Summary: Do yourself a favor and look over this post about gut microbiome manipulation even if your interest in microbiome is not autism or Fecal Microbiota Transplant (FMT) because the microbiome can be manipulated many ways, FMT being only one way. DIET has a major impact on microbiome, and I’m surprised that there are only three clinical trials looking at diet and autism out of the 445 clinical trials looking at diet and microbiome (as of May 28, 2019). More surprising, there’s nearly300 clinical trailsnow going on that look at FMT impact to the microbiome for many of the diseases you guys have, like: IBS, T2D, MS, IBD, melanoma, cancer, depression, anxiety, obesity, metabolic syndrome, liver NAFLD, Alzheimer’s, Parkinson’s, Psoriatic Arthritis, food allergies, recurrent UTIs, Sarcoidosis, antibiotic resistance, Chronic Fatigue Syndrome, epilepsy, Sjogren’s, HIV, malnutrition…. Manipulation of the microbiome is being looked at because the microbiome is known to be altered in inflammatory ways for most all diseases, and it’s health determines your health. For autism for example, [Saghazadeh et al 2019] reported an increase in pro-inflammatory cytokines called IFN-γ, IL-1β, IL-6, and TNF-α. That’s the immune system gone rogue. Here’s the laundry list of pro-inflammatory cytokines that were found to have no significant alteration: IL-1α, IL-2, IL-2R, IL-3, IL-7, IL-8, IL-12, IL-12p40, IL-12p70, IL-15, IL-17, IL-18, IL-23, TBF-β, and TNFRI/II! Your disease will have some mix of pro-inflammatory cytokines going on and manipulating the microbiome can decrease demands on the immune system to send out these enforcers and positively affect disease state. I hope researchers include impact to cytokines in subsequent evaluation for microbiome studies. This post reports on [Kang et al 2019] which is a TWO year follow-up study of [Kang et al 2017], which was a small pilot trial that used an 8 week FMT intervention for 18 children with Autism Spectrum Disorder (ASD). They evaluated FMT impact to GI symptoms, behavior, and the gut microbiome. The conclusion of the 2019 follow-up study was that GI and behavior symptoms continued to increase or improve, and microbial diversity continued to increase and looked more similar to their donors based on 16S ribosomal RNA (rRNA) microbiome sequencing, FOLLOWING the original Microbiota Transfer Therapy (MTT) intervention. Participants still had an average of a 58% reduction in GI symptoms and a 45% decrease in ASD symptoms compared to baseline. In addition, the parents of most participants reported a slow but steady improvement in core ASD symptoms during treatment and over the next two years., and that’s why the 2 year follow-up study was done. The study suggests that the recipients didn’t retain completely the donated microbiome, but rather retained some features of it such as increased overall diversity, and increase in some important microbes such as Bifidobacteria, Prevotella, and Desulfovibrio while finding a NEW state. The authors note that these encouraging observations demonstrate that “intensive MTT intervention is a promising therapy for treating children with ASD who have GI problems.” They recommended future research include double-blind, placebo-controlled randomized trials with a larger cohort. Read on to learn the power of microbiome manipulation, no matter what method(s) you employ! \O/
Category Archives: Blog: Microbiome & FMT
Finally, an IBD microbiome drug goes to clinical trial
Summary: Seres Therapeutics began its Phase 1b placebo controlled clinical trial on Dec 14, 2015, for SER-287, which is the first drug aimed at the microbiome for a non-infectious, chronic condition, ulcerative colitis (UC). This is the first IBD microbiome drug that actually targets the constituents of the microbiome. This approach treats chronic disease without suppressing the body’s immune response. Instead, specific strains of bacteria are introduced that re-balance the billions of different types of bacteria that are in the digestive tract, which then increases immunity and manages the disease. Instead of being immunosuppressive, this treatment targets the root cause of UC which is gut dysbiosis, increasing immunity. SER-287 clinical trial is currently recruiting participants if you are interested; contact information is below.
Note: The immune system outsmarts anti-TNF meds a lot of times — 30 to 80% of the time for IBD. Isn’t that a crazy broad failure range? This post speaks to some of the whys of that failure. And… realize a lot more diseases use these immunosuppressive meds beyond IBD.
I wrote about the immunosuppressant and biologic microbiomes not looking ‘healthy’ in this post, and in fact had the opportunity to have that very question answered and confirmed by Johns Hopkins GI expert Dr. Gerard Mullin, MD at the Evolution of Health Functional Forum, called Microbiome Maximized Medicine, held in NY on October 5, 2015. The YouTube of that dialogue can be linked to on this post.
