This is the 50th edition of our Science column, and to mark the occasion, we are going to revisit as well as update one of the most interesting topics we have brought to you. That topic is the ever popular faecal microbiota transplantation (FMT), otherwise known as stool transplant.
Join our WhatsApp ChannelLast year and also earlier this year, we discussed how faecal microbiota transplantation (FMT) is increasingly becoming popular in the fight against diseases. The use and popularity of this technology is continuing to increase. The latest research is on the application of this technology in cancer therapy.
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Because cancer is such a complex disease, most patients do not respond well to immunotherapy intervention. Faecal microbiota transplantation (FMT), is being used to make cancer patients respond more positively to cancer therapies, including powerful therapeutic drugs. And by responding to these therapies, the patients are able to use their innate immunity to fight cancer tumours.
Before we proceed further, I think it might be good to refresh our memory about gut microbiota. As summarised in the January 2022 edition of the topic:
•A mix of microorganisms live in our bodies including bacteria, fungi, protozoa and viruses.
•Each person’s digestive system (or the gastrointestinal tract) is a hive of microbial activities and contains more than 100 trillion diverse microorganisms.
•Some of the microorganisms are harmful and others are beneficial by helping to protect us against the harmful ones; some help in digesting our foods and some even produce beneficial chemicals like vitamins and essential amino acids we require for growth and development.
•A collection of all the genetic makeup (ie genomes) of the microorganisms in the environment (e.g your body) is called the microbiome, while a collection of those microorganisms seen in specific areas of your body (e.g. stomach) is called the microbiota.
•The largest collection of microorganisms in the body is in the large intestine or colon, in fact the number of microorganisms in the colon runs into trillions, and are recognised as the gut microbiota.
•The gut microbiota is very individualised so that the composition of each person’s gut microbiota reflects on the person’s health.
•The composition of each person’s microbiota depends on many factors such as the type of birth delivery you had when you were born (vaginal or Caesarian delivery), whether the person was breastfed or formula milk-fed, antibiotic use, etc.
•Factors such as lifestyle, dietary and cultural habits contribute to differences in microbiota composition between individuals.
The FMT (or stool transplant) technique aimed at rejuvenating old and unhealthy microbiota of patients simply involves capsulation of healthy donors’ poo, which patients then swallow, or feeding crude poo of screened donors through tubes inserted through the nose to the stomach, and finally down to the small intestine (ie nasojejunal). Stool transplant practice is common and the poo could be delivered by colonoscopy, enema or capsulation.
Poo in the form of FMT has shown a lot of promise in the treatment of gut infections, specifically recurrent diarrhoea caused by the bacterium, Clostridium difficile. It has also shown modest gain in reversing the ageing process, and in the amelioration of cognitive decline in the elderly. But over the years, research into FMT has shown the impact of the technology on cancer tumours, influencing the ability of the immune system to fight cancer cells, and the reduction of side effects from cancer drug therapies experienced by patients.
About 25% of a typical cancer tumour environment is made up of microorganisms. These microbes can promote or block anti-tumour immunity. And depending on the type of cancer, microorganisms from many areas of the body including the intestine, oral cavity and bloodstream, can travel to the site of tumours.
Pancreatic adenocarcinoma (PDAC) is a form of cancer in which only a few patients survive for more than five years. Florencio McAllister and coworkers examined the interplay of forces between microbes found in tumour environments (ie tumour microbiota) and the immune system in influencing long-term survival of PDAC. The result published in the August 2019 edition of the journal, Cell, did show that certain microbes were consistently associated with the tumour of those that survived PDAC for more than five years. These microbes, which include Pseudoxanthomonas, Streptomyces, Saccharopolyspora, and Bacillus clausii, are able to communicate with the gut microbiota. More importantly, patients that survive for more than five years had significantly higher tumour bacteria diversity than patients with shorter survival time.
It has been shown that gut microbiota mediate tumour responses to therapies through activation of the immune system, and promotion of cancer-associated inflammatory responses. A paper published in Science in 2015, did show that bacteria belonging to the genus, Bifidobacterium, one of the genera of bacteria that make up the gut microbiota, increased the response to cancer immunotherapy in mice by boosting the response of some immune cells against cancer cells.
McAllister and coworkers effected a faecal microbiota transplant by feeding mice with poo through a tube leading down the throat to the stomach (ie oral gavage). The poos were from patients with advanced pancreatic adenocarcinoma (PDAC) who died in less than 5 years after diagnosis of PDAC, those who survived for more than five years after diagnosis, and control donors. The study demonstrated the ability of the gut microbiota to modulate tumour microbiota, and also showed that FMT can change the gut microbial landscape of the recipient.
Apotopsis is a programmed cell death event. When cells are surplus to requirements, they simply commit suicide by initiating an intracellular death programme. A protein called programmed cell death protein or PD-1, which is found on the surface of the immune systems (T and B cells), regulates apotopsis. This protein dampens the immune system such that it tolerates the body’s own cells by suppressing the inflammatory activity, which otherwise would destroy the cells. This is why cancer cells are tolerated by the body immune system.
Therefore, one of the ways in which cancer is treated is to target the PD-1 by the use of anti-PD-1 immunotherapies (i.e. PD-1 inhibitors like pembrolizumab and nivolumab). Hassane Zarour and coworkers writing in the February 2021 issue of the journal, Science, reported the synergistic effect of faecal microbiota transplantation and anti-PD-1 therapy in changing the gut microbiota and reprogramming the tumour microenvironment so that patients with advanced melanoma responded positively to anti-PD-1 therapy.
A recent research in Canada investigating whether FMT from non-cancer donors can prevent resistance to immunotherapy in cancer patients, did show that of the 20 people with advanced melanoma who had FMT and immunotherapy, 3 people responded completely to immunotherapy, 13 showed a partial response, 3 showed no response while one died of melanoma.
A study published last year in the journal, Science, did show that cancer patients who ate high-fibre diets responded well to immunotherapy whereas patient who took over-the-counter probiotics had the least response to immunotherapy.
In another study in Israel, a cancer patient who responded well to the powerful immunotherapy drug, nivolumab, was asked to donate his poo for FMT. His poo was screened for disease-causing microbes, processed further before packaging it into capsules. The capsulated poo was given to another cancer patient, and the person has been cancer-free for more than 3 years. In turn the recipient’s poo has been used to treat other cancer patients, making them more receptive to immunotherapy, and in one case eased the toxic side effects of a cancer drug called pembrolizumab.
Faecal microbiota transplantation is an emerging technology, and promises to be cheap and effective if one is brave enough to forget that one is swallowing another person’s poo! But if one wants to make an omelette, one simply have to break some eggs. Comprendre?
P/S: To celebrate our 50th Science column edition, as well as a followup on the FMT emerging technology, we shall be doing a comedy piece in the next instalment. Until then, stay tuned and stay safe.
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