SILVER

Effect of Short-Term Diet Modulation of Donor on the Efficacy of Fecal Microbial Transplant (FMT)

My research focus is to understand if high diversity of the gut microbiota in the donor, seems to best predict a patient's response to FMT and if Short-term changes in donor’s dietary patterns can have some influences on intestinal microbiota composition.
Kaina Bindra
Grade 9

Problem

To analyze and determine if diet modulation of a donor 3 to 5 days prior to stool donation can lead to diverse microbiome engraftment from donor to  IBD  recipient and increase FMT efficacy. 

Method

To address my research questions I did a review of current literature to understand and find:

  • Identify the difference in gut  microbiome diversity  of healthy subjects  and IBD patient 
  • Utilize FMT as a treatment to populate/transplant  the recipient  microbiome
  • Examine  different parameters  affecting FMT treatment response 
  • Understand the  role of donor selection in FMT success and find out if FMT success was donor-dependent 
  • Study  changes in  recipient’s  microbiome  after transplant 
  • Find the difference in microbiome diversity of responders and non-responders by review of microbiological data and explain the variation in recipient responses
  • Establish donor microbiome effect on recipient gut microbiome diversity
  • Establish the  similarity between donor and recipient microbiome  profile after transplant  and the ability of the donor to transfer high levels of specific  species to recipients
  • Establish the factors that can enhance donor gut microbiome diversity
  • Review the influence of dietary changes on donor's gut microbiome
  • Evaluate Meat Vs Plant-Based Diet Effect On Intestinal  Bacteria 
  • Assess the difference in microbiological composition of healthy subjects exclusive on  in vegetarian  diet and subjects on animal  diet and meat diet 
  • Identify  how rapid the diet  can alter the gut microbiome 
  • Examine if  Short-term dietary changes  can have some influences on intestinal microbiota composition

Research

Findings From A Review Of Current Research Studies:

As per a research study on “Fecal Microbiota Transplantation Induces Remission in Patients with Active Ulcerative Colitis in a Randomized Controlled Trial”, FMT success is donor-dependent (as identified through the randomized control trial in the study investigating the efficacy of FMT). 75 patients with ulcerative colitis were given weekly enemas containing either fecal material or placebo for a period of 6 weeks. FMT was superior to the placebo, resulting in higher rates of endoscopic and clinical remission (24 vs. 5%, respectively). Out of the nine patients who achieved remission, seven had received FMT from the same donor.  Thus, it was established  that FMT success is  donor-dependent ((Moayyedi et al.,2015)

FMT success lies in the ability of the donor to transfer high levels of particular species to recipients. For  IBD  transfer of butyrate, producing is important for therapeutic restoration.

Microbial and metabolic profiling data on donors and recipients before and after FMT shows that the microbial diversity of the stool donor to be one of the most significant factors influencing FMT outcome. 

The study on “Increased Intestinal Microbial Diversity following Fecal Microbiota Transplant for Active Crohn’s Disease” found that Responders (those who achieve a clinical response to FMT treatment) typically exhibit a higher microbial diversity and significantly higher bacterial richness than non-responders (Vaughn et al.,2016)

A review of two additional studies, “Increased intestinal microbial diversity following fecal microbiota transplant for active Crohn's disease “ and “Faecal microbiota transplantation for inflammatory bowel disease: a systematic review and meta-analysis“ further corroborated the fact FMT recipients experience a significant increase in intestinal microbiota diversity, typically shifting in composition toward the profile of their respective stool donor.

 

A Specific Microbial and Metabolic Signature:

As per research study on “Fecal Microbiota Transplantation Induces Remission in Patients With Active Ulcerative Colitis in a Randomized Controlled Trial”, specific genera within the Clostridium clusters IV and XIVa  (e.g., Roseburia, Oscillibacter) have been shown to increase relative abundance in responders following FMT.  Likewise, stool donors that are rich in specific members of Clostridium clusters IV and XIVa have been found to be predictive of sustained FMT response in IBD patients. (Rossen et al., 2015)

Furthermore, in accordance with a study on “Multidonor intensive fecal microbiota transplantation for active ulcerative colitis: a randomized placebo-controlled trial”, An increased production of butyrate by key members within Clostridium clusters IV and XIVa has been associated with prolonged clinical remission in IBD in response to FMT therapy..(Paramsothy et al., 2017a) 

The gut microbiota composition of vegetarians and omnivores using qPCR analysis showed the abundance of Firmicutes and Bacteroidetes in the vegetarian group and Proteobacteria being higher in the omnivore group. For  IBD, transfer of butyrate-producing taxa is important for therapeutic restoration. (Lawrence 2014) 

Microbial restoration can lead to alterations in metabolic outputs, which may be responsible for resetting the gut homeostasis in dysbiotic IBD and increase the efficacy of transplant. 

