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Fecal microbiota transplantation to tackle diabetes

Fecal microbiota transplantation to tackle diabetes

Fecal microbiota transplantation, including ‘poop pills’, and good gut health could keep our blood sugar at optimum levels

Fecal microbiota transplantation (FMT) or 'stool therapy' emerging as a key strategy to address gut dysbiosis, the lynchpin of obesity and diabetes.

Sh*t happens, but it need not always be bad news. In fact, it could even be therapeutic — especially for people with diabetes. Researchers working on gut health are hopeful of fecal microbiota transplantation (FMT) or ‘stool therapy’ emerging as a key strategy to address gut dysbiosis, the lynchpin of obesity and diabetes.

“The gut microbiota can control blood sugar metabolism by targeting multiple pathways in different organs including the intestine, liver and pancreas,” Dr Gabriele Deidda, assistant professor, department of medical sciences, University of Padova, Italy, tells Happiest Health in an online interaction.

In an article published in the Journal of Clinical Medicine in July 2022, Dr Deidda and fellow researcher Dr Manuele Biazzo, director, Bio Arte Project, a biomolecular research park based in Malta, have elaborated on the relevance and scope of FMT as an efficient strategy to tackle multiple health conditions, including diabetes and obesity.

What is microbiota in the gut?

Horton Hears a Who!, Dr Seuss’s seminal children’s book, is a good literary tool to explain the diverse gut microbial flora (both good and bad) inside us. Our realisation about the existence of trillions of microbial organisms ­ — including bacteria, fungi, parasites and viruses — in the gastronomical tract would mirror what Horton the Elephant felt when the existence of an entire microscopic universe thriving inside a speck of dust dawned upon him in the book.

Dr Deidda and Dr Biazzo have said that the gut microbiota constantly interact with each other and can even breach the blood-brain barrier to form the bidirectional gut-brain axis (the neural link between the gut and our brain).

“These microbial organisms collectively represent a symbiotic superorganism containing 100 times the number of genes of the human genome and weighing approximately the same as that of human brain,” they say.

According to an article published in the 2012 edition of Nutrition Reviews journal by Harry J Flin, our gut microbiota could weigh over 2kg, slightly heftier than our brain weight, which is normally around 2kg.

Main types of gut microbiota

According to an article published in Microorganisms (Emanuele Rinninella et al., 2019), the dominant gut microbiota is overtly distributed into six categories:

  • Firmicutes
  • Bacteroidetes
  • Actinobacteria
  • Proteobacteria
  • Fusobacteria
  • Verrucomicrobia

Of these, at least 90 per cent is comprised of Firmicutes and Bacteroidetes.

How does gut microbiome affect diabetes

Gut dysbiosis could be defined as an imbalance in the gut microbiome — when a specific type of microbiota is either in larger or lesser number in the gut — thereby triggering a tilt in the gut microbiome equilibrium. Any such imbalance will affect glucose metabolism and also trigger insulin resistance — the precursors to diabetes or obesity.

“The first piece of evidence that suggests that gut microbiota controls glucose metabolism is in fact the appearance of microbial dysbiosis in gut microbiota composition that occurs during the early stages of glucose intolerance,” Dr Deidda and Dr Biazzo say in a joint response to a query from Happiest Health.

According to a research article published in the American Diabetes Association’s journal Diabetes (Junko Sanko et.al, 2014), gut microbiota is an effective marker for diabetes and obesity, and this study conducted in Japan pointed out the presence of gut bacteria in the blood samples of the participants as a result of gut dysbiosis where these microbes were translocated from the gut to their bloodstream, triggering inflammation in people with diabetes.

“People with prediabetes or newly diagnosed with type 2 diabetes show low gut microbial diversity and an altered ratio Firmicutes/Bacteroidetes (F/B ratio),” Dr Deidda says. “The short-chain fatty acids (SCFA, the main metabolites produced in the colon by bacterial fermentation of dietary fibres) are one of the mediators of such effects.” The SCFAs are considered to play a major role in reversing harmful effects triggered by gut dysbiosis.

So, essentially, FMT from a healthy donor should ensure a heathy gut microbiota ratio — especially the F/B ratio — and also ensure minimum insulin resistance and inflammation to keep diabetes under control.

Another article on the use of FMT in endocrine diseases (mainly type 1 diabetes) and obesity, published by researchers and endocrinologists Dr Max Nieuwdorp, Dr Nordin MJ Hanssen and Dr Coco M Fuhri Snethlage (physician) in the May 2021 edition of the journal Best Practise and Research Clinical Endocrinology and Metabolism, describes FMT as an emerging treatment strategy for both type 1 and 2 diabetes. It also says that FMT and gut microbiota could influence insulin secretion from the pancreatic beta cells.

