Mopping up harmful gut metabolites with Carbon (AB 2004) or Silicone (Enterosgel) to improve GI and behavioral problems in Autism

 

We have seen in previous posts that certain metabolites produced in the gut can worsen existing autism and even create autism in mouse models.

Much has been written about propionic acid, which when produced in the gut, rather than the beneficial butyric acid, causes behavioral problems.  This is what underlies the Nemechek Protocol, developed by Patrick Nemecheck, DO.  In his therapy you try to increase butyric acid production using inulin as a dietary fiber.  It does work for some people, but they are in the minority; in a small group it makes matters worse.

We also saw that P-cresol, another chemical produced by fermentation in the gut, can trigger autistic behaviors.

P-Cresol, like Propionic acid – a cause of Transitory Autism for some and a further burden for others

A few years ago in the research we did come across a “wonder” bacteria called B. fragilis (Bacteroides fragilis).  This bacterium was able to reverse autism in the mouse model of maternal immune activation (MIA).  The actual mechanism was by reducing a gut metabolite called 4EPS.  It turns out that 4EPS is closely related to P-cresol. The B. fragilis bacteria is essential to healthy gastrointestinal function, but it must not enter the bloodstream because it can cause a fatal blood infection. 

Antibiotics and Autism(s) – Pass the Bacteroides Fragilis?

 

How to defeat 4EPS

You would think that the easiest way to get rid of that harmful 4EPS would be simply to take B. fragilis, as a probiotic.

An Australian company called Axial decided instead to use a special form of carbon taken orally to “mop up” the 4EPS. The research drug is called AB-2004.

This carbon cannot be selective for 4EPS, so it will also “mop up” other things as well.

It does look like elevated 4EPS in autism is also associated with GI problems and that anxiety is the key feature of autism that is made worse.

I think you could describe AB-2004 as a therapy to restore GI integrity in autism that will also reduce anxiety is a sub-group.

If you have autism with anxiety, but perfect GI function, it does not look like you are going to benefit from AB-2004.

 

What about Silicone rather than Carbon? 

I was recently introduced to a product normally used to treat IBS-D (irritable bowel syndrome with Diarrhea).  The other type is called IBS-C, with C being for constipation.

It seems that some people with autism and GI problems respond very well to the OTC product Enterosgel, which claims to mop up harmful substances using a silicon gel (polymethylsiloxane polyhydrate) in combination with purified water

As with the experimental AB-2004, the silicone gel cannot be selective for any particular metabolite.

There are clinical trials looking at the benefit of Enterosgel in IBS-D.

 

Here is a current trial in the United Kingdom:

 

RELIEVE IBS-D trial

You can actually measure 4EPS in urine, (as you can P-cresol).  It would not be hard to see if Enterosgel lowers the elevated 4EPS found in people with autism + GI dysfunction. 

Of note is that for our reader Dragos in Romania, Enterosgel worked wonders in his adult son with IBS-C plus challenging behaviors, rather than IBS-D. 

  

4EPS  

The microbiota modulates gut physiology and behavioral abnormalities associated with autism 

A Serum Metabolite Induces ASD-Related Behavior

MIA-dependent increases of specific metabolites, and their restoration by B. fragilis, suggest that small molecules may play a role in ASD-related behaviors. To test this hypothesis, we examined whether increasing serum 4EPS is sufficient to cause any ASD-related behavioral abnormalities in naïve mice. Mice were treated with 4EPS potassium salt (Figures S7A–C) or vehicle, daily from 3 weeks of age (when MIA offspring display gut permeability) to 6 weeks of age (when behavior testing begins). Remarkably, systemic administration of the single metabolite, 4EPS, to naïve wild-type mice is sufficient to induce anxiety-like behavior similar to that observed in MIA offspring (Figure 6C). Relative to vehicle-treated controls, mice exposed to 4EPS travel comparable distances in the open field but spend less time in the center arena (Figure 6C). Also, in the PPI test, 4EPS-treated mice exhibit increased intensity of startle in response to the unconditioned primary stimulus, but no significant alterations in PPI (Figure 6D), representing anxiety-associated potentiation of the startle reflex (Bourin et al., 2007). Conversely, there are no significant differences between 4EPS-treated versus saline-treated mice in marble burying or USV behavior (Figures S7D and S7E), suggesting that elevating serum 4EPS levels specifically promotes anxiety-like behavior. While not a core diagnostic criterion, anxiety is a common co-morbidity that may contribute to cardinal ASD symptoms. Furthermore, it is possible that complex behaviors may be modulated by combinations of metabolites. In summary, these data reveal that elevated systemic levels of a metabolite regulated by gut microbes causes an ASD-related behavior, suggesting that molecular connections between the gut and the brain maybe associated with autism.

