Truthbutter

POW: Therapeutic Manipulation of the Microbiome in IBD

Hellooo, friends, and welcome to the first weekly installment of Paper of the Week (POW)! This delightful new feature of my blog is where I read a paper that I want to read, and then I tell you about it. That way you learn something (theoretically), and I actually remember what I read (theoretically).

This Week’s Paper

Title: Therapeutic Manipulation of the Microbiome in IBD: Current Results and Future Approaches

Authors: Jonathan Hansen and Balfour Sartor (gastroenterologists and researchers at UNC aka MY SCHOOL #represent)

Year: 2015

Type: Review paper

Abstract (partial): 

Despite recent major strides in our understanding of the genetic and microbial influences that contribute to the development of the inflammatory bowel diseases (IBDs), their etiology continues to be enigmatic. Results from experiments in animal models of IBDs overwhelmingly support a causal role of the microbiota in these diseases, though whether such a cause-effect relationship exists in human IBDs is still uncertain. Therefore, virtually all currently approved and most often prescribed treatments for IBDs are directed toward the over-active immune response in these diseases rather than the intestinal bacteria. Nevertheless, there is an important need for non-immunosuppressive therapies that may present a more favorable risk-benefit profile such as those that selectively target the disruptions in gut microbiota that accompany IBDs. This need has led to clinical trials of various microbial-directed therapies including fecal microbial transplant, antibiotics, probiotics, and prebiotics. Unfortunately, these published studies, many of which are small, have generally failed to demonstrate a consistent benefit of these agents in IBDs, thus leading to slow acceptance of microbe-focused treatments for these conditions.”

Let’s go!

Background

If you didn’t already know, I got into this whole nutrition/health/reading papers/blogging thing because I was diagnosed with ulcerative colitis awhile ago, so unsurprisingly, IBD is one of my favorite research topics. To give you a quick rundown, IBD:

  • stands for Inflammatory Bowel Disease, and mainly includes ulcerative colitis (UC) and Crohn’s disease (CD)
  • involves autoimmune attack on the digestive tract, causing ulcerations, bleeding, cramps, diarrhea, and other fun stuff
  • has no cure (except in the case of UC, where you can remove the entire colon, thereby “curing” the disease)
  • until recently had no known cause (debatable), but now, most researchers (and hopefully GI docs?) agree that gut microbes play a major role

Now, onto the paper. According to this paper (and several others on the subject), researchers have suspected for a long time that gut microbes might have something to do with IBD. When I was diagnosed 7 years ago, my docs told me that IBD had no known cause, which kinda pisses me off, but that’s a rant for another time. But now one of the prevailing hypotheses is that IBD is caused by “overaggressive immune responses to intestinal microbiota in genetically predisposed individuals.” (This might be obvious, but unless otherwise noted, any quotes or information in the remainder of this blog post is from the above-listed POW.)

IBD has been associated with increased levels of certain types of bacteria (such as Proteobacteria) and decreased levels of other types (such as Firmicutes), as well as an overall decrease in richness (i.e. amount) and diversity. Patients with other digestive conditions (such as C. diff infection) show similar dysbiosis patterns, which is cool because it means that several different conditions might be treatable with similar therapies.

Another cool thing (that I sort of knew, but sort of just learned) is that the functional pathways of intestinal bacteria are significantly altered in IBD patients. For instance, bacteria in IBD patients express more genes involved in oxidative stress and nutrient uptake (bacteria can be sneaky little calcium and iron thieves), and fewer genes involved in biosynthetic (i.e. growth) pathways. But the thing is, we still can’t definitively say whether the gut dysbiosis causes the IBD, or the IBD causes the dysbiosis. I think like most things, it’s probably a little of both.

 

Microbe-Based Treatment for IBD

So, if messed up gut bugs could be causing IBD, how should treatments change? Current treatments are completely focused on suppressing the immune system, which can increase risk of infection and cancer and also often stop working after awhile (or right away). So it would make a lot more sense to treat IBD by addressing gut dysbiosis, right?

 

Fecal Microbiota Transplant (FMT)

Right. As such, researchers have begun to test fecal microbiota transplants (FMT) (i.e. putting healthy person’s poop into intestines of sick person to facilitate re-calibratiion of gut bugs) as a treatment for IBD. It’s super effective for C. diff infections, which is awesome, but so far hasn’t been nearly as effective in IBD.

In uncontrolled trials of both UC and CD, some patients have gone into remission from FMT. But the only RCT on FMT in UC (wow, sorry) thus far was stopped early due to futility, although some participants did experience significant improvement of their UC with FMT. (Isn’t “futility” such a sad word?) So clearly, FMT can be helpful for some people, but there are still too many variables (donor stool composition, delivery method, dose, etc) and not enough strong study results for FMT to be a mainstream treatment option. Boo.

 

Antibiotics

Antibiotics have similarly variable success rates in both UC and CD, with more success in Crohn’s. Broad-spectrum antibiotics had more success in UC than narrow-spectrum. But all I could think while reading this section of the paper is how much I wanted to yell at the authors of all the antibiotic studies. Something along the lines of “what probiotics or prebiotics were given to study participants along with the antibiotics? Oh, none? You can’t honestly think antibiotics would help matters without also replacing the good bacteria??! Were you born yesterday?!! UP YER PROBIOTIC GAME, YA FRUITCAKE!”

