Another Potential Autism Therapy - novel compound E100 from Krakow, a combined histamine H3 receptor blocker (H3R antagonist) and an acetylcholine esterase inhibitor (AChEI)

 

Source:  Sukiennice and Main Square as seen from St. Mary's Basilica

Krakow’s old town is well worth a visit and is notable in Poland for not having been destroyed by the Germans, Russians or the US/UK during World War 2

 

Brain histamine and acetylcholine are implicated in cognitive disorders such as Alzheimer’s, schizophrenia, anxiety, and narcolepsy, all of which are found to be comorbid with autism.  This led a group in the United Arab Emirates (UAE) to test a new compound developed in Krakow, Poland, to see if this new Alzheimer’s compound is effective in two different models of autism. 

The Valproic Acid induced model of autism and the BTBR models were chosen.  The BTBR model is seen as a proxy for idiopathic autism; in this model there is no corpus callosum, which joins the left are right sides of the brain (red part in the graphic below). In an earlier post we looked at agenesis of the corpus callosum, which can be full or partial and is a feature of many types of disabling autism.

 

Source: https://en.wikipedia.org/wiki/Corpus_callosum#/media/File:Corpus_callosum.gif

  

The results of the mouse research were positive and it was concluded that E-100 is a potential drug candidate for future therapeutic management of autistic-like behaviours.

  

Simultaneous Blockade of Histamine H₃ Receptors and Inhibition of Acetylcholine Esterase Alleviate Autistic-Like Behaviors in BTBR T+ tf/J Mouse Model of Autism

Autism spectrum disorder (ASD) is a heterogenous neurodevelopmental disorder defined by persistent deficits in social interaction and the presence of patterns of repetitive and restricted behaviors. The central neurotransmitters histamine (HA) and acetylcholine (ACh) play pleiotropic roles in physiological brain functions that include the maintenance of wakefulness, depression, schizophrenia, epilepsy, anxiety and narcolepsy, all of which are found to be comorbid with ASD. Therefore, the palliative effects of subchronic systemic treatment using the multiple-active test compound E100 with high H₃R antagonist affinity and AChE inhibitory effect on ASD-like behaviors in male BTBR T+tf/J (BTBR) mice as an idiopathic ASD model were assessed. E100 (5, 10 and 15 mg/kg, i.p.) dose-dependently palliated social deficits of BTBR mice and significantly alleviated the repetitive/compulsive behaviors of tested animals. Moreover, E100 modulated disturbed anxiety levels, but failed to modulate hyperactivity parameters, whereas the reference AChE inhibitor donepezil (DOZ, one milligram per kilogram) significantly obliterated the increased hyperactivity measures of tested mice. Furthermore, E100 mitigated the increased levels of AChE activity in BTBR mice with observed effects comparable to that of DOZ and significantly reduced the number of activated microglial cells compared to the saline-treated BTBR mice. In addition, the E100-provided effects on ASD-like parameters, AChE activity, and activated microglial cells were entirely reversed by co-administration of the H₃R agonist (R)-α-methylhistamine (RAM). These initial overall results observed in an idiopathic ASD mice model show that E100 (5 mg/kg) alleviated the assessed behavioral deficits and demonstrate that simultaneous targeting of brain histaminergic and cholinergic neurotransmissions is crucial for palliation of ASD-like features, albeit further in vivo assessments on its effects on brain levels of ACh as well as HA are still needed. 

The observed results in an idiopathic ASD mice model comprehend our previously obtained palliative effects of E100 in VPA-induced ASD in mice. Also, the current observations demonstrate that simultaneous targeting of the CNS histaminergic and cholinergic neurotransmissions is crucial for palliation of several ASD-like features, namely ASD-like social deficits and repetitive/compulsive behaviors and mitigated the levels of cerebellar microglial cells and AChE activity of tested BTBR mice used as idiopathic ASD model. Whether the alleviation of autistic-like behaviors in BTBR mice is obtained after administration of H₃R antagonist or co-administration of an H₃R antagonist and an AChEI was beyond the scope of this project and will require dose-finding experiments for several ratios of the combination of AChEIs and H₃R antagonist. Further in vivo assessments on brain levels of ACh as well as HA in BTBR mice following different systemic treatments of test compound as well as reference drugs including a standard H₃R antagonist (e.g., pitolisant) are still needed to evaluate whether multiple-active compounds, e.g., E100, is superior to AChEIs or H₃R antagonists when administered alone.