In a proof-of-concept test of the this hypothesis, we reveal that the microbially-modulated metabolite 4EPS, which is elevated in the circulation by MIA and restored by B. fragilis treatment, is sufficient to induce anxiety-like behavior in naïve mice. These data indicate that metabolomic changes contribute to the onset and/or persistence of autism-related behavioral abnormalities. Notably, we show that commensal microbes are required for the production of serum 4EPS in mice. Several species of Clostridium are believed to be producers of the precursor 4-ethylphenol (Nicholson et al., 2012), consistent with our findings that levels of the Lachnospiraceae family of Clostridia and serum 4EPS are elevated in MIA offspring, and both are corrected by B. fragilis treatment. Moreover, the structural similarity of 4EPS to p-cresol, which also derives from Clostridium species (Persico and Napolioni, 2013), suggests they may be produced through similar biosynthetic pathways (see Figure S6A). Although not all autism-like behaviors are affected by 4EPS alone, our results warrant the examination of several other serum metabolites, perhaps in combination, for their potential to impact the spectrum of autism-related behaviors. 

 

The Gut Microbiota and Autism Spectrum Disorders

AB-2004, its orally administered, drug candidate that has demonstrated the ability to repair leaky gut and improve repetitive behavior, anxiety, and ASD-related sensorimotor gating deficits by removing key microbial metabolites in animal models with Autism Spectrum Disorder (ASD).

 

The main highlights from the poster presentation titled, “Characterization of GI barrier integrity and gut microbiome-derived metabolites in BTBR, Shank3 and Cntnap2 mouse models of ASD and demonstration of AB-2004 as a potential mitigating therapeutic” include:

 

·     The Cntnap2-/- mouse model accurately recapitulated the leaky gut phenotype and elevated levels of the gut microbiome-derived metabolite 4-EPS that have been reported in ASD patients

·     Treatment with AB-2004 effectively restored GI integrity and reduced elevated 4-EPS levels in Cntnap2-/- mice

·     The Cntnap2-/- model has been identified as a promising and translationally relevant animal model for the development of microbiome-inspired therapies for the effective treatment of GI and behavioral dysfunctions in ASD

·     These data support the development of AB-2004 as a treatment for GI dysfunction in ASD and potentially behavioral symptoms through reduction of pathologically active microbiome-derived metabolites Axial is currently screening ASD adolescents for its Phase 1b/2a clinical trial of AB-2004.

Scientific evidence has shown there may be a link between bacteria commonly found in the digestive tract, and the brain which could contribute to certain characteristics, such as irritability, in children with ASD. AB-2004 is designed to adsorb certain substances produced by gut bacteria to reduce their ability to enter the bloodstream and reach the brain.   

 

The active ingredient in AB-2004 is a highly engineered form of spherical carbon designed with human safety and biological selectivity in mind, making it very different from activated charcoal. Each sphere of AB-2004 consists of a network of pores that allows it to selectively adsorb metabolites that may contribute to characteristics associated with ASD like irritability and anxiety.

 

Axial reports findings of elevated 4-EPS in children with ASD 

The findings showed that concentrations of the bacterial metabolite, 4-ethylphenylsulfate (4-EPS) were elevated as much as six-fold in serum samples from children with ASD compared to healthy controls in replicate analyses.

This research builds on previous work published by Axial's Co-founder and Caltech Professor, Sarkis Mazmanian, Ph.D., that demonstrated causality between 4-EPS and anxiety-like behaviors in the "maternal immune activation" (MIA) mouse model of ASD. The MIA model recapitulates key features of the autism phenotype, including increased anxiety, stereotypic behaviors, and decreased vocalizations and social behaviors. Dr. Mazmanian found changes in the gut microbiome (dysbiosis), increased intestinal permeability (IP), and elevated levels of the putative bacterial metabolite 4-EPS in MIA mice, compared to controls. Oral treatment with B. fragilis, a human commensal gut bacterial species, resulted in restoration of gut microbial profiles, decreased IP, and markedly reduced serum concentrations of 4-EPS.

The current study aimed to evaluate 4-EPS levels in children with ASD compared to samples from control children. Two analyses were performed, a 4-EPS targeted analysis in 103 pediatric subjects and a non-targeted serum metabolomics study involving 230 children (cohorts from the "Childhood Autism Risks from Genetics and the Environment" study ongoing at the Univ. of California Davis). 4-EPS concentrations were found to be significantly elevated in children with ASD vs. healthy controls in both analyses. In addition, elevated levels were associated with worse social performance on two separate measurements. The impact of this elevation on behavior, and the impact of treatment with B. fragilis and with Axial's small molecule therapeutic, AB-2004, will be the subject of subsequent human clinical studies.

