Fecal Microbiota Transplant for Inflammatory Bowel Disease Part I

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In my last blog post I presented the results of a comprehensive stool analysis that looked at the levels of beneficial bacteria that reside in the gastrointestinal tract. Viewing my results of the stool test, it quickly became apparent that many of the types of bacteria I was colonized with, I had never associated as healthy bacteria, or even heard of such as bacteroidetes, firmicutes, prevoltella, fusobacteria, bacteroides, Streptomyces, mycoplasma, clostridium etc.

Most of these organisms I was aware of from flipping through my college microbiology textbook, but we tended to focus on the more pathogenic bacteria in my college course (clostridium Difficile). I was unaware that many of these unheard of bacteria made up the majority of my microbiota.

My functional medicine doctor recommended a probiotic that contained only 3 of the 9 species listed on my stool test. I know that there are studies that support probiotics in the aid of inflammatory bowel disease, but I had a fixation on the theoretical principal of actually replacing the bacteria I was low in (e.g. clostridium) or possibly even extinct types of bacteria in my gut.

My journey into my microbiome was largely motivated by the situation I had found myself in; I was what clinicians call steroid dependent. This occurs when you are unable to come off the drug prednisone without a reoccurrence of ulcerative colitis symptoms, in my case I would get severe gastrointestinal pain and diarrhea at every attempt to lower my dose of prednisone below 10mg.

How We Currently Treat Inflammatory Bowel Disease

The standard treatment for an individual who is steroid dependent like myself at this time, is to wean them on to the next higher class of drugs, the powerful immune suppressing drugs, or as my gastroenterologists calls them “the big Guns”. Unlike prednisone (cortico steroid) these are intended to be used in the long term because they generally take some time for the effects to begin.

These drugs essentially turn off a portion of your immune system in an autoimmune disease, and help to stop the attacks on the body’s own tissue. These drugs do a good job at turning off the immune system where it is over active, but they also turn off beneficial arms of the immune system as well. The immune system plays an important role in detecting and fighting off cancer and pathogens. Consequently one of the terrifying risks associated with these immune suppressing drugs are the increased risk of types of cancer and infections.

The newer immune suppressing drugs are called biologics, examples include humira (adalimumab) and remicade (infliximab). They are administered intravenously or subcutaneously, at the frequency of every other week to every few months and can cost from $19000 to $22000 a year. These work by turning off a portion of the adaptive immune system known as TNF alpha (1). Side effects include but are not limited to T-cell lymphomas, skin cancers, opportunistic infections and an overall increased risk of all cancers may increase as well.

These two drugs carry a black box warning. This serves as a warning from the FDA to healthcare providers and patients that the drug may cause serious adverse effects; this is the most serious alert that the FDA can necessitate (2, 3). Many patients are unaware of this before starting the drug.

Another disturbing fact is clinical trials of these two immune suppressing drugs (anti TNF biologic therapy) is that they have shown incomplete clinical efficacy, in that only half the treated patients respond favorably (4).

The other class of immune suppressing drugs are mercaptopurine, 6MP and azathioprine. These drugs have been around for a while, they are used in cancer patients, organ transplants and many other autoimmune conditions. What turned me away from these types of drugs are the necessity to have routine blood tests to check liver function to ensure that I was not experiencing liver damage.

Side effect of this drug are also increased risk of certain types of cancer, infection, bone marrow suppression (particularly those with thiopurine S-methyltransferase enzyme deficiency), nausea and vomiting. International Agenda for Research on Cancer considers this drug as a known human carcinogen (5, 6). Sadly, I’m only scratching the surface on side effects.

My intent isn’t to convince people that these drugs should never be used, I know they have their place and have certainly saved many lives, but I want to put in context the situation I was in and where my motivation came from to pursue alternative treatments. I refused to accept that the aforementioned treatments or surgery to remove my colon were my only option.

Exploring the microbiome seemed to be the best starting point and upon further research, it seemed to make much more sense than the two standard of care options mentioned above.

After coming to the realization that the microbiome is not entirely comprised of yogurt bacteria, I recognized the necessity for me to take a step back and investigate what was really going on inside of my intestines.

 Increasing Incidence of IBD

An issue many Americans are facing today is that while communicable diseases have decreased, the prevalence of chronic diseases has increased (7). More specifically I’d like to use inflammatory bowel disease (IBD) as an example here, since that is the focus of this blog. IBD seems to be increasing in frequency along with other diseases associated with the western lifestyle. Here is a graph of the incidence and prevalence of Crohns disease from 1960-1979.

Now here is the incidence and prevalence of Crohns from 1980-2006.

Where did all that red come from in just 20 years? This massive increase cannot be fully explained by increased detection, or by genetics. This increase is akin to a massive infectious outbreak (8). Similar information exists for many autoimmune diseases as well.

In my opinion, this should be a red flag to all of those affected by these western diseases. Sadly much of the money, time, and resources from researchers are more focused on a treatment for these diseases after they happen, rather than trying to prevent or find an environmental cause. Watch the documentary Pink Ribbon Inc to learn more about this.