The design and synthesis of E100, namely 1-(7-(4-chlorophenoxy)heptyl)azepane, was carried out in the Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Krakow, Poland and as described in in previous reports.

  

The Dual-Active Histamine H₃ Receptor Antagonist and Acetylcholine Esterase Inhibitor E100 Alleviates Autistic-Like Behaviors and Oxidative Stress in Valproic Acid Induced Autism in Mice

The histamine H3 receptor (H3R) functions as auto- and hetero-receptors, regulating the release of brain histamine (HA) and acetylcholine (ACh), respectively. The enzyme acetylcholine esterase (AChE) is involved in the metabolism of brain ACh. Both brain HA and ACh are implicated in several cognitive disorders like Alzheimer’s disease, schizophrenia, anxiety, and narcolepsy, all of which are comorbid with autistic spectrum disorder (ASD). Therefore, the novel dual-active ligand E100 with high H3R antagonist affinity (hH3R: K_i = 203 nM) and balanced AChE inhibitory effect (EeAChE: IC₅₀ = 2 µM and EqBuChE: IC₅₀ = 2 µM) was investigated on autistic-like sociability, repetitive/compulsive behaviour, anxiety, and oxidative stress in male C57BL/6 mice model of ASD induced by prenatal exposure to valproic acid (VPA, 500 mg/kg, intraperitoneal (i.p.)). Subchronic systemic administration with E100 (5, 10, and 15 mg/kg, i.p.) significantly and dose-dependently attenuated sociability deficits of autistic (VPA) mice in three-chamber behaviour (TCB) test (all p < 0.05). Moreover, E100 significantly improved repetitive and compulsive behaviors by reducing the increased percentage of marbles buried in marble-burying behaviour (MBB) (all p < 0.05). Furthermore, pre-treatment with E100 (10 and 15 mg/kg, i.p.) corrected decreased anxiety levels (p < 0.05), however, failed to restore hyperactivity observed in elevated plus maze (EPM) test. In addition, E100 (10 mg/kg, i.p.) mitigated oxidative stress status by increasing the levels of decreased glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT), and decreasing the elevated levels of malondialdehyde (MDA) in the cerebellar tissues (all p < 0.05). Additionally, E100 (10 mg/kg, i.p.) significantly reduced the elevated levels of AChE activity in VPA mice (p < 0.05). These results demonstrate the promising effects of E100 on in-vivo VPA-induced ASD-like features in mice, and provide evidence that a potent dual-active H3R antagonist and AChE inhibitor (AChEI) is a potential drug candidate for future therapeutic management of autistic-like behaviours.

 

Acetylcholinesterase inhibitor (AChEI)

An acetylcholinesterase inhibitor (AChEI) inhibits the enzyme acetylcholinesterase from breaking down the neurotransmitter acetylcholine, thereby increasing both its level and duration of action.

We know that a surge in acetylcholine improves learning.

Examples of acetylcholinesterase inhibitors include: -

·        Alzheimer’s drugs Donepezil and Galantamine (both used off-label in autism)

·        Caffeine

·        Rosmarinic acid

  

Histamine H3 antagonists

Histamine H3 antagonists bind to H3 receptors in the brain so that histamine cannot activate them, examples include: -

Betahistine

Betahistine/Ciproxifan produces wakefulness and attentiveness in animal studies, and produced cognitive enhancing effects without prominent stimulant effects at relatively low levels of receptor occupancy, and pronounced wakefulness at higher doses. It has therefore been proposed as a potential treatment for sleep disorders such as narcolepsy and to improve vigilance in old age, particularly in the treatment of conditions such as Alzheimer's disease 

Pitolisant 

Pitolisant/ Wakix, is a medication for the treatment of excessive daytime sleepiness (EDS) in adults with narcolepsy. It is a histamine 3 (H₃) receptor antagonist/inverse agonist. It represents the first commercially available medication in its class. Pitolisant enhances the activity of histaminergic neurons in the brain that function to improve a person's wakefulness.

The most common side effects include difficulty sleeping, nausea, and feeling worried

  

There is a lot in this blog about histamine, mainly in relation to mast cells and allergic responses. You do have mast cells in your brain. Science has not fully established the role of histamine in humans, particularly in the brain. 

A quick recap on histamine:- 

H1 receptor

The H1 receptor is what mediates things like pollen allergies, but it plays a role in the brain that affects sleep, appetite, body temperature and cognition.