 

Anxiety Linked to Gut Microbial Metabolite in Mouse and Human

In a small, single-cohort pilot study reported simultaneously in a Nature Medicine article titled, “Safety and target engagement of an oral small-molecule sequestrant in adolescents with autism spectrum disorder: an open-label phase 1b/2a trial“(trial registration no. ACTRN12618001956291), Mazmanian’s team tested an oral drug (AB-2004) that adsorbs 4EPS in the gut in 30 adolescents with autism. In addition to reducing 4EPS levels in blood and urine, and improving gut health, a subset of the tested participants showed reduced irritability and anxiety.

 

  

What is Enerosgel?  (click the link)

 

 

Conclusion 

I imagine both AB-2004 and Enterosgel are removing numerous metabolites from the digestive tract.

We know that at least 3 metabolites (Propionic acid, P-cresol and 4EPS) can induce autism in a previously not autistic mammal.  There are undoubted other metabolites that will be added to this list.  In the case of Propionic acid the autism was reversable using NAC (N-acetylcysteine).

Since you will have to wait years for AB-2004 to become an approved drug, if indeed it ever happens, you might just have to hope that Enterosgel is equally effective at mopping up that 4EPS with silicone.

It is pretty clear that the Australians are targeting anxious Aspies with GI problems, with AB-2004.

Is Enterosgel going to benefit those with autism and without GI dysfunction?  I think it is less likely, but it could happen.  The effect might not relate just to 4EPS. 

 

 

Enterosgel for food allergy? 

I do wonder about the use of Enterosgel following an acute food allergy.

Many people take the mast cell stabilizer cromolyn sodium (Nalcrom) to deal with food allergy.  Indeed, for some people, instead of eliminating the food they are allergic to, they take Nalcrom.

Apparently, some people with food allergies are taking Enterosgel regularly.

What happens if you consume a food substance by mistake that you are allergic too?

This is what happened recently to Monty while on holiday in Greece.  Two small red patches appeared on either side of his face and his mood and behavior changed dramatically.  It was like his pollen allergy triggered summertime raging, but it was not due to pollen allergy.

The effect of an allergic reactions continues even after you remove the allergen.  If you are allergic to bee stings you might end up needing a steroid injection to settle your immune system down.  In the immediate term you can take an oral H1 antihistamine.

Monty had his H1 antihistamine and a single oral dose of Prednisone; after 3 days he was back to his usual self.

People who get severe allergic reactions carry an Epipen (an epinephrine autoinjector).

In Monty’s case there is never a severe allergic reaction, but there is a severe behavioral reaction to a modest allergic reaction.  I think this is likely to be quite common in people with autism and challenging behaviors.  It often goes untreated, or is poorly treated using anti-psychotic drugs, which then cause serious side-effects including tardive dyskinesia (motor tics), obesity, males growing breasts (drug-induced gynecomastia) etc.

Even though Monty has no GI problems, perhaps I should acquire some Enterosgel to use in case of a future acute food allergy attack?

Eubiotics for GI Dysfunction and some Autism

  

Today’s post is about some drugs/supplements that have already been discussed in earlier posts.  Rifaximin, used in cycles, is an effective part of our reader Maja’s therapy, while Sodium Butyrate was highlighted long ago by our reader in Switzerland, Alli.

I had a consultation with a gastroenterologist last week and came away with a prescription for Rifaximin, microencapsulated Sodium Butyrate and Lactobacillus Plantarum 299v. Where we live, these are all inexpensive. Rifaximin is an antibiotic with extra benefits and costs about 7 euros (9 dollars). 

A course of Rifaximin can cost $2,000 in the United States.

I was pleased to read that the private equity owners of a pharmaceutical company that raised the price of a common thyroid drug by 6000% have just been fined $140 million in the UK.

Advanz Pharma and former private equity owners were fined £100m by markets watchdog

Perhaps some of our US readers should query the crazy price of drugs in the US with their congressman? Very many cheap old drugs are ultra expensive in the US, even insulin is over-priced. Not a good model of a market economy. 

 

Eubiotics – a big business

You may very well never have come across the term eubiotic before, but it is already a multi-billion dollar business.  A eubiotic is something that changes the gut microbiome to improve health. The big business to date are additives to animal feed, rather than products for human health.

Eubiotics work for humans as well. Rifaximin is an antibiotic but it also has the additional properties of a eubiotic. 

“These include: modulation of the microflora of the gastrointestinal tract by promoting the growth of Lactobacilli and Bifidobacteria strains (the so-called “eubiotic” effect) as well as modulation of bacterial metabolism, including inhibition of the hydrocarbon-derived pathways.  This drug is also capable of reducing the virulence of enteropathogenic Escherichia coli strains by inhibiting the expression of enterotoxins or adhesive factors. Interestingly, Rifaximin is distinguished by several anti-inflammatory activities mainly exerted by the pregnane X receptor (PXR), expressed primarily in the gastrointestinal tract, the small intestine, and the colon. Due to the activity described above, Rifaximin is called a eubiotic, not an antibiotic.”

