|
 
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| REVIEW ARTICLE |
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| Year : 2023 | Volume
: 3
| Issue : 2 | Page : 44-48 |
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Fecal microbiota transplantation: Applications and challenges in India
Suranjana Banik1, Balamurugan Ramadass2
1 Department of Anatomy, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India
2 Center of Excellence for Clinical Microbiome Research, All India Institute of Medical Sciences; Department of Biochemistry, All India Institute of Medical Sciences, Bhubaneswar, Odisha, India
| Date of Submission | 02-Dec-2022 |
| Date of Decision | 06-Jan-2023 |
| Date of Acceptance | 16-Jan-2023 |
| Date of Web Publication | 09-Mar-2023 |
Correspondence Address:
Balamurugan Ramadass
Department of Biochemistry, Center of Excellence for Clinical Microbiome Research, All India Institute of Medical Sciences, Bhubaneswar - 751 019, Odisha
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/ghep.ghep_37_22
Fecal Microbiota Transplantation (FMT) involves a noninvasive technique of transferring fecal microbiota in patients from healthy donors. Donors are generally chosen from spouses or relatives, though the anonymous donation is also common. FMT is particularly useful in diseases like recurrent clostridium difficile infection, ulcerative colitis, hepatic encephalopathy, metabolic syndrome, autism spectrum disorders, anxiety, graft versus host disease, multiple sclerosis, multi drug resistance etc. FMT is gradually being adapted in India in the major cities but there are various regulatory challenges. Despite the promising nature of FMT in different pathologies, the different barriers ranging from the selection of a healthy donor, high quality control, uniform protocol maintenance, to ensuring effective mode of administration have to be addressed for FMT to become a widely accepted modality of therapy.
Keywords: Challenges, fecal microbiota transplantation, India
How to cite this article:
Banik S, Ramadass B. Fecal microbiota transplantation: Applications and challenges in India. Gastroenterol Hepatol Endosc Pract 2023;3:44-8 |
| Introduction | |  |
Human gastrointestinal (GI) tract harbors about 1013-1014 bacterial cells apart from trillions of other organisms like archaea, phages, and protozoa which constitute the gut microbiota. With the advent of next-generation sequencing, the bacterial genome has been studied extensively. Furthermore, it has been found that bacteria encode 100 folds more genes than the human genome.[1] The complex microbes, along with their genes, are called the microbiome. The gut microbiome is unique to each individual in its composition.[2] The microbiome is a dynamic entity subjected to variation under the influence of the atmosphere, climate, food, medical, and genetic determinants. Combined data from MetaHIT[3] and Human Microbiome Project[4] have characterized and distributed the major gut bacteria into four phyla: Firmicutes (60%–75%), Bacteroidetes (30%–40%), Actinobacteria, and Proteobacteria.[5] Apart from bacteria, archaea make up 0.2% of the microbiota. The gut virome is made of bacteriophages, and fungal microbiota (also known as “mycobiome”) contains Candida spp. and Saccharomyces spp. predominantly with Candida albicans.[6]
Gut microbiota is implicated in various illnesses, including GI diseases such as ulcerative colitis (UC), irritable bowel syndrome, and constipation; metabolic syndrome (MS); neuropsychiatric disorders; and cancers. In quest of their treatment modalities, it has been found that replacing the patient microbiome with that of a healthy donor may be adequate. Fecal microbiome transplantation is the simultaneous replacement of the intestinal microbiota of a sick recipient with fecal material from a healthy donor. This review summarizes the imperatives and the contemporary utility of fecal microbiota transplantation (FMT) in GI and extraintestinal pathologies.
