Gastrointestinal disorders affect an estimated 70 million people(1) and this number is likely to grow.  If you’re one of these people, you know the burden that digestive disorders creates.  I imagine few disorders present with symptoms as suddenly and with as large of an impact on daily life.

Whether you’re dealing with IBS symptoms, Crohn’s disease, SIBO, or ulcerative colitis, rifamycin based antibiotics are the drugs du jour.  Specifically, the popular drug Rifaximin/Xifaxan.

Responses to the drug can cause total remission, remission only when taking the drug, or increased symptoms before and after.  While most people taking the drug know it’s an antibiotic, it has other beneficial effects as well.  These include:

• Improved detoxification
• Improved “leaky gut”
• Decreased inflammation

While these side effects are generally beneficial, they are situation specific.  In this blog we’ll take a look at how Xifaxan alters these 3 processes.  We’ll also try to find out what your response to this drug says about your personal situation.  Let’s dig in.

Xifaxan and how it works

Xifaxan is an antibiotic that works specifically in the intestine; it’s not systemically absorbed.  This unique quality of Xifaxan is also why it induces the beneficial effects mentioned above.

Detoxification is a misnomer for what’s actually called biotransformation.  The same process that makes toxins easier to dispose of metabolizes pharmaceutical drugs.  It also transforms endogenous hormones in to active or inactive forms.

When a fat soluble molecule enters a cell, it binds to a receptor called the pregnane X receptor(PXR).  Binding to this receptor induces the 3 phases of “detoxification”.  These 3 phases turn the toxin more water soluble and spit it out of the cell.  This allows them to be passed in feces or urine.  This happens the same way for hormones and pharmaceutical drugs.

Note: Phase 3 is elimination transport out of the cell

In the same way, Xifaxan binds to PXR and induces these biotransformation pathways in the gut(3).  In fact, rifamycins are the most powerful inducers of this pathway known to date.  While Xifaxan isn’t the strongest, it’s effects stay in the gut.  This makes it ideal for GI problems.

Inducing these pathways doesn’t just affect Xifaxan.  Other fat soluble molecules in the cell go through the same process due to the powerful induction of these pathways.  Evidence for this comes from studies on the many drug-drug interactions seen with rifamycins(4).

Regulation of “leaky gut” by Xifaxan

The purpose of biotransformation in intestinal cells is to prevent things from migrating from the gut to the circulation.  The few that do escape the intestine, go to the liver for more “detoxification”, and get sent back to the intestine via bile.  An important factor for preventing toxins and drugs from leaving the gut is the permeability of the intestinal wall.

The detoxification process wouldn’t be efficient if these molecules were spit back in to a “leaky gut”.  When a molecule binds to PXR, there is an increase in tight junction proteins.  Thus, the processes known as “detoxification” and ‘leaky gut” or intestinal permeability get regulated together.  Xifaxan, due to its powerful induction of PXR, decreases intestinal permeability.  This can fully or partially resolve a “leaky gut”.  At least while you’re taking it.

Regulation of inflammation by Xifaxan

A major factor that regulates the leakiness of the gut is inflammation.  An inflamed gut has greater intestinal permeability because inflammation decreases tight junction proteins.  This is not an ideal scenario for “detoxification”.

When a molecule binds to PXR, detoxification isn’t the only process that gets affected.  PXR binding also blocks nuclear factor kappa-beta(NF-kB) activation.  NF-kB is a powerful inducer of cellular inflammation.  Blocking NF-kB has a strong anti-inflammatory effect that promotes intestinal barrier integrity.

In fact, inflammation and “detoxification” are reverse regulators of one another.  This means that the more inflammation you have, the lower your ability to detoxify.  In turn, the more you induce your detoxification pathways, the lower you inflammation levels.  Activation of PXR by xenobiotics should maintain lower levels of inflammation via this process. (It’s important to note that inflammation in the gut impairs detoxification in the gut.  Detoxification in the liver is only impaired if there is inflammation in the liver or systemic inflammation migrates there.)

Decreased detoxification is a symptom of inflammatory bowel disease.  This is due to decreased expression of the PXR(5) and PXR regulated transporters(6).  The detoxification/inflammation axis also explains the proposed link between IBS/IBD and multiple chemical sensitivities.  Fewer pregnane X receptors in cells due to chronic inflammation allow environmental toxins to accumulate.

There is a good amount of research on Xifaxan that supports this link.  Clinical evidence shows that Xifaxan decreases inflammation and increases tight junction proteins in the gut(7, 8).  It also increases the abundance of Lactobacillus in the ileum.  This is great if you have a pathogen invading the ileum.  Not so much if you have an overgrowth of Lactobacillus there.  This may explain some of the differential responses to Xifaxan, which we’ll cover next.