Stool therapy: ‘Just like an organ transplant’

Dr Deidda and Dr Biazzo told Happiest Health that since obesity and type 2 diabetes are two conditions characterised by gut dysbiosis, it (gut dysbiosis) could be tackled by transferring the entire, complete, stable fecal microbial community of gut microorganisms contained in the feces from healthy donors.

“It is like doing an ‘organ transplant’,” says Dr Deidda. “A healthy organ carries beneficial effects. In comparison to administering probiotics that could transfer only few microbial species into the host gut, FMT has the greater advantage of transferring the entire gut micro-ecology as a proper ‘organ’.”

FMT vs probiotics

In an article published in the October 2021 edition of Frontiers in Neuroscience journal, Dr Deidda and Dr Biazzo say that one of the major advantages of FMT over probiotic administration of gut microbiota is that only very limited number of gut microbes are available in specific probiotic servings.

They also told Happiest Health that the main beneficial effects of FMT in tackling obesity are the improvement of insulin resistance and the decrease of the small intestinal permeability (high intestinal permeability allows inflammatory molecules from the gut to reach the bloodstream; it thereby has a pro-inflammatory effect), together with the improvement in body composition.

How does fecal microbiota transplantation work?

According to Dr Deidda and Dr Biazzo, donor identification, sample collection, storage and then safe transplant procedure are the crucial aspects in FMT. Dr Deidda says that FMT sample is introduced into the body either through the upper gastrointestinal pathway (nose and mouth) or through the lower ones (rectum).

The two doctors say that the very first version of FMT was done by the injection of the donor’s stool sample into the lower bowel via rectum as an enema shot. Colonoscopy was soon introduced where the donor’s liquified stool is administered into the end of the small intestine or the beginning of the colon.

“The great disadvantage of both techniques is the discomfort of the patient, and it can’t be performed in subjects with colon inflammation,” Dr Deidda says. “Coloscopy, moreover, requires a trained endoscopist and it is costly.”

After colonoscopy, FMT was also done by inserting nasal tubes to deliver stool samples either in the stomach or in the duodenum or in the jejunum (small intestine). “Again, here also there is discomfort and requires trained people,” Dr Deidda says.

Can FMT cure diabetes?

In an attempt to circumvent the procedural complication and stigma attached to FMT, researchers have been trying to develop fecal capsules or the oral ‘poo pill’ method.

“Instead, the capsules can be taken orally comfortably by the patient,” Dr Biazzo says. “They are processed in a way that they contain with higher purity the gut microbiota (in comparison to a fecal slurry). And they have been reported to have same efficacy as the other traditional methods.”

A pilot controlled clinical trial on 22 obese individuals was conducted in 2020, close on the heels of some successful experiments on lab mice. The results — published (Jessica R Allegretti et. al 2020) in the April 2020 edition of American Gastroenterological Society’s Clinical Gastroenterology and Hepatology journal — pointed out that the oral capsules were found to lead to sustained changes in the intestinal microbiome and bile acid profiles of the obese individuals similar to that of the lean donor. The clinical trial did not record change in the body mass index (BMI) of these obese individuals.

Gut-liver-adipose-tissue-pancreas axis and diabetes

Prof Dr Ullas S Kolthur, department of biological sciences, Tata Institute of Fundamental Research (TIFR), Mumbai, told Happiest Health that the interplay between gut, diet/metabolism and microbiota is now considered to influence multiple aspects of human physiology. Emerging research findings, including using mice models, have provided conclusive evidence in this regard.

“Apart from the gut-brain axis, we have the gut-liver axis, gut-adipose-tissue axis and the gut-pancreatic axis,” says Prof Kolthur. “Gut microbiota have been implicated in mediating such cross talk both via the hormones released from the gut and also through metabolites. Some of these have been shown to affect health and regulate glucose and fat metabolism. Notably, gut dysbiosis involving microbiota has emerged as being key in tackling obesity and diabetes through the gut-liver-adipose-tissue-pancreas link.”

‘Panchkarma’ therapy and gut cleansing

Dr Manu Madhav M, consulting physician, Cochin Arya Vaidya Sala, Kerala, says Ayurveda always rely on natural laxatives to wash away the harmful gut microorganisms before healthy repopulation of the gut.

“According to Ayurveda, the digestive fire is agni, which acts upon the food we eat and breaks it down to transform it into dhatus that are responsible for tissue building and the rest of the physiological processes in our body,” Dr Madhav says. “Most chronic health conditions cannot be treated in Ayurveda without addressing the functional dynamics of this digestive fire.”

