Fecal transplants - many studies

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Faecal transplants are just the start for microbiome medicine  - Economist Nov 2023

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Gilead Amit
Science correspondent
Sitting in a small windowless lab watching Désirée Prossomariti strain solids through a sieve, I am reminded, despite myself, of jam-making. “I’ve never looked at it that way,” she says. “But yes, I’ve seen my mother making jam.” 

Dr Prossomariti is making something much more important, if much less palatable. She manufactures a medical therapeutic known as a faecal microbiota transplant (FMT)—oral capsules derived from freeze-dried human stool that are extraordinarily effective at relieving some nasty bacterial infections.

The logic is surprisingly sound. The gut microbiome is a complex entity, containing many hundreds of species and a total number of cells that rivals those of the host’s body. When this ecosystem is damaged, the consequences can be felt all over the body. Diabetes, obesity, Parkinson’s disease, Alzheimer’s disease and atopic dermatitis have all been linked to the (mis)activity of the gut microbiome. Some have called the microbiome an organ in its own right. And where there is an organ, there is hope of transplantation.
Not long ago, FMT was regarded as fringe. “People would talk about it in conferences, and people would laugh and giggle,” says Simon Goldenberg, who manages the laboratory at Guy’s and St Thomas’ Hospital in London, where Dr Prossomariti works. Then, in 2013, a Dutch clinical trial of FMTs showed such positive results that it was ended early—a supervisory board deeming it unethical to withhold the treatment from the placebo group. That was a turning-point.
Many patients now benefit from FMT, and their number is set to rise as more positive results filter in from clinical trials. All the same, as we report this week, its time in the Sun is likely to be short-lived. Crucially, stool is impossible to standardise, and its contents challenging to determine. Its long-term safety profile is also largely unknown. This makes FMT hard to regulate consistently.
At present

• Americans and Canadians regard it as an investigational drug with limited uses, while
• in Belgium, Italy and the Netherlands it is viewed as a tissue transplant.
• In Britain, meanwhile, it is viewed as a medicinal product, which allows for more flexible regulation.

More practical issues abound. Few donors pass screening tests, and those that do tend to find the donation process—which requires samples to arrive in the lab no more than two hours after being produced—awkward and off-putting. All this strongly limits supply.
The future of microbiome manipulation is likely to involve more bespoke intervention. Designing a microbiome to meet a specific patient’s needs, in other words, rather than copying a template. This is a Herculean task, but some progress is already being made. From creating designer microbial communities that can restore balance to an off-kilter gut, to using hand-picked viruses to kill off the most noxious bacteria, the future of microbiome manipulation looks brighter than ever. And perhaps will smell sweeter too.

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Fecal Transplants for Ulcerative Colitis, MS, Depression, Bipolar, and Alcoholism - Dr. Greger April 2023

Video has the following transcript
Plant-based foods and the microbiome in the preservation of health and prevention of disease: We have evidence that high-fiber, plant-based diets can prevent many different common diseases, maybe through the effect that these diets have on the composition and metabolic activity of our microbiome, the bacteria in our gut. Good gut bugs in our colon eat the plant residues, and spit out health-promoting and cancer-suppressing metabolites. Like fiber is metabolized to short-chain fatty acids, which have profound anti-inflammatory, anti-cancer properties. And we have special fiber-feeding microbes that chew through the plant cell walls and release all the anti-inflammatory, antioxidant, and anticancer goodies inside. How many whole plant foods do we have to eat?

All the evidence points to a physiological need for about 50 grams of fiber a day, which is what is contained in the traditional African diet, and is associated with the prevention of common Western chronic diseases. This is up to twice the recommended minimum, and three times the current intake in the United States. How can you prove the microbiome is involved, though? Fecal transplantation—stool transplants. One man’s trash; another man’s treasure.

Currently, donor fecal microbiota transplantation (DFMT) is the optimum therapeutic approach for recurrent Clostridium difficile (C. diff) infection. C. diff is today considered the most common hospital-acquired cause of diarrhea. It’s a life-threatening infection that can rear its ugly head when your good gut bugs have been wiped out by antibiotics. So, to get rid of it, all we need are more good gut bugs, which can be provided by a healthy donor through the infusion of a liquid suspension of the donor’s stool. We are winning with poo.

Fecal transplants have proven their worth in the management of recurrent C. diff diarrhea, with cure rates up to 90 percent. Because of this success, fecal transplants have been suggested as a potential treatment in other gastrointestinal diseases. For example, the inflammatory bowel disease known as ulcerative colitis. There have been four randomized controlled trials, and fecal transplants appear to nearly double clinical remission rates. But what about non-gastrointestinal disorders?