What the Research says about the Microbiome

Before we begin talking about the microbiota it is important to define some terms. The human microbiota are the particular community of bacteria in or on the human body including bacteria, archaea, microeukaryotes and viruses in the hair, skin, gut, nose, ear, etc. With increasing interest, research is primarily focused on the bacteria portion of the microbiotia because it is a bit easier to study.

Our microbiome has taken a turn for the worst, in terms of both biodiversity and the microbial makeup of our gut. The term biodiversity is used often in biology; this is a measure of organisms present in an ecosystem. You can think of the gut as an ecosystem like a rainforest, the more biodiversity the better, as each of these organisms have specific beneficial functions.

Intestinal biodiversity

Image source                                                            OTU stands for operational taxonomic units, a measure of intestinal biodiversity.

Our environment and lifestyle seems to be linked to our individual microbiota (9) Compared to the US, the non-industrialized societies tend to have far greater intestinal biodiversity. Damages in the western gut ecology has come as result of increases in antibiotic over use, frequent elective C-sections, antiseptic soaps, antibiotics in the food and water, formula fed infants and insufficient fiber in the western diet. It is now thought that the changes in the microbiota are fueling many of the modern diseases we face today.

How We Study The Microbiome

In the past we had issues identifying many of the bacteria that resides inside us because it is hard to identify bacteria based only on morphology (shape) as many bacteria look alike.

Another method that has in the past been faulty at studying a majority of the gut microbes is culturing them on a petri dish. The issue with this is that a majority of the microbes living in the gut cannot be cultured on a petri dish.

A good example of this is in my college microbiology lab we grew microorganisms on non-selective media (a petri dish) from different sites of our bodies to see what bacteria was present. It was interesting to find that E. coli was the main bacteria that was cultured from my intestinal tract, even though E coli only makes up a small percentage of out gut microbiota.

With the help of new bacterial 16sRNA PCR DNA sequencing technology and bioinformatics, we can now see many bacteria that cannot be grown on a petri dish, or identified based on morphology and gram stain (10). This technology works by identifying bacteria based on its individual genes; you can think of the DNA like a blueprint to each and every bacteria cell, we use this blueprint as a means to identify them. Up until this point, most the bacteria that resides in our gut could not be identified.

Recently more and more research is focused on the study of the microbiome. Thanks to the 173 million dollar project funded by the National Institute for Health, the Human Microbiome Project and the crowd funded American Gut Project is utilizing this new technology PCR DNA sequencing. These two research projects are helping us to more fully understand the interactions the microbiota has on the individual.

The study of the microbiome has opened up a whole new world of research and has led to a new way of thinking about disease. It was once thought that most bacteria was mostly bad, but now we are finding out that a vast majority of bacteria is ether neutral or beneficial, and only a small portion of bacteria is actually pathogenic; medical science has done an excellent job of identifying these pathogenic species.

We carry around 3 lbs of microbes in our bodies. Another interesting point is our bacterial cells outnumber our human cell in numbers by 10 to 1. We have about 10 trillion human cells, whereas we have 100 trillion microbial cells (11). One could say we are more microbes than human.

When I first started looking over the scientific literature on the microbiome I found that it influences almost every major organ system of the body. Here is a quick overview of what I learned.

Benefits of a healthy microbiome

Immune

  • Gut microbiota constantly interacts with the adaptive immune system.
  • The microbiome can stimulate the development of the immune system: mice without a gut microbiota are more susceptible to viruses, bacteria and parasite infections (12)
  • Increases T regulatory cell production.
  • Early exposures to pathogens may tune the immune system by lowering the levels of natural T killer cells (13).
  • People who have more diverse microbiota tend to have less allergies and asthma.
  • Protection from IBD (14).
  • Protection from certain autoimmune diseases.

Digestion

  • Makes vitamin K
  • Secretes antimicrobial peptides

Detoxification

  • Interestingly, sulfate reducing bacteria seems to play a role in determining the toxicity to the liver of the over the counter analgesic acetaminophen (Tylenol) on the host (15).

Metabolism

  • Obese mice seem to have bacteria that can extract much more calories from food than non-obese mice in the same diet, meaning the gut microbiome can determine the amount of calories harvested from the diet. This study shows that individuals with less microbial gene richness (bacterial biodiversity) had a low metabolism and higher inflammation (16).
  • In a study of no biotic mice (germ free mice), and the germ free mice that received bacteria from the lean mice stayed lean. The mice that were implanted stool bacteria from the obese mice also became obese (17). This study showed a cause and effect relationship.
  • Our bodies have receptors that help recognize bacteria. One receptor is called toll like receptor 5 (TLR 5). TRL5 knock out mice gained significantly more weight than regular mice. When the TLR 5 knock out mice stool bacteria was put into the genetically normal mice, they also gained weight. This shows your gut microbiota may be encouraging you to eat more (18, 19).
  • Characteristics of lean animal models.
  • Reduced hydrogen and methane production.
  • Increased potential to manage oxidative stress.
  • Generally harbored a greater number of microbial genes (biodiversity) than obese ones.
  • The short chain fatty acid acetate, produced by a healthy microbiome, seems to pass through the blood brain barrier and suppress appetite (20).
  • Agriculturalists have known for 50 years that feeding livestock antibiotics can fatten up an animal up to 15% and increase profits. Recently studies are proving this observation made by agriculturalists in animal models (21, 22)
  • May protect against malnutrition (23)

 Neurological

It is now evident that there is a connection between the microbiota and the brain; this is known as the microbiota–gut–vagus–brain axis or gut brain axis for short. This microbiota may influence the learning memory and decision making.