What does my Xifaxan response tell me?

Now that you know the finer points of Xifaxan, what does your response to the drug show about your situation?  For people who go in to remission and stay there, you’re lucky.  The pathogen or commensal overgrowth triggering your issue is susceptible to the antibiotic effect of Xifaxan.  Another option is that your detoxification/inflammation axis was thrown off, and the drug set you straight.  Either way, you’re good to go.  Although, I wouldn’t altogether rule out a relapse.

If you saw improvement in your symptoms while taking the drug but they came back, there are a couple of issues.  First and most obvious, the pathogen or overgrowth is still there.  It’s either resistant to the antibiotic effect Xifaxan or it was a stronger infection.  If it’s the former another antibiotic may be of help.  If it’s the latter, another round of Xifaxan may do the trick.

Fat soluble vitamins are critically important

Another option is a deficiency in fat soluble vitamins.  The fat soluble vitamins play a major role in mucosal defense in the gut.  Vitamins A & K are crucial for the detoxification/inflammation axis.  A deficiency in either one may be hidden by the PXR inducing effects of Xifaxan.

Fat soluble vitamin deficiency is also a common symptom of IBS/IBD.  I recommend increasing your intake of these fat soluble vitamins while taking Xifaxan.  This should help correct any deficiency caused by IBS/IBD.  A deficiency in fat soluble vitamins or fatty stool indicate fat malabsorption.  This is something that absolutely must be corrected if you want full recovery.  In my opinion the problem here is most certainly going to be in bile acid output or activity.

Bile regulates the GI environment

This brings us to the enterohepatic circulation, of which bile is a part of.  A defect in the enterohepatic circulation will most certainly cause all sorts of GI problems and needs to be corrected.  Bile, a primary component of the enterohepatic circulation, plays a pivotal role in gut health.  Bile is required for the absorption of fat and fat soluble nutrients but has other powerful effects.

Bile flow is also a powerful modulator of the gastrointestinal environment and bolsters mucosal defense.  Bile acids are antimicrobial throughout the small intestine but have more powerful effects in the ileum.  Bile has detergent-like effects which disrupt bacterial membranes throughout the small intestine, killing pathogens.  Additionally, bile acids bind to receptors in the ileum and get recirculated.  This also causes the secretion of antimicrobial peptides by intestinal cells.  The ileum is an area ripe for bacterial overgrowth due to its proximity to the colon.  There are 10,000-100,000x more bacteria in the colon than any part of the small intestine, including the ileum.

The antimicrobial qualities of bile also help set the micobiome.  Commensal organisms such as Lactobacillus and Bifidobacteria have developed tolerance to bile acids(11).  This gives these commensal microbes an environmental advantage over pathogenic bacteria.  It also makes most of the small intestine a poor environment for pathogens to grow.

While commensals are tolerant to the detergent-like effects of bile, they aren’t immune to the antimicrobial peptides secreted when bile binds to receptors in the ileum.  Therefore, the antimicrobial proteins secreted in the ileum keep overgrowth of commensals and pathogens at bay.  Improving bile flow should be a primary goal for people who experience IBS or IBD, especially those with fat malabsorption.

An important note, however.  If you have methane predominant SIBO, this is a clear indication that there’s something wrong with your bile production.  Bile inhibits methanogens in the small intestine(9, 10).  An overgrowth of methanogens indicates that bile may not be doing what it’s supposed to be doing.

Another issue is that Xifaxan is fat soluble and absorbed in to cells in the same way as any fat soluble molecule.  Bile is absolutely necessary for Xifaxan to work properly.  This may explain the clinical observation that Xifaxan is ineffective for methane predominant SIBO.

In people who experience more bloating or other symptoms while on Xifaxan, the infection may be too strong.  The antibiotic could also be  killing off commensal bacteria.  Commensal bacteria keep pathogens from gaining an edge.  Killing them with antibiotics gives the pathogens more real estate to proliferate.

People with an overgrowth of Lactobacillus species may also experience increased symptoms while taking Xifaxan.  Xifaxan promotes the growth of Lactobacilli in the ileum, not ideal for those with ileal Lactobacillus overgrowth.

Optimizing mucosal defense is key

These issues can be prevented or at least limited by living a lifestyle that supports mucosal defense and bile production.  Bacteria won’t grow where the environment restricts their growth.  This goes for commensals and pathogens.

Under normal conditions, the body promotes the growth of commensals and restricts the growth of pathogens.  It also does a pretty good job of keeping commensal bacteria from overgrowing.  Mucosal defense regulates all of these processes.