These disease microbiome drugs are not immunosuppressive, rather their mechanism of action is to enhance and increase immunity.
Incidentally, healing diets also introduces microorganisms and food substrate matter into the gut that cause mucosal healing with increased immunity to manage chronic disease
I wrote about the microorganisms we ingest at: AVG NUMBERS AND KINDS OF MICROORGANISMS CONSUMED IN A DAY. Interestingly, the USDA dietary pattern had the highest total microorganisms for the day, due to yogurt and cottage cheese consumption, whereas the AMERICAN and VEGAN dietary patterns had 3 orders of magnitude fewer total microorganisms primarily due to heating probiotic type food such as cheese (which kills microorganisms) or the diet lacks consumption of probiotic type foods. I am certain the FODMAP type foods omitted or ingested also impact microbiome richness since these food substrates are food for bacteria which if provided, will accordingly bloom bacteria. See here for a FODMAP post. Healing diets contain unheated live fermented foods and tolerable FODMAPS and have been shown to increase microbiome diversity and immunity in compromised guts. See this post for IBD: 50 IBD SCD REMISSION PATIENTS: RUSH PAPER.
“Bugs as drugs” idea for disease treatment
Startups are harnessing the trillions of bacteria inside us to eradicate chronic disease such as diabetes, obesity, arthritis, MS, autism, depression, and more. This “bugs as drugs” idea for disease treatment packages live strains of bacteria originating from a healthy donor’s microbiome to be used as therapy.
This all began as a fecal microbial transplant (FMT) which is currently approved for antibiotic resistant CDiff infection and has over 90 percent cure. A startup that provides FMT substrate matter originated out of a not-for-profit from MIT and is called OpenBiome. Mark Smith is OpenBiome’s founder who considers that the oral application wouldn’t just reduce the discomfort of the FMT transplant, but that “swallowing a capsule of someone else’s healthy digested material — [that’s where the live strains of bacteria are coming from] or eventually swallowing strains cultivated in a lab,—could become a maintenance therapy for sufferers of a variety of gastrointestinal disorders, and for that, “We’re in the testing and evaluation phase.” Side bar: Anecdotal evidence from my follow of numerous DIY groups does lean towards needing repeat FMT for some diseases. Diet impact post-FMT microbiome is not well understood (nor is it understood pre-FMT for the donor) which could impact acceptance of the transplanted microbiome sooner.
“FMT are not the way of the future. They are just a transitional solution… [for OpenBiome’s capsule, the first patient to test will be] a quadruple amputee with C. diff. She’s not a good candidate for a fecal transplant, but her doctor thinks this pill might be perfect.” –MIT Lab Hosts Nation’s First Stool Bank, But Will It Survive? and WHAT’S LURKING IN YOUR MICROBIOME? POSSIBLY, A CURE FOR DISEASE
Why start with IBD for “bugs as drugs”?
The short of it is, they are picking diseases with known causation being gut dysbiosis; there is a difference with correlation and causation. “If you’re going to leverage the microbiome for drug discovery, it’s not the correlations that matter. It’s the causal relationships. How are the bacteria interacting with the host in a way that’s driving our biology? Did patients with bowel or intestinal diseases—colitis, for instance—have different gut bacteria profiles because they were ill? Or were they ill because they had different gut bacteria profiles? For example, children with autism often have significant gastrointestinal problems. Yet is that a reason for their autism, or is it just a related fact?” -WHAT’S LURKING IN YOUR MICROBIOME? POSSIBLY, A CURE FOR DISEASE
The diseases in the right quadrant represent those with known causation as microbiome dysbiosis. Left quadrant diseases have been associated with gut dysbiosis. DiLaura, of Second Genome, explains, “So our efforts, right now… aims to create a drug for IBD. Difficult as that sounds, it is a modest goal compared to the company’s second order of business: create a drug for metabolic diseases like type 2 diabetes. The first drug, if effective, could affect hundreds of thousands of people; the second, millions”. -WHAT’S LURKING IN YOUR MICROBIOME? POSSIBLY, A CURE FOR DISEASE
Background on Seres medicines
All of Seres’ medicines are made up of biologically-sourced bacterial spores (which are very different from fungal spores) which can be collected in a capsule for easy administration.