Here’s a case study of a series of fecal transplants for multiple sclerosis (MS). The patient experienced improvements in their microbiome, more of those fiber-feeding anti-inflammatory bacteria, and there was a significant increase in the levels of brain-derived neurotrophic factor, which is suggested to play a neuroprotective role in MS, as well as both subjective and objective evidence of improved walking, which was the patient’s primary MS symptom. Now, to give the new fiber feeders something to chew on, the patient was put on a high fiber diet, which is great. But just putting people on a plant-based diet alone may help––stool transplants or not, since standard Western diets promote dysbiosis, a bad bug gut imbalance, and neuroinflammation in MS, while plant-based high-fiber diets decreased MS risks. Randomized, placebo-controlled trials will be needed to tease that out, but in the meanwhile, we can certainly build up good gut bugs the old-fashioned way by eating fiber-rich whole plant foods.

What about fecal transplants for depression? Interest in the gut microbiome and its role in health has exploded just in the last few years. Does any of this have relevance in psychiatry? Maybe so. Several studies demonstrate microbiome differences between depressed persons and non-depressed persons. And after all, an imbalance in neurotransmitters is implicated in the cause of depression, and the gut microbiome is known to synthesize large quantities of these same neuroactive substances, like serotonin and dopamine. And there’s a major information highway from the gut to the brain, called the vagus nerve, that could potentially alter mood states. Early fecal transplants were delivered from the bottom up, through colonoscopy, but now we have “crapsules” —encapsulated feces to make it easier to swap stool.

Here’s a case report of a 79-year-old woman who suffered a tragedy and subsequently lost her appetite, became introverted, drowsy, and stayed in bed all day, wasting away 55 pounds over the next six months. She was hospitalized for depression, and prescribed multiple anti-depressant drugs, but to no avail. So, what the heck, they stopped the drugs and tried a fecal transplant. The stool donor was her own six-year-old great-grandson, who had a good appetite, an outgoing personality, and a disciplinary stool—I don’t even know what that means. Four days after the fecal transplant, she started feeling better, and by two weeks she was frankly euphoric. She was able to go back home, and within six weeks all was back to normal.

What about a fecal transplant for bipolar disorder? The poor woman was in and out of psych hospitals with manic depression until she got a fecal transplant with stool from her husband—that’s romantic—and within six months she was symptom free. This case report was published in 2020, so symptom-free for years, no longer on medication, and has lost more than 70 pounds to boot––either because she got slim hubby stool, or just being off her psych meds. She went from being functionally disabled to running a small business and has published two books.

What about alcohol dependence? Alcoholism has traditionally been considered exclusively a brain disorder, but hey, all these other psychiatric syndromes seem to have links to the gut. So, they compared the guts of alcoholics to nonalcoholics, and they found that some alcohol-dependent subjects developed gut leakiness, which was associated with higher alcohol cravings. Okay, but maybe instead of the gut issues somehow leading to alcohol cravings, the alcohol led to the gut issues. Alcohol may have a toxic effect on the gut wall, but both groups were consuming the same amount of alcohol at the time. So, maybe there is some kind of gut connection after all.

This was the study that blew people’s minds. The transplant of feces from alcoholics into mice induced an alcohol preference. These were mice without any previous contact with alcohol, all of a sudden spontaneously preferring alcohol. Normally mice don’t really like alcohol, but feed them some feces from an alcoholic human, and they do a 180-degree switch. So, wait. Are you saying that gut bugs can determine alcohol cravings? There’s only one way to find out, and that’s put it to the test.

A randomized, double-blind, clinical trial of fecal microbiota transplant for alcohol use disorder (which is the current clinical term for alcoholism). They took alcoholics with liver cirrhosis and active problem drinking, and randomized them to get either a placebo enema or a fecal transplant enema. And within two weeks, alcohol craving reduced significantly in 90 percent of the fecal transplant cases versus just 30 percent in the placebo cases. And this was validated by pee tests showing they were drinking significantly less too, with improved cognition and psychosocial quality of life.

Now, this is all still just experimental, and not without potential downsides. Yes, they’re working on ways to make stool transplants more palatable. On balance, they’ve largely been found to be safe, though there have been cases of bad bugs being transferred from donors, even a fatal case. And there’s even a theoretical risk you could be transplanted with cancer cells, making it the gift that keeps on giving, but in a bad way.