| Fecal Microbiota Transplantation | | |
It involves a noninvasive technique of transferring fecal microbiota in patients from healthy donors. Various randomized controlled trials (RCTs), meta-analyses, and systematic reviews have claimed the supremacy of FMT compared to probiotics and antibiotics in recurrent Clostridium difficile infection (rCDI) because a single transplant contains almost all the bacteria, viruses, eukaryotes, and metabolites.[7] After FMT, rCDI patients had reduced antibiotic resistance to a large extent for up to 1 year, along with the resolution of symptoms.[8]
| Donor Screening | | |
Donors are generally chosen from spouses or relatives, though the anonymous donation is also common. Donors are rigorously screened for any history of antibiotic intake within the last 3 months: patients who have undergone any GI surgery; patients with inflammatory bowel disease (IBD), rCDI, HIV, hepatitis B, C, diarrhea, or constipation; GI malignancy or polyposis; people in high-risk sexual behaviors; use of illicit drugs; and history of recent incarceration or travel to areas with endemic diarrhea are not selected to be donors. Donor blood test for serology, a stool test for the presence of ova and parasites, clostridium toxin, giardia, Cryptosporidium antigen, and Helicobacter pylori (if the oral route is used) should be done.[9]
| Processing, Preparation, and Storage of Stool for Fecal Microbiota Transplantation | | |
Most FMT centers report using frozen FMT preparations or a combination of fresh and frozen preparation to maintain routine quality control. The fresh stool collected under aseptic conditions is processed to make fecal suspension, and cryoprotectant is added. Storage of all donor feces suspensions is done in a biobank (−80°C), and aliquots of original donor feces and fecal suspension for quality control are stored separately, and a donor database is maintained.[10]
| Rescreening, Distribution of Donor Feces Sample, Safety, and Follow-Up | | |
The sample is re-screened for the presence of any infectious disease. The sample transport to the transplantation site should be done on a cold chain and contamination free. Reporting the transplant and any adverse outcome in the process and treatment is a part of quality assurance.[10]
| Stool Banking | | |
Stool banks strive to safely collect, store, and distribute stool products to treat diseases. In addition, the effectiveness of frozen feces suspensions was shown to be equivalent to that of fresh suspensions. An international consensus meeting on stool banking for FMT produced detailed instructions for institutions interested in establishing a stool bank. With the increasing popularity of FMT, stool banks are evolving. Stool banks may engage in research studies as long as they adhere to stringent protocols. According to specific proposals, if stool banks are established, they must follow federal regulatory standards for FMT, and the Director of the stool bank, in conjunction with a scientific committee, must oversee compliance with such standards.[11] Stool banks can make FMT more patient-friendly by supplying prescreened and well-defined donor pools with high-quality, ready-to-use suspensions of donor feces. This will make fecal transfusion simple and affordable.
| Fecal Microbiota Transplantation in Various Pathologies | | |
Recurrent clostridium difficile infection
FMT is the treatment of choice in rCDI. It has been found to effectively cure approximately 85% of affected patients compared to only about 30% treated conventionally with vancomycin.[12],[13] In around 15% of normal adults, colonization with Clostridium difficile is found, but colonization does not essentially cause infection. Transient colonization is seen in children, too; however, due to the development of antibodies against the toxin, the protective mechanism of breastfeeding, and specific receptor binding to the toxin, the harmful effects are compensated.[14] The principle behind using FMT in this infection is restoring a healthy gut microbiota (symbiosis) from an altered gut microbiota state (dysbiosis). The normal flora repopulates and competes with the toxigenic strain for the resolution of symptoms. Three primary indications for considering FMT are: (1) multiple recurrent Clostridium difficile infection (CDI) episodes, (2) moderate CDI with no response to standard therapy (vancomycin or fidaxomicin) for at least 1 week, and (3) severe or fulminant CDI with no response to standard therapy in 48 h.[15]
Ulcerative colitis
RCTs showed that participants with active UC taking a 3-dose, 1-week induction course of FMT could induce clinical and endoscopic remission within 8 weeks.[16] Multiple studies have now shown the advantage of FMT over Placebo therapies. However, many recent case series in adults have shown mixed results for FMT as a treatment for UC. A few subjects improved, although none reached remission, and the benefit appeared to be short-term.[17] Interestingly, one study showed that in 12 patients, the clinical benefit of FMT was associated with a higher proportion of butyrate-producing bacteria in their feces following transplant, suggesting a possible mechanism behind those successful.[18]
Hepatic encephalopathy
This is an end-stage liver disease, and patients with cirrhosis have severe gut microbiota dysbiosis. It results in a proinflammatory environment in the gut[19] and increased colonization of ammonia-producing bacteria such as Enterobacteriaceae and Streptococcaceae.[20] Hyperammonemia in this altered gut microbiota can accelerate neuronal dysfunction and hepatic encephalopathy (HE).[21] FMT can replenish commensal taxa such as Lachnospiraceae, Ruminococcaceae, and Clostridiales XIV, which have protective roles against neuronal damage. Compared to the sole standard of care consisting of lactulose or rifaximin or both, FMT having high relative abundances of Lachnospiraceae and Ruminococcaceae, has proved more effective.