Overactive Phase 1 activity can overwhelm the system

There is one other possibility for people who see an increase in bloating and symptoms while on Xifaxan.  It’s possible that Xifaxan induces the biotransformation pathways too much for some people.  There are a bunch of genetic factors that can come in to play here.  For example, I have an overactive phase I response.  This sometimes overwhelms the Phase II pathways.

Overactive Phase I pathways often lead to an increase in symptoms because toxins accumulate.  It’s like a back up on a conveyor belt because the first part moves faster than the second can accommodate.

There are also foods and food components that induce or inhibit Phase I enzymes.  St. John’s Wort(12), alcohol(13) and organophosphorous pesticides(14) are great examples of Phase I inducers.  Phase I inhibitors include grapefruit(15), and pomegranate(16).  Turmeric is an interesting example because it inhibits phase I pathways while increasing Phase II.

It wouldn’t surprise me to find out that this is a reason why different people react to certain foods.  It’s definitely a reason why people react differently to drugs and environmental toxins.  Induction/inhibition of different phases of “detoxification” alters a significant number of outputs.  This is why I’m pro-food journal, this stuff is highly individual.

If that doesn’t make your head spin, there are at least 50 different phase I enzymes that each process many different molecules.  The benefit with Xifaxan is that it hits a large majority of them, but it also increases your chance of an adverse reaction.

Optimizing the GI environment

In most situations, people don’t think much about what they eat when they take an antibiotic.  If you’re taking an antibiotic for a digestive disorder, diet is integral for the healing process.  Eating a proper diet while dropping an antibiotic bomb on the battlefield provides reinforcements to the good guys.  Eating a terrible diet of nutrient poor processed food only helps the bad guys.  Limiting FODMAPS and other fermentables that cause bloating helps to reduce bloating and other symptoms, but it doesn’t solve the problem.

From there, optimizing bile flow and detoxification can be addressed with proper supplementation.  In future posts I’ll go over which supplements can help with this.  Probiotics can be effective, but unless you’re addressing the GI environment I wouldn’t expect much help from them.  Probiotics just won’t flourish in an environment that isn’t conducive to their growth.  The evidence also indicates that probiotics from pills are only transient in nature.

 

Conclusion

Your individual response to Xifaxan can tell you a lot about your situation. People who experience remission likely had a lighter infection or pathogens susceptible to the antibiotic effect of Xifaxan.  I wouldn’t take this as a license to go back to eating whatever you want, though.  100% eradication is not likely and all you need to do is tip the environmental conditions back in favor of the pathogen to have another problem.  I don’t believe it’s common for diet to be the only factor here, but if it happened once it could happen again.

People who feel better for a while but then see symptoms resume may be experiencing this phenomenon.  Another option is that Xifaxan gets their detoxification/inflammation axis working properly and this reverses when they stop.  Xifaxan is a sure fire way to decrease inflammation and improve a “leaky gut” due to the co-regulation of detoxification and inflammation.  At least as long as Phase I enzymes don’t outpace Phase II.

If you see an increase in symptoms while on Xifaxan or right after, Phase I  outpacing Phase II is something you may want to look at.  Having your genome sequenced by 23andme will give you definitive answers, and a food journal is extremely valuable in this regard.  You could also have a pathogen that’s resistant to the antibiotic effect of Xifaxan.  or be making a Lactobacillus overgrowth worse.  In a pathogenic infection or an overgrowth the antibiotic effect is a desirable one.  I just don’t think this means you can ignore the environment you’re creating in the gut.

I’m a big fan of letting the body and its defense systems do their job.  You have an innate system of checks and balances that regulates the gastrointestinal environment.  These systems can promote the growth of commensal organisms and prevent the growth of pathogens.  Does this mean that antibiotics aren’t necessary?  Of course not.  What it means is that before you go dropping a bomb on the battlefield, you need to make sure that your mucosal defense system is up and running.  Otherwise, there’s a good chance that you’ll quickly be back where you started.

My goal with this blog is to clue you in to this.  How is the innate mucosal defense in the gut regulated?  Is there something we can do to prevent it from going off the rails?  Is there something we could do once this happens?  Can this improve the efficacy of pharmaceutical approaches?  I think the answer to all of these questions is yes, and I have a bunch of blogs in the works to describe just how these processes work.

Are you interested in learning more?  Do you want to know some of the nutrients that you should be eating to help your healing process?  What about some recipes and exercise recommendations?  All of this will be coming out in the next few months, but most of the specific recommendations will only come out in private facebook group.  If you want to join, all you have to do is request it here.