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POW: Therapeutic Manipulation of the Microbiome in IBD

Alyssa Luck · Aug 11, 2015 · Leave a Comment

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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Hi! I’m Alyssa. I like thunderstorms and cats, hate wearing shoes, and enjoy devising extensive research projects for myself in my free time. This is me in Bali with a monkey on my shoulder. And this is my blog, where I muse about health-related topics and document my relentless self-guinea pigging. If you want to know more about me, click here!

alyssa.luck

alyssa.luck
Photo dump from the last year. Thanks to everyone Photo dump from the last year. Thanks to everyone who made 28 the best yet - excited for 29🥰

(PS. In case anyone wants to know what it’s like in my head, I was going to write something like “year 28” or “my 28th year” but then I realized that the year between your 28th and 29th birthdays is not your 28th year of life, it’s your 29th year. I am turning 29 because I have been alive for 29 years. So then I had a whole thing about how to word it without being inaccurate and ended up going with what you see above which is vague and weird but the point is it was a good year and I love all the people in my life dearly)
Biology of Belief (2005) was written by Bruce Lipt Biology of Belief (2005) was written by Bruce Lipton, who earned a PhD in developmental biology in 1971 and was an anatomy professor and academic researcher in the 70s and 80s. Despite the book's presentation and Lipton's background, this is not a science book. It is an exposition of an ideology, supported by haphazard and poorly contextualized nuggets of evidence, rhetorical leaps, and a mind-boggling overuse of analogies. 

The book largely failed to deliver on its promised content. What it does is argue for the primacy of the environment over DNA in controlling life; propose that the cell membrane rather than the nucleus is the "brain" of the cell; invoke quantum physics to explain why modern medicine fails; explain that our behavior is largely controlled by our subconscious mind; inform parents that they therefore have a great deal of control over the destiny of their children; and conclude that humans must become nonviolent protectors of the environment and of humanity because Everything Is Connected.

It’s not that these points aren’t relevant to the topic at hand - they are. But they were not connected in a coherent way that would explain how “belief” actually works (like…biologically), and the treatment of scientific concepts throughout was careless, or perhaps disingenuous.

I think he's correct about many things, some of them being common knowledge. For instance, the "new" science of epigenetics is now old news, as is the critical role of parenting and early environment in shaping a child’s future. But however important these and attendant concepts may be, the book did not do a good job explaining, supporting, or connecting them. 

As far as practical guidance, he refers the reader to a list of resources on his website, which is fine, but I expected some scientific insight into how/why those modalities work. None was given. 

On the plus side, the book was quite thought-provoking, and I came away with loads of references and topics to follow up on. My favorite line? "There cannot be exceptions to a theory; exceptions simply mean that a theory is not fully correct."
Friedrich Nietzsche, The Gay Science (section 382) Friedrich Nietzsche, The Gay Science (section 382), as quoted in the introduction to Thus Spoke Zarathustra because I like the translation better.
This paper totally changed the way I think about e This paper totally changed the way I think about early nervous system development and the relationship between physiology and sociality. 

The authors propose that newborn babies are not inherently social, and have just one goal in life: physiological homeostasis. I.e. staying alive. This means nutrients, warmth, and regulation of breath and heart rate, i.e. autonomic arousal (it’s well-accepted that newborns sync their breathing and heart rate with caregivers through skin to skin contact). 

All these things are traditionally provided by a loving caregiver. So what the baby experiences during the first weeks of life, over and over, is a shift from physiological perturbation to homeostasis (a highly rewarding event inherently) REPEATEDLY PAIRED with things like the sound of a caregiver’s voice and seeing their face. Thus, over time, the face/voice stimuli become rewarding as well. 

The authors argue that THIS is the beginning of humans’ wiring for sociality, and may explain why loving social interactions can have such a profound regulating effect on physiology throughout life: because the brain was trained for it at an early age. 

This framework holds all kinds of fascinating implications for what happens if that initial “training” isn’t so ideal. What if the return to nutritional homeostasis via feeding is paired with negative expressions and vocalizations rather than loving ones, perhaps as could occur with PPD? What happens if the caregiver has poor autonomic regulation, such that social stimuli become paired with cardiorespiratory overexcitement in the baby? Could that have potential for influencing later introversion vs extroversion? (Because if social interaction is paired with autonomic overexcitement, that could lead to social interaction literally being more energetically draining, which is what introverts experience. Thoughts?)

For my energy metabolism enthusiasts: Table 1 in the paper draws a link between metabolic rate and sociality across species. Swipe for a screenshot. 

Anyway, check out the paper! It’s free, just google “growing a social brain pdf.”
I’ll be under general anesthesia in a couple day I’ll be under general anesthesia in a couple days to have two tooth implants placed, and I think I’ll take the opportunity to have a little heart-to-heart with my subconscious mind. A bit of medically-assisted self-hypnosis, if you will. 

I randomly stumbled upon these papers a couple months ago - an RCT showing reduced post-op pain in patients who listened to recorded positive messages while under general anesthesia, plus a post-hoc analysis of the same data that found reduced post-op nausea and vomiting in a subset of high-risk patients. 

The full review paper from the first slide is unfortunately in German, but it has long been recognized that even when unconscious, the patient is listening (for better or for worse). 

It boggles my mind that it isn’t standard of care to have patients listen to recordings like this while under sedation, considering that almost nothing could be easier, safer, or cheaper, and we have at least some evidence of significant efficacy. I mean c’mon, what more could you want from an intervention? 

(Yeah, I know. Profit. If anyone still thinks that our medical system operates with patient well-being as the foremost goal, you’re deluding yourself.)

“There should be a fundamental change in the way patients are treated in the operating room and intensive care unit, and background noise and careless conversations should be eliminated.”

“Perhaps it is now time to finally heed this call and to use communication with unconscious patients that goes beyond the most necessary announcement of interventions and is therapeutically effective through positive suggestions. When in doubt, assume that the patient is listening.”
If you've seen "vagus nerve exercises" that have y If you've seen "vagus nerve exercises" that have you moving your eyes or tilting your head, you've probably encountered the work of Stanley Rosenberg. The exercises he created and introduced in his 2017 book now appear in instructional videos all over the internet. 
 
The book itself has much to recommend it: it's accessible, it's practical, it's inspiring. But it has one major flaw: the solid practical and informational content regarding the cranial nerves is framed in terms of the scientifically dubious polyvagal theory. 
 
I particularly enjoyed the book as an introduction to the therapeutic arena of bodywork, of which Rosenberg is a skilled practitioner. His book is full of case reports that demonstrate how immensely powerful extremely subtle movements and physical manipulations can be. These do need to be kept in perspective: it's a small sample size of the most remarkable cases, and the results were achieved within the supportive clinical environment of a skilled practitioner. You can tell from his descriptions how refined his technique is. But nevertheless, it was a paradigm-shifting read for me, and the exercises give you something concrete to play around with. 
 
The book also brought the cranial nerves and the concept of “social engagement” to the fore as arbiters of health. Rosenberg has a solid background in cranial nerve anatomy and shares many interesting tidbits and considerations that you don’t typically hear; for instance, the potential impact of dental and orthodontic work on cranial nerve function.
 
So, is it worth reading? If any of the above piques your interest, go for it! Just read my post on polyvagal theory first – you can use the book to practice separating the wheat (solid informational content) from the chaff (pseudoscientific framing). If nothing else, the book is a nice reminder that genuine healers who get lasting results for their patients do exist.

But if you just want to try the exercises, you can easily find them all on YouTube. 

“You learn techniques to understand principles. When you understand the principles, you will create your own techniques.” -Stanley Rosenberg
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