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5497137/

Rifaximin, like vancomycin, is usually thought of as a GI antibiotic; it stays in your gut and almost none ends up in your blood.  Both drugs are used to kill off bacteria in your gut. This is all vancomycin does, so it is not classed as a eubiotic. Rifaximin, however, goes on to perform further functions as a eubiotic, so it models your gut flora in a beneficial way.

Rifaximin is almost a wonder drug for IBS-D (irritable bowel syndrome with diarrhea).  It is also a common therapy for SIBO (small intestinal bacterial overgrowth), but while it works well for some, it actually makes things worse for some others.

Rifaximin is used both as a therapy for an acute GI problem and preventatively. It can be used in cycles, like a few days every month.

Maja is in a good position, because where she lives Rifaximin costs a few euros/dollars.

People with IBS-D in the United States often cannot afford monthly cycles of Rifaximin.

Other kinds of eubiotics include prebiotics, other probiotics, all kinds of clever fiber, inulin, fructooligosaccharides (FOS), galactooligosaccharides (GOS) etc.  I did cover psychobiotics in an earlier post, these are probiotic bacteria that are used to reduce anxiety, ADHD and other psychiatric symptoms.

Psychobiotics (PS128) for Autism, Stereotypy and Sometimes Effective Therapies for what might be SIBO (Rifaximin and Herbal)

  

Sodium Butyrate

Sodium buyrate produces butyric acid when you swallow it.  Butyric acid is what gives rancid butter its smell.  Butyric acid is one of the big eubiotics used in the animal feed industry. I did cover the very old Japanese probiotic MIYAIRI 588 (full name is Clostridium butyricum MIYAIRI 588) a long time ago in this blog.  This probiotic, in use since the Second World War, produces butyric acid in your gut by fermentation.  In Japan this probiotic is used in humans and more recently as an additive to animal feed, to produce healthier, bigger, chickens and pigs. 

Our reader MG in Hong Kong recently reported that MIYAIRI 588 was beneficial in his case. 

My gastroenterologist prescribed me Microencapsulated Sodium Butyrate, which is covered in the research and has encouraging results. When you see the word microencapsulated, you might start feeling some pain developing in your wallet, rather than in your gut, but again, this product called Integra and made in Poland,  was not so pricey - about EUR 10 ($12) for 60 capsules. One capsule contains 150 mg of sodium butyrate in tiny particles covered in triglycerides.  I have no idea if it is going to do me any good, but the research suggests it is beneficial for certain types of GI dysfunction and will strengthen the intestinal gut barrier (the equivalent of the blood brain barrier). 

Butyric acid has several different modes of action, one is as an HDAC inhibitor, which was covered in earlier posts. HDAC inhibitors can change gene transcription, which is potentially very useful, including in the prevention and treatment of some cancers. The potent HDAC inhibitors from cancer therapy show effect in some types of single gene autism.

Autism-Like Social Deficits Reversed by Epigenetic Drug 

There are different classes of HDAC inhibitor and you would need to match the type of autism with the appropriate type of HDAC inhibitor.  Valproic acid is another common HDAC inhibitor sitting on the shelf of many people with autism plus epilepsy. 

Lactobacillus Plantarum 299v 

Lactobacillus plantarum 299v has been shown to improve symptoms of IBS (Irritable Bowel Syndrome).  It prevents Clostridium difficile-associated diarrhea among patients receiving antibiotic treatment.  It is also known to be immunomodulatory, shifting the balance away from pro-inflammatory cytokines.

The role of Lactobacillus plantarum 299v in supporting treatment of selected diseases 

Alterations in composition of human gut microbiome can lead to its dysbiosis. It is associated with gastrointestinal side effects during anti-cancer treatment, antibiotics administration, or infectious agents. There are studies confirming positive effect of consuming Lactobacillus plantarum 299v on intestinal microflora. This review summarizes the current knowledge about the role of L. plantarum 299v in supporting treatment of selected diseases, such as cancer, irritable bowel syndrome (IBS), and Clostridium difficile infection. The immunomodulating properties of L. plantarum 299v include an increase in the level of anti-inflammatory cytokines, which reduce the risk of cancer and improve the efficacy of regimens. The intake of L. plantarum 299v provides benefits for IBS patients, mainly due to normalization of stool and relief of abdominal pain, which significantly improves the quality of life of IBS patients. In addition, the intake of L. plantarum 299v prevents C. difficile-associated diarrhea among patients receiving antibiotic treatment. Due to the limited possibilities of treating these diseases and numerous complications of cancer treatment, there is a need for new therapeutic strategies. The administration of L. plantarum 299v seems to be useful in these cases. 

 

Bacteria could aid autistics

Might a daily dose of friendly bacteria help treat autism? UK researchers hope probiotics will soothe the gut problems linked to autism and may even ease psychological symptoms. They are planning a clinical trial to test the idea.