 

H2 receptor

The H2 receptor in the gut is the target of acid lowering drugs. These receptors do exist in the brain, but nobody has figured out their function.

 

H3 receptor

The H3 receptor is mainly in the central nervous system where it regulates the release of brain histamine (HA) and acetylcholine (ACh); it also affects the release of serotonin and norepinephrine. Elsewhere in the body H3 receptors play a role in the release of gastric acids. 

H4 receptor

The H4 receptor is not well understood. It plays a role in mast cells, but its role in cognition, allergy and inflammation is not fully understood.

 

Histamine-gated Chloride Channels

It does not seem to have a cute name like H5, but there appears to be another target for histamine, that is a histamine gated chloride channel, which seems to be present in the brain 

 

Histamine is produced from the amino acid histidine.  Some food contains histamine.

Somewhat bizarrely, it seems that if you supplement the amino acid histidine you get an anti-allergy effect; it is like more histidine makes/releases less histamine.  One of nature’s feedback loops at work, I suppose.

Histamine is mainly stored in mast cells (the target of mast cell stabilizer drugs), some is stored in basophils. Within the brain histamine functions as a neurotransmitter and you have so-called histaminergic neurons.

Once released, histamine is supposed to be deactivated by the enzymes HNMT or DAO (histamine-N-methyltransferase or diamine oxidase).  If you lack HNMT or DAO you will have problems with histamine.

  

Is there a synergistic benefit from blocking the H3 receptors in the brain and increasing the level of acetylcholine? 

The researchers from the UAE seem to believe that the new Polish drug E-100 has the unique benefit of doing two clever things at once that together might be helpful in human autism, as well as in the original target, Alzheimer’s.

 

 

Conclusion 

I did write in length in this blog about histamine; there are 18 posts tagged with Histamine. 

https://epiphanyasd.blogspot.com/search/label/Histamine

This did take me to the world of mast cell stabilizers and then L-type calcium channel blockers, so it was productive; but there were clearly huge gaps in the science that still remain.

The interesting substances from my original investigation include: -

·        H1 anti-histamines that also stabilize mast cells (Azelastine, Rupatadine, Ketotifen).

·        Pure mast cell stabilizers like Cromolyn Sodium

·        L-type calcium channel blockers such as Verapamil

 

It seemed highly likely that H3 and H4 receptors might also be useful targets, let alone the even less understood histamine gated chloride channels.

Is the new Polish drug E-100 going to be effective in human autism? and in which people?  Are the people with mast cell problems likely to be among the responders?  

 

 

Navigating "Medical" Approaches to Treating Autism

One doctor/autism parent recently mentioned to me that readers need to be made aware that drug interventions for autism can take time to show effect and that since parents see their child every day, they may not notice such gradual changes and potentially throw away a drug that actually is effective in their case.  This is indeed true.

On the other hand, as noted in their critique of Vitamin B6 use in autism, the Lurie Center for Autism at Massachusetts General for Children advised:

“It is difficult to track improvement or decline in children with autism because many have cycles of better, then worse, behavior, and many are also involved in more than one therapy that may change while the child is on supplements …

In our experience, although parents may see a change (positive or negative) in the short term, few continue to give megadose vitamin B6 to their children because of the difficulty in teasing out whether or not it really makes a difference and because of the activation and irritability seen in long term treatment.”

Some parents do not value small improvements, but if you combine five therapies, each with small improvements, the net effect can be substantial.

Some interventions have no side effects, unlike many B vitamins, and so it is just a question of whether there is a genuine benefit that is sustained.  If you stop the therapy, is the effect lost? albeit possibly gradually, and does the same benefit return when you restart the therapy?

As the child gets older, does the therapy continue to have value?  I recall being asked by Dr Ben Ari, how do I know after 8 years my son still benefits from Bumetanide? Every now and again we make a pause from Bumetanide and see how he responds.  How would you measure the response?  I use how good my son is at his online math tutoring program as an objective measure of cognitive status. I also ask him in the afternoon what he had for lunch that day; without bumetanide he usually cannot answer.

Another doctor who was treating his son with bumetanide and also low dose clonazepam for some years, told me that he ran out of clonazepam and decided to see if it still provided a benefit.  He concluded that clonazepam was no longer needed.  It is important to check; there is no point using a drug just for the sake of it.