Metabolic syndrome
MS is a cluster of conditions such as insulin resistance, dyslipidemia, high blood pressure, and increased abdominal girth, which increases the risk of heart disease, stroke, and type I diabetes. Leaky gut syndrome, a condition with impaired mucosal barrier function and dysbiosis of the gut, is associated with MS, and FMT aims to correct it. In an RCT, FMT from a lean stool donor to obese Caucasian males with MS enhanced glucose clearance.[22]
Autism spectrum disorders
The gut-brain immune axis is disrupted due to the prescription of antibiotics in early life, causing dysbiosis in autism spectrum disorder (ASD) patients. Children between 7 and 16 years old received an intense FMT regimen either orally or rectally in an open-label research,[23] and the impact on GI symptoms and ASD was assessed. GI and neuropsychiatric symptoms were significantly reduced, and this improvement was maintained for 8 weeks after treatment.
Graft versus host disease
Any organ may be impacted by graft-versus-host disease (GVHD) after an allogeneic hematopoietic stem cell transplant. Systemic immunosuppressants are used in this condition with a high mortality rate. A small percentage of patients experience steroid-refractory GVHD, which has no known cure. Dysbiosis in GVHD deprives intestinal epithelial cells' of butyrate in a mouse model, which might contribute to the proinflammatory state of the Gut. FMT could considerably reverse the GVHD phenotype in these mice, with 17 strains of Clostridia known to improve butyrate levels. This discovery offers support to FMT in GVHD.[24]
Multidrug-resistant organisms
A rising hazard to patient safety is colonizing multidrug-resistant organisms (MDRO) in vulnerable patients. In a prospective cohort study, FMT offered colonization resistance to MDRO with varying degrees of success. Especially compared to Gram-negative MDROs, Gram-positive vancomycin-resistant enterococci are easier to eradicate with FMT. The transfer and manufacture of bacteriocins during and after FMT may be more efficient at eliminating Gram-positive organisms. Further research is required to discover whether rationally chosen donors are required to eradicate MDROs.[25]
Multiple sclerosis
Increased intestinal permeability is seen in 20%–73% of MS patients. An imbalance of circulatory cytokines was described in MS patients with higher concentrations of the proinflammatory cytokines tumor necrosis factor-alpha, granulocyte macrophage-colony stimulating factor, interleukin (IL)-1, and IL-6, and a drop in regulatory cytokines favoring an inflammatory environment. However, with FMT, the patients had improved MS-protective gut microbiota and reduced permeability and cytokine expression.[26]
Anxiety
Microbes have been found to influence a lot of neuropsychiatric conditions. Although the exact pathogenesis is unclear, the steady state intestinal microbial imbalance is connected to derangement in the hypothalamopituitary adrenal axis (HPA). In a mice study using germ-free (GF) mice, specific pathogen-free mice, and the most popular model for chronic stress, that is the chronic-resistant stress model, it was found that GF mice had significant changes in hormone and hormone receptors as well as in HPA axis. Intestinal microbes can cause changes in the circulating metabolic products reaching the brain and affect the blood-brain barrier, circulating neurotransmitters causing a change in response to stimuli. Apart from affecting the HPA axis, the microbes can modulate the secretion of enterochromaffin cells, 5 hydroxy tryptamine, leading to changes in mood, mainly anxiety and depression, cognition, reward, learning as well as memory.[27] In human studies, increased abundances of Morganella and Klebsiella are implicated in having a casual effect on depression.