Gut microbes can influence mental health and is associated with a wide range of mental diseases. The gut microbiota and central nervous system (CNS) seem to be bidirectional, meaning one may affect the other and vice versa. You brain may determine how your gut microbiota develops, and your gut microbiota may also influence your CNS. The picture below shows that there are a few different ways that the gut microbiota gets the messages to the brain (24).

  • Immune cells in gut sense the gut bacteria and release cytokines (immune signaling chemicals), the changes in the levels of these cytokines influence the brain. The gut microbiota can also activate cells in the gut that can produce peptides, these peptides can actually activate nerve endings.
  • Microbes can communicate by producing neurotransmitters; these are signaling molecules that the nervous system uses to communicate. A good example of this is the well-known neurotransmitter serotonin, it is a drug target for many antidepressant medication. 90 percent of serotonin is found in the gut, not in the brain. So gut Microbes can interact with the CNS numerous ways (25).
  • The brain may also modify the composition of the gut microbiota as well (26). In a stressful situation cortisol can alter gut barrier integrity (cause leaky gut). So in other words, stress can cause bacteria to leak into your body that normally remains inside the gut.
  • Manipulating the microbiota with probiotics may become a treatment for neurological disorders (27).

“Bifidobacterium longum NCC3001 normalizes anxiety-like behavior and hippocampal brain derived neurotrophic factor (BDNF) in mice with infectious colitis (28).”


“in this study we observed that L. rhamnosus (JB-1) administration reduces the stress-induced elevation in corticosterone, suggesting that the impact of the Lactobacillus on the CNS has an important effect at a physiological level (29).”

Behavioral

  • Lean mice that are transplanted with fecal matter from obese mice became obese and began to engage in activities of over eating. The obesity was cured in this study by administering antibiotics or by limiting the amount of food the mouse could eat, this suggests that the transplanted bacteria from the obese mouse may have behavioral changes that make them eat more (30).
  • In another study the gut microbiota was responsible for the mating preferences of fruit flies. Fruit flies eating molasses preferred to mate only with other flies who ate molasses whereas flies who ate starch based diet tended to only want to mate with other flies eating starch. When these flies were given antibiotics it ended the mating preferences of the flies (31).
  • A majority of autistic children suffer from gastrointestinal disorders and seem to have gut barrier dysfunction. Studies of children on the autism spectrum seem to have different microbes and less diversity than children without autism (32).
  • In the mouse model the symptoms of autism were partially restored with the bacterium fragilis. This suggests that restoring the gut microbiome maybe a future treatment for autism (33). There are currently studies being conducted for the therapeutic value of fecal transplants in autistic children.

Why We Are Treating IBD the Wrong Way

Considering all the effects we are beginning to understand that the gut microbes have on the human body as listed above, we can begin to formulate treatments to modulate the gut microbiota for a wide variety of different conditions, anywhere from autoimmune conditions, fighting infections, allergic conditions and diseases of the central nervous system. This is exactly why I started looking deeper into the microbiota research to see if I could extract any clinical perils and or modifiable factors I could implement to treat my disease. I was very encouraged when I came across this in a meta-analysis study.

“T1D (type 1 diabetes) is likely an autoimmune disease, whereas CD and UC are likely caused by inappropriate inflammatory responses to components of our microbiome (34).”

 

According to the paper above IBD should not be treated as an autoimmune condition. The way we currently treat IBD is by turning the immune system off with dangerous drugs. A more sensible appropriate approach based on this research would be to manipulate the microbiota so the immune system is not attacking components of the microbiota. In other words, instead of truing off the immune system, we should change the bacteria in the gut that the immune system is attacking. This would be treating the root cause of IBD. In order to do this we would need to formulate accurate tests to measure the microbiome.

“A critical clinical question is whether we can develop quantitative microbial biomarkers to monitor differences in microbial composition associated with established IBD, because the absence of such biomarkers is currently a barrier to developing and accessing treatments targeting IBD-associated dysbiosis (35).”

“Comparing the microbial signatures between the ileum, the rectum, and fecal samples indicates that at this early stage of disease, assessing the rectal mucosal-associated microbiome offers unique potential for convenient and early diagnosis of CD (36).”

This along with identification of risk factors may be essential for the diagnosis and treatment of IBD.

In my next post I will go deeper into the science of what influences the microbiota and how a deviation of normal healthy ancestral microbiota sets up the perfect storm for disease to manifest.

 

Further Reading:

Fecal Microbiota Transplantation for Inflammatory Bowel Disease Part II

Fecal Microbiota Transplantation for Inflammatory Bowel Disease Part III

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