The proposed health benefits of probiotic bacteria are well known. The beneficial bugs are thought to out-compete other gut bacteria that can cause diarrhoea and ill health.

Children with autism are known to have higher levels of one group of 'bad' bacteria, Clostridia, in their guts, explains Glenn Gibson from the University of Reading. So he hopes probiotic food supplements that lower levels of Clostridia will allay some symptoms of autism.

He is not suggesting that the bad bacteria cause autism: genetic and environmental factors are both likely to contribute to the complex disorder, the cause of which is unknown. But toxic by-products of the bacteria may be absorbed into the blood and travel to the brain, where they may play a role in ill health.

At present, the researchers are honing their choice of bacteria. There are many different types of good bacteria, so it is important to choose one that can compete effectively against Clostridia.

One candidate, called Lactobacillus plantarum 299v, looks especially promising. The bacterium binds to the gut lining and stimulates its growth. As well as out-competing other bacteria, it also lowers gut pH, which helps the digestive tract to fight infection. It stays in the gut for days and has never been associated with any health problems.

 

Conclusion

I am always surprised how many common drugs that you come across have potential to be repurposed to benefit  some people with autism.

It really shows how effective therapy, for at least some people with autism, is already in the medicine cabinet at home, or more likely over at the grandparents’ house.

(statins, calcium channel blockers, asthma/COPD drugs, other blood pressure drugs, diuretics, type 2 diabetes drugs)

I thought my gastroenterologist’s therapy was quite enlightened. I hope his diagnosis is accurate; I am not entirely convinced, but time will tell.  The diagnosis from doctor number one was kidney stones and now I am on doctor number three. An accurate diagnosis is not always a simple matter, as autism parents know only too well.

I did meet Dr Federico Balzola a while back. He is an Italian gastroenterologist with a keen interest in autism. He is an associate of Dr Arthur Krigsman, a US gastroenterologist heavily involved with autistic patients. In some countries the connection between GI problems and autism is still a taboo subject, seemingly because Dr Andrew Wakefield was a gastroenterologist.  

 

I am always surprised how many young Aspies have symptoms of IBS or IBD. I would actually like to know if this is mainly a problem in childhood and adolescence, which I suspect is the case. 

One of my most popular posts was another one about gastroenterology, which really surprised me.

Eosinophilic Esophagitis – another Granulocyte Disorder Associated with Autism

 

FMT (Fecal Microbiota Transplantation) Super-donors and Abandoning the “One Stool Fits All” Approach

Not all stools were created equal

There was a comment recently left on this blog posing the question of what makes a good donor for FMT (Fecal Microbiota Transplantation), or a “poop transplant” in plain English.

FMT is actually an approved therapy for Clostridioides difficile infection (CDI). Research has shown  FMT to be more effective than the antibiotic vancomycin. To quote from the research, “The infusion of donor feces was significantly more effective for the treatment of recurrent C. difficile infection than the use of vancomycin”.

FMT might not be for discussion at the dinner table, but it is highly effective in some instances.

FMT is actually far more widely used than you might imagine.  In one of today’s papers from China they had treated 1,387 people using 20 donors, for a wide variety of conditions.

In the US, autism researchers at Arizona State University showed a benefit that was maintained after a period of two years.

Autism symptoms reduced nearly 50 percent two years after fecal transplant

At two years post-treatment, most of the initial improvements in gut symptoms remained. In addition, parents reported a slow steady reduction of ASD symptoms during treatment and over the next two years. A professional evaluator found a 45% reduction in core ASD symptoms (language, social interaction and behavior) at two years post-treatment compared to before treatment began.

An earlier study with only vancomycin (an antibiotic) had found major temporary improvements in GI and autism symptoms, but the benefits were lost a few weeks after treatment stopped despite use of over-the-counter probiotics.

The obvious question to ask is whether FMT has a potential benefit to people with autism who do not have GI dysfunction.  I think this question is far from being answered.

We have seen in earlier posts that modifying the microbiome has great potential to fine-tune the function of the brain.  Researchers at UCLA showed that the high fat ketogenic diet controls epileptic seizures not through the action of ketones in the brain, but via the high fat intake changing the mix of bacteria in the gut.

The Gut Microbiota Mediates the Anti-Seizure Effects of the Ketogenic Diet

FMT is just one way to modify the microbiome.  The UCLA researchers are developing a medical food to produce similar effects on the microbiome as the ketogenic diet.

Very likely a personalized bacteria transfer, customized to the symptoms of the person, might effectively treat many more conditions than just GI problems.  

It does look likely that for some conditions there may be super-donors, people whose microbiome is particularly effective, when transferred to others.

But the research cautions against what is called the “One Stool Fits All” Approach.  The donor and recipient need to be “compatible”.