The first drug candidate from Seres to reach clinical trials is for treatment of Clostridium difficile infection (CDI) in adults; this drug. SER-109, is now in Phase 2 trials and is a mixture of bacterial spores from 50 bacterial species taken from healthy donors. Currently, FMT is used to treat recurrent antibiotic resistant CDI with over 90 percent cure.
SER-287 is the second Seres drug joining alternative capsule treatment for FMT but this time for UC. SER-287 is a microbial cocktail capsule containing “a complex and diverse bacterial spore ecology.
I am concluding the specific microbial composition of SER-287 is sourced from healthy donors as is SER-109; the trial is looking at engraftment of SER-287 bacteria into the intestinal microbial community. Ordinarily, commercial probiotic bacteria such as in yogurt, does not engraft into the microbiome. These bacteria are transient and repeated consumption is required to maintain and sustain benefit. Benefit often ceases about 3 days post consumption.
If you want further detail on Seres, see Seres therapeutics website.
Clinical Trial details for SER-287, the first IBD microbiome drug that targets the microbiome
The link to the study is: A Study to Evaluate the Safety, Tolerability and Microbiome Dynamics of SER-287 in Subjects With Ulcerative Colitis. About 55 patients are expected to enroll; the trial is currently recruiting participants. The drug used, SER-287, treats UC without suppressing the body’s immune response. Instead, SER-287 delivers specific strains of bacteria to re-balance the billions of different types of bacteria that are in the digestive tract, which then manages the disease. This treatment is not immunosuppressive; instead it targets the root cause of UC which is gut dysbiosis.
The current standard of care for UC treatment uses drugs that suppress the immune system to reduce inflammation in the colon and rectum which makes patients susceptible not only to infectious diseases, but to cancers that would otherwise be killed off by the immune system.
Primary Outcome Measures of the Clinical Trial:
- Safety and tolerability of SER-287 vs. placebo in adult subjects by analysis of AE’s, lab values, vital sign, physical exam findings, medical history, and ECG.
- Examination of baseline composition of the intestinal microbiome to the composition. Changes in the composition of the microbiome will be characterized by rDNA 16S V4 genomic data sets. Changes will be assessed by total number of unique bacteria and microbial composition.
- Engraftment of SER-287 bacteria into the intestinal microbial community. Microbiome will be characterized by rDNA 16S v4 Genomic Data Sets. Engraftment will be assessed as the outgrowth of bacteria that compromise the SER-287 spore ecology in the subjects GI tract post treatment.
The time frame for the study
December 2015 to June 2017.
Contact for the study
Michele Trucksis, PhD, MD at clinicalstudies@serestherapeutics.com
Study Locations are:
- United States, Florida. Advanced Gastroenterology Ctr, Port Orange, Florida, United States, 32127. Contact: AMMAR HEMAIDEN, MD 386-763-4920
- United States, Maryland. Capital Digestive Care, LLC – Metropolitan Gastroenterology Group (MGG), Chevy Chase, Maryland, United States, 20815. Contact: ROBERT HARDI, MD 240-737-0085.
- United States, Massachusetts. Community Clinical Research Network, Marlborough, Massachusetts, United States, 01752. Contact: JOHN CURRAN, MD 508-320-9248
You can read more about Seres and SER-287 here:
CEO: Seres Therapeutics ‘walks into flying’ with new trial in ulcerative colitis:
As to why they are targeting UC and not a larger population affected condition such as Type 2 Diabetes or Metabolic Syndrome: Pomerantz, CEO of Seres explained, “As someone who’s worked on eight infectious disease drugs, I know that you want to walk into flying. You don’t want to fly into flying.” Seres intends to target metabolic diseases in addition to inflammatory and infectious ones, but other recent microbiome startups are looking even further, at fields like autism or others. Pomerantz maintains that while such diseases may be in the realm of those which can be treated by rebalancing the microbiome, “we don’t think that was smart” to start with them.
Preserve & Restore Loss of Microbiome Diversity is Aggressive Preventative Medicine
SUMMARY: Aggressive Preventative Medicine means preserving the microbiome you have and restoring any loss incurred. See how far that thought goes with your doctor! Diet really does work to alter the microbiome and can help to restore loss of microbiome; for example, fermented kimchi actually positively impacted metabolic syndrome factors including systolic and diastolic blood pressures, percent body fat, fasting glucose, and total cholesterol.
⇒⇒ This post teaches how to reduce the loss of microbiome diversity and restore such – crowding out concept.