Some people find a positive effect is lost and they need to readjust their dosage.  This seems quite common with sulforaphane.

As some readers have found, interactions between drugs and supplements mean that dosages may need to be adjusted. Low-dose clonazepam in particular has only a very narrow effective dosage range. Very many drugs, including verapamil, reduce the excretion rate of clonazepam and so increase the level in your blood. Vitamin E increases the metabolism of clonazepam.

An even more fundamental issue is whose interventions should you consider and where is line between potentially helpful therapies and crank therapies.

I am surprised how different clinicians react to other people’s therapies. For example, one US neurologist when introduced to the idea of potassium bromide as a therapy for autism and indeed pediatric epilepsy thought the idea was very interesting and lamented not being able to try it, while another US neurologist’s immediate reaction was “call child protective services”.  Both neurologists are well known autism doctors.

There are many widely shared approaches to treating autism, some are dietary like the gluten and casein free diet, the ketogenic diet or the popular GAPS diet; some use dietary supplements like fish oil and vitamins.  All approaches have their committed followers.

Most medical doctors are critical of any therapy claiming to treat autism; the few progressive mainstream doctors who do attempt to treat autism can be very disparaging about the methods used by others.  Of course, the most open-minded medical doctors are the ones successfully treating their own child's autism.

Some “protocols” that are put forward are presented as treating a very wide range of conditions (chronic pain, Alzheimer’s etc), far beyond just autism and this does naturally raise suspicions, but some conditions with very different symptoms can share similar underlying biology.

Mainstream medicine is by its very nature extremely conservative, cautious and slow moving.  Different countries may practice very different mainstream therapies and some techniques take 20 years to become adopted from one continent to another.  There is no single mainstream, it varies.

Progressive mainstream medicine gradually pushes the boundaries. In the world of autism such practitioners are mainly in the United States and surprisingly in Italy.

Science driven autism therapy stretches beyond progressive mainstream medicine. It takes many years for ideas in the scientific research to become part of medicine.  If you do not have a couple of decades to wait, you can choose to look at the science and identify what might eventually become medicine.

Applying an open mind to what might seem far-fetched alternative therapies can reveal alternative modes of action which are very much science based. Dr Yu has therapies for autism based on treating parasites.  It turns out that some anti-parasite drugs like Ivermectin and Suramin have modes of action that really should benefit some types of autism, but have nothing to do with parasites. 

If someone finds their Alpha Lipoic Acid (ALA) chelation therapy beneficial, this is not a surprise because ALA is an antioxidant widely used in medicine to treat diabetes and will benefit those with oxidative stress (autism, mitochondrial disease, cardiovascular disease etc).  It might have nothing to do with chelating metals from your brain. 

The DAN! (Defeat Autism Now) protocol was very popular and many people in the US still have a “DAN Doctor” who is applying the ideas of Sidney Baker, Jon Pangborn and others.  These are so-called biomedical therapies and mainly use dietary supplements rather than prescription drugs.  Defeat Autism Now!, closed down in 2011, was a project of the Autism Research Institute (ARI).

In North America there are doctors of functional medicine, integrative medicine, holistic medicine. There are naturopaths, homeopaths, doctors of Osteopathic Medicine (look for the DO after the name and not MD) and doctors of chiropractic medicine (DC after their name).

What is clear is that most autism parents prefer the idea of special diets, supplements and the simple protocols like that promoted by Nemechek, which are often claimed to work for everyone. 

I do not think many turn to Dr Chez and his book on medically managing autism; he does not claim to offer a simple answer and that is what parents want. 

I am amazed how popular Nemechek is and that people have even informally translated his book into different languages and then it gets shared virally.  It is like the new DAN! Protocol. I should note that his ideas do indeed work for some people.

You would think that having a doctor of medicine (MD) is best, but then nothing much about autism is taught at medical school.  Nemechek is a DO, not an MD.

I would have thought a clever neurologist like Dr Chez would be best, but I take note that many people have found an open-minded psychiatrist, who helps them trial off-label therapies, is best. This seems to be particularly true of adults with mild autism / Asperger’s.

There is no one-stop-shop for treating autism, no matter how big your budget is.  You have to navigate your own path, rather than just hoping for the best.  If you rule out off-label drugs, you are ruling out many potent therapies; it is rather like the "warrior" going into battle wearing a blindfold or having their hands tied behind their back.  The result likely could have been better.

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.