The Super-Donor Phenomenon in Fecal Microbiota Transplantation

The microbial diversity of the donor is a good predictor of FMT success in the recipient. However, donor-recipient compatibility also plays an influential role in determining FMT success. Donor-recipient compatibility can stem from genetic factors such as differences in innate immune responses, or environmental factors including diet, xenobiotic exposure, and microbial interactions.

FMT for Inflammatory Bowel Disease (IBD): The Emergence of the FMT Super-Donor

IBD encompasses both Crohn's disease and ulcerative colitis; two debilitating disorders characterized by chronic relapsing inflammation of the intestinal. In contrast to CDI, there is no evidence that IBD results from an overgrowth of one specific pathogen. Rather, the disease is likely brought on by complex interactions involving the host's genetics, immune system, and gut microbiota. Both Crohn's disease and ulcerative colitis are broadly characterized by a reduced diversity of the gut microbiota with lower relative abundances of the Bacteroidetes and Firmicutes phyla and higher proportions of Proteobacteria. A specific reduction in the abundance of butyrate-producing bacterial species, particularly Faecalibacterium prausnitzii, has been observed for both Crohn's disease and ulcerative colitis. Meanwhile, for Crohn's disease, an increase in a pro-inflammatory form of Escherichia coli has also been reported.

The first successful case report of an FMT for the treatment of IBD was published in 1989 when a male with refractory ulcerative colitis achieved clinical remission for 6 months following a retention enema with healthy donor stool. Subsequently, a large number of FMT studies have been conducted on IBD patients with variable clinical outcomes, remission rates, and longevity of effect. Recently, Paramsothy et al. performed a systematic review and meta-analysis of 53 studies (four RCT, 30 cohort, 19 case studies) of FMT in IBD patients. Avoiding publication bias, their analysis of cohort studies revealed FMT was more effective at inducing remission in Crohn's disease patients when compared to patients with ulcerative colitis (52 vs. 33%, respectively). With regard to ulcerative colitis, a larger number of FMT infusions and a lower gastrointestinal tract administration were associated with improved rates of remission.

In contrast to studies of CDI, FMT studies conducted on IBD patients have frequently identified differential recipient responses that have been associated with variability in the donor stool. Currently, the stool used for FMT is not standardized in terms of donor selection (related vs. unrelated), preparation (fresh vs. frozen, aerobic vs. anaerobic), or the dose that is administered (single vs. multiple doses). While inconsistencies in FMT protocols make it difficult to compare different studies, there is a large degree of variability in clinical responses to FMT between recipients who have been subjected to the same study design. It is unfortunate that information on a recipient's genetic background or dietary intake is not yet routinely assessed, particularly given that some instances of IBD have an underlying genetic component. Due to the lack of genetic information, investigators have instead focused on the donor-dependent effect and proposed the existence of so called super-donors to explain the variation in recipient responses.

The first study to record the super-donor effect was a randomized control trial that was investigating the efficacy of FMT for inducing clinical remission in patients with ulcerative colitis. Moayyedi et al. assigned 75 patients with active disease to weekly enemas containing either fecal material or water (placebo) for a period of 6 weeks. FMT was shown to be superior to the placebo, resulting in significantly higher rates of endoscopic and clinical remission, albeit of modest effect (24 vs. 5%, respectively), after 7 weeks. Of the nine patients who entered remission, seven had received FMT from the same donor. Thus, it was argued that FMT success was donor-dependent.

Currently, it is not possible to predict the clinical efficacy of a donor before FMT in IBD patients. It has been suggested that remission rates could be improved by pooling donor's stool together, limiting the chances a patient will receive only ineffective stool. This stool pooling approach was recently investigated on an Australian cohort of 85 mild to moderate ulcerative colitis patients, in the largest randomized control trial of FMT for IBD to date. Rather than receiving FMT from just one donor, patients in the treatment arm were administered a stool mixture that contained contributions from up to seven different donors with the hope that donor-dependent effects could be homogenized. In addition to this, a far more intensive dosing program was adopted with an initial FMT delivered by colonoscopy that was followed by fecal enemas, five times a week for 8 weeks. Despite the multi-donor and intensive dosing approach, Paramsothy et al. achieved post-FMT remission rates (FMT, 27% vs. placebo, 8%, p = 0.02) that were similar to those reported previously. Notably, however, both clinical and endoscopic remission were required for primary outcome achievement in this study, whereas previous studies have mostly focused on either endoscopic or clinical remission rates alone. The pooled stool mixture was demonstrated to have higher microbial diversity than individual stool alone based on OTU count and phylogenetic diversity measures. Subsequent analysis of the different stool batches discovered that one donor appeared to exhibit a super-donor effect. Specifically, patients that received FMT batches that contained stool from this one donor exhibited a higher remission rate than those whose FMT batches did not include the super-donor (37 vs. 18%, respectively).

FMT for Other Disorders: Is There Also a Super-Donor Effect?