 

Effect of Meat Vs Plant-Based Diet on Gut:

As per a research article on “Diet Rapidly and Reproducibly Alters the Human Gut Microbiome”, an Animal diet alters the gut microbiome significantly and immediately. One type of bacterium that flourishes in a meat-laden diet is Bilophila (David, Lawrence A, et al.)

Diets rich in complex carbohydrates show fewer pathogenic species of bad bacteria such as Enterobacteriaceae than diets higher in fat or protein.

Modifying the diet can lead to rapid changes in microbiota within the first day.

The study reported human gut microbiome changes after only 24 hours after shifting between plant and animal protein-based diets. 

 

Optimal Duration of Diet Modulation:

The study on “Diet Rapidly and Reproducibly Alters the Human Gut Microbiome” used 16S rDNA pyrosequencing to look into the effects of short-term diet on the microbiota of six healthy American volunteers over five consecutive days after being administered two different diets: an animal-based diet and a plant-based diet. (Lawrence 2014)

Animal diet led to a decrease in the levels of Firmicutes, in particular Roseburia spp. 

In another study, nine volunteers were put on two extreme diets (vegetarian and meat) for five days each to find out whether fibre or its absence could alter gut bacteria more rapidly.

The abundance of various bacteria species shifted within a day after the food reached the gut and after the volunteers had spent about three days on each diet, the bacteria in the gut even started to change their behaviour. 

Data

Analysis:

FMT recipients experience a significant increase in gut microbiota diversity, typically shifting in composition toward the profile of their respective stool donors. Thus, this study recommends altering the donor microbiome by diet modulation. 

Increased production of butyrate by members within Clostridium clusters IV and XIVa has been associated with clinical remission in IBD in response to FMT therapy. 

Animal-based diet led to a decrease in the levels of Firmicutes, in particular, Roseburia and an increase in Proteobacteria.

Vegetarian diet increase levels of clostridium clusters IV and XIVa which In turn result in increased butyrate production within merely 2 days and shows microbiome alteration in 5 days.

A meat diet alters the gut microbiome significantly and immediately within 24 hours. 

 

Impact of Diet on Response to FMT:

Diet is one of the most important determinants of gut-microbial composition, and as such should be closely monitored to ensure the success of FMT.

However, as per the research study on Fecal Microbiota Transplantation for Ulcerative Colitis: An Evolving Therapy” the current limitation is that a donor who is screened and selected at pre-screen visit may not still be a qualified or viable donor at the time of stool donation in case there are significant deviations in dietary patterns or lifestyle before the donation. Yet, In current FMT clinical trials, there are no significant studies focused on the understanding alteration of donor diet prior to stool donation. (Ajit Sood 2020)

My project suggests a novel approach to model the donor stool microbial composition by diet alteration prior to stool donation. 

 

Analysis - Alternate Point Of View:

During my literature research, I found that numerous studies focused on long-term diet modulation were able to statistically establish that long-term diet intervention changes microbiota. While dietary changes have a relatively fast impact (within a week) on the microbial composition and consequently on its metabolites, these effects are modest and reversible. For example, the study on “Impact of a 3-Months Vegetarian Diet on the Gut Microbiota and Immune Repertoire” shows changes of microbiota and immune parameters after a 3-month vegetarian diet are significant but do not reflect the degree of change that occurs with a long-term vegetarian diet. (Chenchen Zhang et al)

However, my research from the study “Diet Rapidly and Reproducibly Alters the Human Gut Microbiome”, shows Animal diet alters the gut microbiome significantly and immediately. One type of bacterium that flourishes in a meat-laden diet is Bilophila ( Lawrence, et al.) 

Conclusion

Conclusion:

My research project recommends and shows a novel approach of altering donor diet  5 days prior to stool donation by not only introducing a vegetarian diet to increase butyrates but strictly eliminating meat diet to enrich donor microbiome with specific bacterial strains.

This intervention can lead to enriching the microbiome in the recipient with specific strains which are missing in IBD patients geared to induces remission in patients. 