Greger References

• O'Keefe SJD. Plant-based foods and the microbiome in the preservation of health and prevention of disease. Am J Clin Nutr. 2019;110(2):265-266.
• Gupta N, Hanauer SB. One man's trash-another man's treasure: fecal transplantation. Hepatobiliary Surg Nutr. 2019;8(6):623-625.
• Rokkas T, Gisbert JP, Gasbarrini A, et al. A network meta-analysis of randomized controlled trials exploring the role of fecal microbiota transplantation in recurrent Clostridium difficile infection. United European Gastroenterol J. 2019;7(8):1051-1063.
• Groves HE, Allen UD. Winning with poo? Fecal microbiome transplantation as an emerging strategy for the management of recurrent Clostridioides difficile infection in children. Pediatr Transplant. 2020;24(1):e13651.
• Blanchaert C, Strubbe B, Peeters H. Fecal microbiota transplantation in ulcerative colitis. Acta Gastroenterol Belg. 2019;82(4):519-528.
• Engen PA, Zaferiou A, Rasmussen H, et al. Single-Arm, Non-randomized, Time Series, Single-Subject Study of Fecal Microbiota Transplantation in Multiple Sclerosis. Front Neurol. 2020;11:978.
• Wens I, Keytsman C, Deckx N, Cools N, Dalgas U, Eijnde BO. Brain derived neurotrophic factor in multiple sclerosis: effect of 24 weeks endurance and resistance training. Eur J Neurol. 2016;23(6):1028-1035.
• Green J, Castle D, Berk M, et al. Faecal microbiota transplants for depression - Who gives a crapsule?. Aust N Z J Psychiatry. 2019;53(8):732-734.
• Cai T, Shi X, Yuan LZ, Tang D, Wang F. Fecal microbiota transplantation in an elderly patient with mental depression. Int Psychogeriatr. 2019;31(10):1525-1526.
• Hinton R. A case report looking at the effects of faecal microbiota transplantation in a patient with bipolar disorder. Aust N Z J Psychiatry. 2020;54(6):649-650.
• Leclercq S, Matamoros S, Cani PD, et al. Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of alcohol-dependence severity. Proc Natl Acad Sci U S A. 2014;111(42):E4485-E4493.
• Zhao W, Hu Y, Li C, et al. Transplantation of fecal microbiota from patients with alcoholism induces anxiety/depression behaviors and decreases brain mGluR1/PKC ε levels in mouse. Biofactors. 2020;46(1):38-54.
• Bajaj JS, Gavis EA, Fagan A, et al. A Randomized Clinical Trial of Fecal Microbiota Transplant for Alcohol Use Disorder. Hepatology. 2021;73(5):1688-1700.
• Fadda HM. The Route to Palatable Fecal Microbiota Transplantation. AAPS PharmSciTech. 2020;21(3):114.
• Dailey FE, Turse EP, Daglilar E, Tahan V. The dirty aspects of fecal microbiota transplantation: a review of its adverse effects and complications. Curr Opin Pharmacol. 2019;49:29-33.
• DeFilipp Z, Bloom PP, Torres Soto M, et al. Drug-Resistant E. coli Bacteremia Transmitted by Fecal Microbiota Transplant. N Engl J Med. 2019;381(21):2043-2050.
• Turse EP, Dailey FE, Ghouri YA, Tahan V. Fecal microbiota transplantation donation: the gift that keeps on giving. Curr Opin Pharmacol. 2019;49:24-28.

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Fecal microbiota transplants: A review of emerging clinical data on applications, efficacy, and risks (2015–2020) - Feb 2021

Qatar Medical Journal, Volume 2021, Issue 1, Apr 2021, DOI: https://doi.org/10.5339/qmj.2021.5
Dana Al-Ali1, Aamena Ahmed2, Ameena Shafiq1, Clare McVeigh1, Ali Chaari1, Dalia Zakaria1, Ghizlane Bendriss1
View Affiliations

As the importance of the gut microbiota in health and disease is a subject of growing interest, fecal microbiota transplantation (FMT) was suggested as an attractive therapeutic strategy to restore homeostasis of the gut microbiota, thereby treating diseases that were associated with alteration of the gut microbiota. FMT involves the administration of fresh, frozen, or dried fecal microorganisms from the gut of a healthy donor into the intestinal tract of a patient. This rediscovery of the potential benefits of an ancient practice was accompanied by a rapid progression of our understanding of the roles and mechanisms of gut microbes in the pathogenesis of disease. With a growing number of diseases being associated with dysbiosis or the alteration of gut microbiota, FMT was suggested as an attractive therapeutic strategy to “reset the gut” and initiate clinical resolutions or remissions. The number of FMT clinical trials is increasing worldwide, but no trials are registered in the Gulf region; this suggested the need for raising awareness of the latest studies on FMT. This review presented the emergent preclinical and clinical data to give an overview of the potential clinical applications, the benefits, and inconveniences that were worth considering for eventual future testing of fecal transplants in Qatar and the Middle East. This study highlighted the diversity of methods tested and commented on the variables that can affect the assessment of the effectiveness of FMT in specific diseases. The risks associated with FMT and the threat of antimicrobial resistance for this therapeutic approach were reviewed. From gastrointestinal diseases to neurodevelopmental disorders, understanding the roles of the gut microbiota in health and disease should be at the heart of developing novel, standardized, yet personalized, methods for this ancient therapeutic approach.
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148 citations as of Nov 2023