Evidence of FMT super-donors in other disorders outside of IBD is currently lacking. Case series and reports limit the capacity to identify super-donor effects because of limited sample sizes. However, despite the lack of large cohort studies, several studies have hinted at the possibility of a donor-dependent effect on FMT outcome. For example, in a short-term FMT pilot trial on 18 middle-aged men with metabolic syndrome, FMTs from lean donors (allogenic FMT) were found to correspond with a 75% increase in insulin sensitivity and a greater diversity of intestinal bacteria in the recipient compared to autologous FMTs (recipient-derived). It was later noted that the patients who experienced a more robust improvement of insulin sensitivity post-FMT had all been in receipt of the same donor. In a subsequent study on 38 Caucasian men with metabolic syndrome, lean donor FMT also resulted in a significant improvement in peripheral insulin sensitivity at 6 weeks. However, this effect was lost by the 18 week follow up. For the allogenic FMT, 11 lean donors were used, seven of which were used for more than one recipient. Whilst donor-dependent effects were not reported, the authors noted that the “multiple fecal donors might explain the transient and variable effects seen in the allogenic group.” As FMT research in this field progresses from small-scale case series to larger-scale randomized placebo controlled clinical trials, it remains to be seen whether the super-donor phenomenon generalizes to other conditions outside of IBD.

Abandoning the “One Stool Fits All” Approach

Microbial dysbiosis is a blanket term for an unhealthy or imbalanced gut community. As such, the population structure that is considered to represent microbial dysbiosis is variable between different disorders. Moreover, the microbiome deficit of one individual may not necessarily mirror that of another individual and therefore it is not surprising that patients respond differently to FMT. As more FMT-related clinical and microbial data are generated, it is becoming clear that “one stool does not fit all” in the context of treating chronic diseases with microbial dysbiosis. Equally so, the selection of donors based solely on clinical screening guidelines provides no guarantee of FMT success. It appears a patient's response to FMT predominantly depends on the capability of the donor's microbiota to restore the specific metabolic disturbances associated with their particular disease phenotype. If this is true, a donor-recipient matching approach, where a patient is screened to identify the functional perturbations specific to their microbiome, may be the best way forward. The patient could then be matched to a specific FMT donor known to be enriched in taxa associated with the metabolic pathway that needs to be restored. Immune tolerance screening would also be beneficial for reducing the impact of donor-recipient incompatibilities stemming from underlying differences in innate immune responses.

Framework for rational donor selection in fecal microbiota transplant clinical trials

Early clinical successes are driving enthusiasm for fecal microbiota transplantation (FMT), the transfer of healthy gut bacteria through whole stool, as emerging research is linking the microbiome to many different diseases. However, preliminary trials have yielded mixed results and suggest that heterogeneity in donor stool may play a role in patient response. Thus, clinical trials may fail because an ineffective donor was chosen rather than because FMT is not appropriate for the indication. Here, we describe a conceptual framework to guide rational donor selection to increase the likelihood that FMT clinical trials will succeed. We argue that the mechanism by which the microbiome is hypothesized to be associated with a given indication should inform how healthy donors are selected for FMT trials, categorizing these mechanisms into four disease models and presenting associated donor selection strategies. We next walk through examples based on previously published FMT trials and ongoing investigations to illustrate how donor selection might occur in practice. Finally, we show that typical FMT trials are not powered to discover individual taxa mediating patient responses, suggesting that clinicians should develop targeted hypotheses for retrospective analyses and design their clinical trials accordingly. Moving forward, developing and applying novel clinical trial design methodologies like rational donor selection will be necessary to ensure that FMT successfully translates into clinical impact.

Association Between the Clinical Efficacy of Fecal Microbiota Transplantation in Recipients and the Choice of Donor

Objective: To examine the association between the clinical efficacy of fecal microbiota transplantation (FMT) in recipients and the choice of donor, and to observe the characteristics of intestinal flora and metabolites among different donors. 

Methods: A retrospective case-control study was conducted. Donor whose feces was administrated for more than 30 recipients was enrolled. Data of 20 FMT donors and corresponding recipients at Intestinal Microecology Diagnosis and Treatment Center of the Tenth People's Hospital from October 2018 to December 2019 were collected retrospectively.

During follow-up, the efficacy of each recipient 8-week after FMT treatment was recorded and analyzed. Based on the efficacy of each donor, the donors were divided into three groups.Association of the efficacy of each donor group with the morbidity of complications, and association of efficacy of recipients with donors were analyzed. The evaluation indicators of FMT efficacy included objective clinical effectiveness and/or subjective effectiveness. Objective effectiveness indicated clinical cure plus clinical improvement, and subjective effectiveness indicated marked effectiveness plus medium effectiveness through questionnaire during follow-up. 