So I’m going to go ahead and talk about probiotics and prebiotics, before I start calling any more researchers fruitcakes. For the record, I think antibiotics are powerful and very useful sometimes and also a little scary but would fully support more research on treating IBD with a combo anti-pro-biotic therapy. If anyone has come across research on that, let me know!

 

Probiotics and Prebiotics

Anyway, ‘probiotics’ (as a uselessly general category) are not consistently effective at inducing remission in UC, but two formulas in particular have been able to induce remission in a few clinical trials. One is E. coli 1917 Nissle, and the other is my homeboy (homebug? homebiotic?) VSL#3. (Is it just me, or do both of those sound vaguely like rapper names? Like, “yo, 1917 Nissle in the hizoussseeee!” No? Okay.) Their success in clinical trials is why VSL#3 costs upwards of $700 for a one-month supply, BUT is also covered by insurance if your doc prescribes it. Score!

VSL#3 is also incredibly effective for managing pouchitis*. In one study, VSL#3 maintained remission in 100% (!!) of experimental patients, compared to the placebo group’s 15%. Unfortunately, VSL#3 (and probiotics in general) have not been very successful thus far in studies on CD.

Now, prebiotics. Prebiotics are indigestible (by us) carbohydrates that feed and promote the growth of beneficial bacteria like bifidobacteria and lactobacillus strains. In response, these beneficial bacteria produce short-chain fatty acids such as butyrate, which is the primary fuel for colon cells and helps regulate the immune system. Prebiotics have been successful in treating animal models of colitis, but have had mixed results in human trials. Nothing very exciting.

 

Concluding Remarks

The authors note that it’s important to keep in mind the potential risks of manipulating the gut flora, especially with more powerful therapies like antibiotics and FMT. Adverse reactions to FMT have been reported, and mouse studies have shown us that transferring fecal bacteria can also transfer conditions like obesity and metabolic syndrome. (Crazy, right?? I’m gonna have to make those POWs soon.) And we know the dangers of antibiotics are nothing to scoff at.

The authors also conclude that even though current studies on microbial therapies for IBD are disappointing, this is likely because the therapies just aren’t that good yet, rather than because the idea behind them is incorrect. This is what they suggest:

First, personalized microbial-based therapies based on an individual’s particular intestinal microbiota profile can be designed to reduce/eliminate a person’s pro-inflammatory bacterial, viral or fungal species while simultaneously increasing the number or function of decreased anti- inflammatory species…Second, alternative novel approaches to microbial-based therapeutics should be developed, in- cluding administering synthetic bacterial products rather than viable organisms, using recombinant bacteria to secrete protective proteins directly to the distal ileum and/or colon, and using bacteriophages in targeted viral therapies.”

YES. Yes please.

 

Things I Didn’t Know

  • Genome association studies have found IBD-associated loci in or near genes involved in immune responses to microbes
  • IBD is associated with increased diversity and richness of fungi (which is opposite from the association with bacteria)
  • THE FIRST PUBLISHED USE OF FMT FOR IBD WAS IN 1989. ARE YOU KIDDING ME?? THE GUY WENT INTO A MED-FREE REMISSION ONE WEEK AFTER THE TRANSPLANT. AND IT’S TAKEN US 26 ADDITIONAL YEARS FOR FMT TO BECOME A MAJOR RESEARCH TOPIC?? It’s cool. I’m good. Sorry for the caps.
  • Antibiotics have long been used as a primary treatment option for Crohn’s. I had no idea. Why not for UC?? When I first got sick, docs thought it was parasites, so they gave me an antibiotic and my symptoms went away for 6 months. Why wouldn’t they explore that type of treatment again when my symptoms came back and I was diagnosed with UC? I don’t get it.
  • Considerable data indicates that early life antibiotic exposure is a risk factor for developing CD, but not UC. I totally thought it was implicated in UC, too!

 

Well, that concludes the first Paper of the Week! Hopefully I’ll actually be able to do this weekly, but if not, a POW will still be the paper of that given week, even if the previous and subsequent weeks don’t have a POW. So it works. Also, sorry that this one got a little ranty. I’ll work on it. Really. Right after this last asterisk.

 

*I’d like to rant talk for a moment about how dumb “pouchitis” is. First, the name. Pouchitis. It sounds dumb. Second, the thing itself. It refers to inflammation of the pouch that surgeons create out of the end of the small intestine in UC patients (such as myself) who have had their entire colon removed. Symptoms of pouchitis (according to Mayo Clinic) include diarrhea, abdominal pain and joint pain, cramps, fever, increased number of bowel movements, nighttime fecal seepage, fecal incontinence, and a strong feeling of the need to have a bowel movement.

WOW, that sounds a lot like UC! But it can’t be, because having your colon removed “cures” UC! So it’s not UC, it’s “pouchitis,” a condition that makes you feel like you have UC, which occurs in 23-46% of patients who have undergone a complete colectomy to cure their UC, and who now get to feel like they have UC but without the hassle of actually having a colon! Swell.

 

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