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Relationships Between Vitamin D, Gut Microbiome, and Systemic Autoimmunity - Jan 2020

Front. Immunol., 21 January 2020 Volume 10 - 2019 | https://doi.org/10.3389/fimmu.2019.03141
Erin A. Yamamoto1* and Trine N. Jørgensen2*
1Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, United States
2Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States

There is increasing recognition of the role the microbiome plays in states of health and disease. Microbiome studies in systemic autoimmune diseases demonstrate unique microbial patterns in Inflammatory Bowel Disease, Rheumatoid Arthritis, and Systemic Lupus Erythematosus to a lesser extent, whereas there is no single bug or pattern that characterizes Multiple Sclerosis. Autoimmune diseases tend to share a predisposition for vitamin D deficiency, which alters the microbiome and integrity of the gut epithelial barrier. In this review, we summarize the influence of intestinal bacteria on the immune system, explore the microbial patterns that have emerged from studies on autoimmune diseases, and discuss how vitamin D deficiency may contribute to autoimmunity via its effects on the intestinal barrier function, microbiome composition, and/or direct effects on immune responses.
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Fecal transplants as a microbiome-based therapeutic - Aug 2020

Current Opinion in Microbiology Vol 56, pg 16-23 https://doi.org/10.1016/j.mib.2020.05.008 PDF behind paywall
Nadeem O Kaakoush

Highlights

• Fecal transplants, despite associated risks, are now a widely accepted therapeutic.
• Bacterial species and functions consistently associated with efficacy have been identified.
• Recent research indicates fungi and viruses are associated with therapy outcomes.
• Limited data exists on the influence of host diet and genetics on therapy efficacy.
• Modified fecal communities and lab-based microbial therapies have been tested.

Impaired microbiome diversity and composition can develop into a potent etiological agent of disease and increase susceptibility to infection. Given this, interventions targeting the microbiome have developed rapidly, with healthy donor feces being a de facto source of beneficial communities employed to rebalance patients’ microbiomes. Recent evidence has demonstrated that bacterial and viral richness, short chain fatty acid production, bile acid conversion as well as presence of bacterial and fungal pathobionts are associated with therapy efficacy; however, little is known of the influence of host factors such as genetics, medications, and diet. Here, current knowledge on factors associated with fecal transplant efficacy, as well as efforts to transition to other forms of therapy are reviewed.

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Fecal Transplant: The Benefits and Harms of Fecal Microbiota Transplantation book chapter Feb 2024

Fecal microbiota transplant (FMT) involves the therapeutic manipulation of the gut microbiome by delivering fecal material from a donor into the intestinal tract of the recipient. Mechanisms of delivery can include colonoscopy, upper endoscopy, nasojejunal tube, enemas, or orally delivered capsules. Several studies have evaluated the therapeutic effects of FMT for the treatment of recurrent or refractory Clostridioides difficile infection (CDI), for which FMT is highly effective and generally safe.
FMT has been studied in

• inflammatory bowel disease,
• irritable bowel syndrome, and a
• host of systemic, neurologic, metabolic, and neoplastic conditions.

While generally considered safe, case reports of the transmission of severe and even fatal infections reinforce the need for careful donor screening and safety assessments.
Two FMT products are currently FDA approved for the treatment of CDI, while regulatory enforcement discretion has been generally applied for FMT since 2013 when performed for recurrent/refractory CDI and when material has been obtained from a stool bank. This chapter summarizes the available evidence for the efficacy and safety of FMT in the setting of various clinical conditions, and suggests further areas for clinical and cost-effectiveness research to help clarify the most appropriate use for FMT across multiple indications.

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Fecal Transplant looks promising for Cardiovascular diseases too - Aug 2023

Faecal Transplant Therapy: A Promising Treatment Modality for Cardiovascular Diseases
K Pushkala and Purshottam D Gupta*
Published: 28 August, 2023 | Volume 8 - Issue 2 | Pages: 108-113

Cardiovascular diseases (CVD) are considered as “lifestyle” diseases and so far “No unified procedure” or medicines are effective in the management of this group of diseases. Researchers and clinicians have indicated that no safe therapeutic window is available in therapeutics at present. Recent research showed that gut microbiota are effective in managing lifestyle diseases therefore we introduced the influence of gut microbiota in the prognosis of the CVDs.
Faecal transplant therapy (FMT) has been anticipated to treat many diseases similar to recurrent bacterial Clostridioides difficile infection which has been used worldwide. Recently, FMT was tried on an animal model to treat CVDs, and recent human trials that were tried to manage CVDs in humans by FMT showed encouraging results. The mechanism of action of transplanted bacteria to manage CVDs in the human population is also discussed. In-depth knowledge on the pros and cons of FMT will pave the way to standardize the procedure once the lacuna existing at present in treating CVDs, is paved, this technology will be useful for the masses.
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