Results: A total of 1387 recipients were treated by 20 donors, including 749 cases of chronic constipation, 141 cases of chronic diarrhea, 107 cases of inflammatory bowel disease (IBD), 121 cases of irritable bowel syndrome (IBS), 83 cases of autism, and 186 cases of other diseases, such as radiation bowel injury, intestinal pseudo-obstruction, paralytic intestinal obstruction, functional bloating and allergic diseases. There were 829 cases, 403 cases, and 155 cases in high efficacy group, moderate efficacy group and low efficacy group respectively. Baseline data among 3 groups were not significantly different (all P> 0.05).

In comparison of bacterial abundance (operational taxonomic unit, OTU) among different effective donor groups, the high efficacy group was the highest (330.68±57.28), the moderate efficacy group was the second (237.79±41.89), and the low efficacy group was the lowest (160.60±49.61), whose difference was statistically significant. 
In comparison of butyric acid content among three groups, the high efficacy group had the highest [(59.20±9.00) μmol/g], followed by middle efficacy group [(46.92±9.48) μmol/g], and the low efficacy group had the lowest [(37.23±5.03) μmol/g], whose difference was statistically significant (F=10.383, P=0.001). The differences of acetic acid and propionic acid among three groups were not statistically significant (all P>0.05). A total of 418 cases developed complications (30.1%). Morbidity of complication in low efficacy group, moderate efficacy group and high efficacy group was 40.6% (63/155), 30.0% (121/403) and 28.2% (243/829) respectively, and the difference was statistically significant (χ(2)=9.568, P=0.008). The incidence of diarrhea in low efficacy group, moderate efficacy group and high efficacy group was 7.1% (11/155), 4.0% (16/403) and 2.8% (23/829) respectively, and the difference was statistically significant (χ(2)=7.239, P=0.027). Comparing the incidences of other types of complications, no statistically significant differences were found (all P>0.05). Follow up began 8 weeks after the FMT treatment. The total follow-up rate was 83.6% (1160/1387). The overall effective rate 58.3% (676/1160). Effective rates of various diseases were as follows: chronic constipation 54.3% (328/604), chronic diarrhea 88.5% (115/130), IBD 56.1% (55/98), IBS 55.1% (59/107), autism 61.6% (45/73), and other diseases 50.0% (74/148). Comparing the effective rate of three groups of donors for different diseases, there was no statistically significant difference in chronic diarrhea (P>0.05); there was a positive correlation trend in IBD, IBS and autism, but the differences were not statistically significant (all P>0.05). For chronic constipation and other diseases, high efficacy group had the highest effective rate [65.0% (243/374) and 63.2% (55/87)], followed by moderate efficacy group [49.4% (86/174) and 38.1% (16/42)], and low efficacy group had the lowest [16.1% (9/56) and 15.8% (3/19)], whose differences were significant (all P

Conclusions: Different donors have different efficacy in different diseases. Chronic constipation, radiation bowel injury, etc. need to choose donors with high efficacy. IBD, IBS and autism may also be related to the effectiveness of donors, while chronic diarrhea is not associated to the donor. The efficiency of the donor is negatively correlated to the morbidity of complications. The abundance and diversity of intestinal flora and the content of butyric acid may affect the efficacy of the donor.

Conclusion

FMT in practice today does look rather primitive, but seems to be beneficial more than half of the time, even in autism in the Chinese study.

As expected, different donors have different efficacy in different diseases.  As FMT becomes more popular you would expect that more super-donors will be stumbled upon and then clinicians will have a better chance to match the donor to the recipient.

For certain GI conditions that do not respond well to current drug therapy, FMT does look a good option to investigate.  The level of success is likely to vary depending on the availability and selection of the donor.

It does seem that orally ingested bacteria in the form of probiotics often do not colonize the gut as hoped for, and just past straight through, with only a limited and transient effect.  The fact that FMT can have a very long-lasting effect is remarkable and likely due to the fact that these bacteria are direct from another human.

Modifying the microbiome is only now emerging as a treatment idea and it will take many decades to fully develop it.

Ingesting a mix of another human’s bacteria is not without risk.  

Massachusetts General Hospital oversaw trial that led to the first death from a fecal transplant, a new paper shows

This spring, a 73-year-old man with a rare blood condition became the first person to die from drug-resistant bacteria found in a fecal transplant. New details about that unprecedented incident emerged on Wednesday.

The man was a participant in a clinical trial run at Massachusetts General Hospital and received fecal transplant capsules made in November with fecal material from one stool donor, according to a paper published Wednesday in the New England Journal of Medicine. Tests after the man’s death revealed that material contained a rare type of E. coli bacteria.

FMT seems to be becoming fashionable, with all kinds of people offering it.  The American Journal of Gastroenterology even published a study on Do-it-Yourself FMT. "Almost all indicated that they would perform DIY FMT again, though many would have preferred to have FMT in a clinical setting."  I would vote for the clinical setting and a carefully selected/screened donor.