Thus, the research question “if diet modulation of a donor 3 to 5 days prior to stool donation can lead to diverse microbiome engraftment from donor to  IBD  recipient and increase FMT efficacy” is correct. 

Citations

Bibliography:

David, Lawrence A, et al. “Diet Rapidly and Reproducibly Alters the Human Gut Microbiome.” Nature, U.S. National Library of Medicine, 23 Jan. 2014, www.ncbi.nlm.nih.gov/pmc/articles/PMC3957428/. 

Nagpal R;Shively CA;Register TC;Craft S;Yadav H; “Gut Microbiome-Mediterranean Diet Interactions in Improving Host Health.” F1000Research, U.S. National Library of Medicine, pubmed.ncbi.nlm.nih.gov/32704349/. 

Pigneur, B, and H Sokol. “Fecal Microbiota Transplantation in Inflammatory Bowel Disease: the Quest for the Holy Grail.” Nature News, Nature Publishing Group, 27 July 2016, www.nature.com/articles/mi201667. 

Sokol, Harry, et al. “Fecal Microbiota Transplantation to Maintain Remission in Crohn’s Disease: a Pilot Randomized Controlled Study.” Microbiome, vol. 8, no. 1, 2020, doi:10.1186/s40168-020-0792-5. 

Wilson, Brooke C, et al. “The Super-Donor Phenomenon in Fecal Microbiota Transplantation.” Frontiers in Cellular and Infection Microbiology, Frontiers Media S.A., 21 Jan. 2019, www.ncbi.nlm.nih.gov/pmc/articles/PMC6348388/#B21. 

“Fecal Transplant for Crohn's: A New Cure for Crohn's Disease Symptoms.” Designer Shit Documentary, 5 Jan. 2019, designershitdocumentary.com/fecal-transplant-crohns-disease-cure/. 

Senghor, Bruno, et al. “Gut Microbiota Diversity According to Dietary Habits and Geographical Provenance.” Human Microbiome Journal, Elsevier, 23 Feb. 2018, www.sciencedirect.com/science/article/pii/S2452231717300143#! 

Feltman, Rachel. “The Gut's Microbiome Changes Rapidly with Diet.” Scientific American, Scientific American, 14 Dec. 2013, www.scientificamerican.com/article/the-guts-microbiome-changes-diet/. 

Doucleff, Michaeleen. “Chowing Down On Meat, Dairy Alters Gut Bacteria A Lot, And Quickly.” NPR, NPR, 11 Dec. 2013, www.npr.org/sections/thesalt/2013/12/10/250007042/chowing-down-on-meat-and-dairy-alters-gut-bacteria-a-lot

Paramsothy S;Paramsothy R;Rubin DT;Kamm MA;Kaakoush NO;Mitchell HM;Castaño-Rodríguez N;. (n.d.). Faecal microbiota TRANSPLANTATION for inflammatory Bowel disease: A systematic review and meta-analysis. Retrieved March 18, 2021, from https://pubmed.ncbi.nlm.nih.gov/28486648/

Sood, A., Singh, A., Midha, V., Mahajan, R., Kao, D., Rubin, D., & Bernstein, C. (2020, August 15). Fecal microbiota TRANSPLANTATION for ULCERATIVE COLITIS: An EVOLVING THERAPY. Retrieved March 18, 2021, from https://academic.oup.com/crohnscolitis360/article/2/4/otaa067/5892959

Senghor, B., Sokhna, C., Ruimy, R., & Lagier, J. (2018, February 23). Gut microbiota diversity according to dietary habits and geographical provenance. Retrieved March 18, 2021, from https://www.sciencedirect.com/science/article/pii/S2452231717300143

David, Lawrence A, et al. “Diet Rapidly and Reproducibly Alters the Human Gut Microbiome.” Nature, U.S. National Library of Medicine, 23 Jan. 2014, www.ncbi.nlm.nih.gov/pmc/articles/PMC3957428/. 

Khanna, S. (1970, January 01). Microbiota replacement therapies: Innovation in gastrointestinal care. Retrieved March 19, 2021, from https://pesquisa.bvsalud.org/portal/resource/es/mdl-29071710

Jain, S (n.d.). Treatment of inflammatory bowel disease (IBD). Retrieved March 19, 2021, from https://pubmed.ncbi.nlm.nih.gov/21857074/

Acknowledgement

Acknowledgements:

Dr. Anureet Malhotra, MBBS

Ms. Lai - Westmount  Charter School