absorption in the colon. This, in effect, reduces the risk for diarrhea.
An interesting finding in studies with mice is that TGR5 is absolutely necessary for proper defecation(11). Mice that do not have TGR5 have slower transit times(1.4x slower) and defecate 2.6x less than mice with TGR5. Data in humans is absent.
You’ve experienced the migrating motor complex before and never knew it. Do you know that growling you experience when you haven’t eaten in a while? That’s not your body telling you you’re hungry; that’s the migrating motor complex.
When you eat, peristalsis helps move your food through the gut to promote digestion and absorption of nutrients. These are considered digestive periods.
During inter-digestive periods, another process unfolds called the migrating motor complex. The migrating motor complex functions as the housekeeping system of your digestive tract.
After you’ve fasted for an extended period of time(5-11 hours), the migrating motor complex(MMC) cleans out debris in your gut. Digestive enzymes get secreted and waves of peristalsis move debris and bacteria towards the colon.
A malfunctioning migrating motor complex predisposes to the growth of bacteria in the small intestine(15, 16, 17). Bile plays a large role in both motility of the MMC as well as sweeping away bacteria that may begin to grow. It may even be involved in initiating the MMC(12).
Recall from above that bile acids bind to FXR in the ileum. Not only does this cause the release of antimicrobial peptides in the ileum, it recycles bile acids. Binding to TGR5 also causes the gallbladder to fill with bile for another round of the MMC.
When bile acids bind to FXR and TGR5, they block inflammation by inhibiting nuclear factor kappa beta(NF-kB). While this is great, it’s important to note that bile acids can also have a pro-inflammatory effect.
Water soluble bile acids are anti-inflammatory because they bind to receptors on cells. This changes gene expression which is good. Fat soluble bile acids can just enter cells and cause cell death. This effect is regulated by your microbiome and is not good.
Other receptors are also important for the anti-inflammatory effects of bile acids. Lithocholic acid(LCA), a liver toxic secondary bile acid, requires detoxification before getting sent to the liver. PXR starts this process.(19).
Anytime a ligand binds to PXR, including LCA, it blocks NF-kB. LCA also binds to the vitamin D receptor(VDR) and causes the same effect(20).
9)Bile promotes commensal bacteria and keeps them where they should be
Bile has been a component of the animal digestive tract forever. Because of this, human commensals that live in the small intestine have adapted genes that promote bile resistance(21, 22). This gives them a competitive edge over pathogens that compete for nutrients.
Since bile is antibacterial through its detergent-like effects, bacteria that aren’t bile resistant can’t colonize the small intestine. Unless, of course, the host isn’t producing enough bile. Keep in mind that some pathogens are also bile resistant so it’s not all rainbows and lollipops.
In the ileum, bile resistance isn’t necessarily a good thing. The ileum is an area ripe for over-colonization of commensals due to its proximity to the colon. In this area, bile resistance is overcome through the release of antimicrobial peptides by enterocytes. This happens when bile acids bind to FXR.
Thus, the overall effect of bile acids is to provide an environment where commensals have a competitive advantage over pathogens. At the same time, bile must keep commensals in check and prevent them from overgrowing in the ileum.
10)Bile is required for vitamin A absorption which optimizes all the above
Throughout this blog I’ve discussed a bunch of somewhat complex topics. You’ve already heard about VDR, but FXR and PXR are something you’ve just become aware of. Well, it’s time to learn about another “XR”…RXR.
RXR refers to the retinoid x receptor. The retinoid x receptor does so many things that we’ll only focus on one thing here. RXR makes the other “XRs” work better.
To work, VDR, PXR, and FXR bind to RXR to form something called a heterodimer. A heterodimer gets formed when two large molecules bind together. When RXR binds to any of the above, it forms a super receptor.
Note: In this image, the liver x receptor(LXR) is used. It’s the same process for all partners
When a ligand binds to PXR, it causes genetic expression of that receptors target genes. For example, when LCA binds to PXR, you get a certain level of expression of the genes that process LCA. If PXR forms a heterodimer with RXR and the ligand for RXR is bound to it, you get greater levels of expression of those genes.
It shouldn’t surprise you that the natural ligand for the retinoid x receptors is retinol, a form of vitamin A, specifically, 9-cis retinoic acid. Other receptors that form a heterodimer with RXR include the thyroid receptor and liver x receptor.
This means that adequate vitamin A intake optimizes all the processes regulated by these receptors. Conversely, inadequate vitamin A intake can make these processes run poorly.
Now, when we talk about vitamin A, we’re not just talking about any form of vitamin A. Retinol, the form found in animal products, is the form we’re looking for. Pro-vitamin A, which come from plant sources, requires conversion to retinol to activate RXR. In some people, including myself, this conversion is sluggish.
Since vitamin A is fat soluble, bile is required to bring it in to cells. With inadequate bile, you can’t absorb vitamin A from food or supplements. This spells bad news for people who have SIBO.
Proper bile output is important for preventing SIBO. Bile:
- Aids in fat/fat soluble vitamin digestion and absorption
- Is antimicrobial
- Regulates the microbiome and gut environment,
- Has anti-inflammatory effects
The ability of bile to promote the growth of commensal bacteria while keeping them where they should be is important to prevent and reverse SIBO. It also maintains the gut in a way that prevents pathogenic infection and leaky gut.
You can manage bile output and the content of bile via lifestyle modification. It’s tempting to take ox bile supplements but no ideal. If you choose to, it should be done for short periods of time and in the face of a nutritionally replete diet. The goal with its use should be to improve nutrient deficiencies quickly so you can get to work on your own bile production.
The use of ox bile is not without its drawbacks. Bile has great effects in the small intestine and colon but can cause problems in the stomach. Another issue is that you must first increase receptors that handle bile. Not doing this can can damage the gut.
In future blogs we’ll take a look at ways that modifying your lifestyle can improve your bile.
Question or comment? Hate my writing or love it? Is this stuff too complex? Leave a note in the comment section, I’d love to hear from you.