Dr Anjana S, consulting physician, Cochin Arya Vaidyasala, says that in Ayurveda there are three doshas (or energy flow) that determine the state of health and normalcy: vata, pitta and kapha. “These are similar to what is referred to as our nervous system, metabolic system and immune system in modern medicine,” she says. “There has to be a balance (homeostasis) between these three doshas and any imbalance indicates health issues.”

Ayurveda follows the process of drawing out excess vata, pitta and kapha elements from the tissues into the digestive tract and then expelling them from the body to cleanse the internal system, unblock the flow of energy and restore balance.

“This cleansing process is called panchkarma in Ayurveda, and there are five types of treatment — as the name suggests,” Dr Anjana says.

Vamana chikitsa (therapy) in Ayurveda is also called emesis or medically induced vomiting. It deals with the cleansing of the upper gastrointestinal tract to the duodenum.

Virechana chikitsa in panchkarma deals with the Ayurvedic administration of enema where toxins are removed using herbal laxatives from the duodenum to the rectum and out of the body. It is practised as anuvasana vasti in which vata imbalance mainly triggered by food and external factors is addressed through enema therapy using medicated oils.

The laxatives are administered into the colon through the rectum after massaging the lower abdomen to loosen the muscles and toxins inside. The herbal oil mix initially heals the toxins in the colon and detoxes it through defecation. Similarly, instead of oils, an Ayurvedic decoction consisting of natural salts, honey, oil and other decoction (kashaya) is used as an enema in asthapana vasti treatment.

“Both anuvasana vasti and asthapana vasti are important therapeutic procedures in Ayurveda and are not just limited up to rectal expulsion of toxins and mala samsodhana (fecal detoxification),” says Dr Anjana. “It ensures positive systemic changes in our health. Virechana chikitsa itself deals with the effective management of obesity due to reduction in Escherichia coli [E. coli] colonisation in our gut and the resulting gut flora dysbiosis.”

Limitations of gut health therapy and FMT procedures

Dr Deidda and Dr Biazzo dispel most of the doubts raised by people about whether FMT could lead to any infection. They say only mild adverse events during or shortly after treatment have been reported so far.

“Obviously, it is essential to perform an accurate prescreening of the donor feces to process and transplant, so that do not contain parasites or pathogenic bacteria or phages,” says Dr Deidda. “This is actually challenging because only a low percentage of screened donors actually become a donor.”

Prof Kolthur says FMT and gut health will be effective only if the individual ensures a disciplined dietary pattern and healthy lifestyle since food has a major influence on establishing and maintaining the microbial populations.

“While FMT has a lot of promise, it cannot substitute balanced nutrition, physical activity and energy expenditure,” Prof Kolthur says. “FMT in combination with these measures will be crucial in tackling metabolic syndromes.”

Researchers Dr Deidda and Dr Biazzo, and Ayurveda practitioners Dr Madhav and Dr Anjana unanimously agree with Prof Kolthur on this aspect.

“The positive outcome of gut microbiome repopulation would be ensured only through proper follow-up comprising ideal dietary pattern and physical exercise,” Prof Kolthur says. “When compared to regular diabetes and obesity management, through diet and exercise, FMT might be a bit complicated. But it could hold lots of promise in people who are not benefitting from other standard methods of therapy.”

Dr Deidda points out the need for stringent screening of donors and setting up of stool banks to ensure proper extraction, storage and delivery of healthy stool samples.

“It will be important also that FMT is regulated by law and approved by regulation authorities worldwide, including the Food and Drug Administration (FDA), the European Medicine Agency, etc,” Dr Deidda says.

Recent good news about FMT

If there is a condition FMT therapy should be indebted to for helping stool therapy go mainstream, then that would be Clostridium difficile (C. diff), an infection in the colon and bowels.

Majority of FMT and colonoscopy trials and experiments have been conducted on people with C. diff and irritable bowel syndrome (IBS). In a landmark development in the last week of August 2022, the National Health Service (NHS), England, found that C. diff patients could be administered FMT if they have been already treated twice or more for C. diff infections without much success.

The National Institute for Health and Care Excellence, UK, gave the green signal for fecal transplants in such cases after much deliberation and parleys.

Similarly, in the United States, a section of advisers from the FDA department voted in favour of approving a pharma company’s fecal transplant therapy for C. diff in September 2022. However, the voting was not unanimous, and a detailed discussion has been called for before giving final clearance to the FMT-based therapy in the US.

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