In an antibiotic-induced dysbiosis mice model, the gut microbiota influenced brain brain-derived neurotrophic factor levels and exploratory behavior, and these changes were reversed after the antimicrobials were stopped. Notably, the modulatory effect of FMT on the brain-gut-microbiota axis was demonstrated.[28]
| Challenges of the Transplantation | | |
FMT may potentially trigger the onset of chronic disorders like obesity, diabetes, atherosclerosis, IBD, asthma, autism, and other conditions because of changes in the gut flora.[29] Furthermore, several bacterial species, such as Escherichia coli, Bacteroides fragilis, and Enterococcus faecalis, are linked to cancer.[30] The potential of disease transmission of undiscovered infectious organisms that cause illness years later will exist despite the standardization of donor screening and defined processes for adverse event monitoring.[31]
There have been cases of transmission after FMT extended-spectrum beta-lactamase E. coli bacteremia with a history of death.[32] Furthermore, there is a risk of transmitting unwanted pathogens to a vulnerable recipient. FMT is considered a generally safe therapy approach based on recent research. Most acute adverse events are short-lived GI symptoms that go away in 1–2 days. However, because of the brief post FMT follow-ups, the long-term effects of FMT have not been fully understood. European FMT consensus conference on clinical practice has advised potential donors to undergo an exhaustive medical interview and testing before the procedure to avoid undesired side effects, but it is time-consuming and expensive.[33]
It is difficult to identify a potential healthy donor. Healthy spouses or close relatives are chosen since they share a typical environment and a reduced risk of infection. In addition, the mucosal immune system's adaptive immunity may exhibit greater tolerance. However, unrelated FMT volunteer donors are preferred over near relatives for disorders like IBD, where genetics may play a role. It has been found in a study that only 2 out of 322 (0.6%) potential stool donors made it through the FMT stool donor program's screening process.[34]
| Fecal Microbiota Transplantation in Indian Scenario | | |
FMT is gradually being adapted in India. The first case was reported in Western India in a 44 years old male who has been an UC patient for the last 11 years with relapse and emission history. FMT was performed three times, 2 weeks apart, with the donor being a 34-year-old relative who had never had a GI illness, had not taken antibiotics in more than 3 months, and was healthy, according to the procedure. At 4.8 and 12 weeks after FMT, there was a clinical, colonoscopic, and histological improvement with Mayo scores of 4.1 and 0, respectively, and maintained significant remission both endoscopically as well as clinically.[35]
The effect of steroids, nutritional support, drugs, and FMT was studied in 1271 patients with severe alcoholic disease in a tertiary center in Kochin, India. It was found that patients receiving FMT had a 75% survival rate at the end of the 1st and 3rd months. Compared to other groups, the hazard ratio for death and relative risk was lower in those getting FMT, and FMT is suggested as a cost-effective bridge to liver transplantation and transplant-free survival improvement.[36] The latest case was in the capital Delhi, where a 78-year-man who had bloody diarrhea and recurring large intestine inflammation recovered with FMT.[37] A Cohort of 24 patients with steroid-dependent UC was studied for induction FMT maintenance FMT and rescue FMT using FMT, and promising results were found with improved mayo scores, reduced relapse, and early remission.[38]
| Regulatory Challenges of Fecal Microbiota Transplantation | | |
FMT still has a long way to go in becoming the standard care regimen from an experimental phase. One of the most significant regulatory challenges remains the route of administration; the efficacy via different routes varies according to the diagnosis. For example, a study showed that in patients of Primary Sclerosing Cholangitis, biliary microbiota plays a significant role in the progression. Thus upper small bowel route was found to be more effective for FMT than the colonoscopic route.[39]
The stool is a complex mixture containing many unidentified microbes, which may be detrimental in an immunocompromised individual; thus, consensus on how FMT should be classified or regulated is essential. The time interval between two sessions should have a definite interval.
The “one stool fits all” strategy may not be effective when treating chronic disorders linked to microbial dysbiosis, and multiple donors can increase the response rate.[40]
Efficacy may be improved by personalizing FMT by comprehensively characterizing donors and receivers using a multi-omics approach (metagenomics, metatranscriptomics, and metabolomics) to address functional inadequacies through the proper matching.[41] For instance, one study analyzing a cohort of 5959 genotyped individuals with matched gut microbiome metagenomes used Genome-Wide Association Analysis to scrutinize 2802 microbial taxa and 7,967,866 variants from the cohort. Five hundred sixty-seven independent single-nucleotide polymorphism –Taxon associations at genome-wide significance in 411 loci were found in the conditional analysis. The strongest association was seen in members of class Actinobacteria and rs3940549, a variant in the LCT-MCM6-ZRANB3 locus region. Apart from host genetics, diet also plays a significant role in host-microbiota interaction, disease association, and, subsequently, FMT sensitivities.[42]
| Conclusion | | |
FMT is a highly efficacious procedure and a New Testament in science. However, the safety data should be profound to integrate FMT into daily clinical practice. Additional high-quality randomized control trials are required to assess the longer-term safety of FMT and its effect on the quality of life. Apart from all the beneficial roles, the issue posed by bacterial antibiotic resistance may be addressed by FMT-driven microbial rebalancing. In the future, it will be essential to determine if microbial-targeted therapies can be improved by personalized treatment strategies.
Author contributions
The author's responsibilities were as follows: SB and BR were responsible for the manuscript's conception, writing, and reviewing.
Acknowledgments
We are grateful to the MoHFW, India, and Prof. Subrat Acharya, the President, AIIMS Bhubaneswar, and Prof. Ashutosh Biswas, the Director, AIIMS Bhubaneswar, for their kind support in establishing and functioning the Center of Excellence for Clinical Microbiome Research.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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