Riwes MM, Golob JL, Magenau J, et al. Feasibility of a dietary intervention to modify gut microbial metabolism in patients with hematopoietic stem cell transplantation. Nat Med. 2023;29(11):2805-2813.
To evaluate the feasibility and effects of providing resistant potato starch (RPS) to patients undergoing allogeneic stem-cell transplantation. Specifically, investigators studied changes in the microbiome and its metabolites, including short-chain fatty acids (SCFAs), as well as resultant plasma metabolites from the microbiota.
A supplement of resistant starch from potatoes is associated with increased butyrate levels in patients during stem-cell rescue.
Single-center, prospective, single-arm, longitudinal, interventional study conducted as the first part of a phase 2 clinical trial
The study included 10 patients, aged 55 to 62 years, 6 of whom were female and all of whom were undergoing planned allogeneic hematopoietic stem-cell transplantation (HCT) as treatment for a blood cancer. Three of these participants were diagnosed with myelodysplastic syndrome (MDS), 2 with acute myeloid leukemia (AML), 4 with B-cell acute lymphoblastic lymphoma (B-ALL), and 1 with follicular non-Hodgkin lymphoma (NHL).
The intervention consisted of 20 grams of RPS twice daily. D0 was the day the transplant occurred. On D7, all participants received 20 grams RPS, which they continued for 3 days. They were then given 20 grams RPS twice daily thereafter until D100, which was 100 days after the transplant took place.
Bob’s Red Mill provided the RPS, but a pharmacy packaged it to look like a pharmaceutical. Twenty grams is slightly less than 2 tablespoons of powder.
Study Parameters Assessed
This was a preliminary investigation to assess whether patients could adequately tolerate the intervention protocol and, if so, move forward to a larger second phase with more participants.
Investigators collected stool specimens from study participants at baseline before conditioning (D7), nadir (approximately D5 to D7), engraftment (approximately D14), and D100. They performed metabolomic analyses on stool specimens, using high-performance liquid chromatography (HPLC) to quantify the absolute amount of butyrate, acetate, and propionate.
Investigators also performed 16S rRNA gene sequencing of stool microbiome DNA to determine the effects on microbial community structure at baseline in preHCT conditioning and then compared it to changes at nadir, engraftment, and D100. They measured plasma metabolites during the study and compared with levels preHCT and with historic controls.
The objective of this preliminary analysis of the ongoing study was to determine feasibility; the set goal to justify continuation was for a minimum of 70% adherence in 60% of patients.
Eight out of 10 patients (80%) received 70% or more of the scheduled doses, exceeding the minimum goal, so a larger study is feasible and is moving forward. Fecal butyrate levels were significantly higher when participants were taking RPS than when they were not (P<0.0001).
Dominant plasma metabolites were more stable compared to historical controls with significant difference at engraftment (P<0.05). These results indicate that RPS in recipients of allogeneic HCT is a feasible intervention and, in this study, was associated with significant alterations in intestinal and plasma metabolites.
Although the purpose of the phase 2 study is to assess whether RPS supplementation will lower complications and graft-vs-host-disease (GVHD) in transplant patients, this initial study was too small to determine so.
However, only 1 of the 10 patients (10%) developed stage 1 acute gastrointestinal (GI) GVHD with overall grade 2 acute GVHD. Such a rate of incidence is a fraction compared to what is expected during this treatment.
No apparent conflicts of interest were reported. ClinicalTrials.gov ID: (NCT02763033).
Practice Implications & Limitations
Allogeneic and autologous hematopoietic stem-cell transplantation have grown to be routine therapy for patients with otherwise incurable cancers and other nonmalignant conditions. The first successful stem-cell transplant was reported in 1968 by Gatti et al, and by 2019, an estimated 1.5 million HCTs had been performed worldwide.1,2 These were split between autologous (self-donor) and allogeneic (other-donor) procedures. Allogenic transplantation is accompanied by the risk that the grafted cells, obtained from another person, may react and attack the new host’s body. This immune response may spill over and attack residual tumor cells, so it’s not considered a bad thing. But this graft vs tumor (GVT) reaction may spill over further into graft vs host disease, which occurs when the new immune system attacks its host, damaging the GI tract, skin, and liver. GVHD is a major cause of morbidity following allogenic transplants.
While this study was too small to answer the underlying question of whether resistant-starch consumption reduces the incidence of GVHD, the reported results are nevertheless significant. We know that the gut microbiome is vital in maintaining health.3,4 We have also witnessed great enthusiasm regarding the potential of fecal material transplants (FMT) for treating various health conditions. Yet efforts to identify the crucial bacterial species that mediate and regulate these benefits have generally proven to be challenging and have yet to match the benefits seen with FMT. The hope of developing specific probiotic combinations to treat specific health conditions remains largely unfulfilled.
Entrepreneurial success at developing specific probiotics to treat clostridial gastroenteritis has been successful, yet the products are prohibitively expensive. For example, a course of treatment for clostridial infection using a product developed by Seres Therapeutics reportedly costs $20,000. Recently, the research focus seems to be shifting away from specific bacterial members of the gut microbiome and toward a closer examination of the metabolites these bacteria produce. It is now understood and appreciated that a range of possible bacteria may have the capacity to produce the same metabolites and so affect parallel health outcomes. This ongoing study by Riwes et al examines a specific prebiotic, which provides a specific substrate that bacteria can use as a food source, which affects their resultant metabolites. The type of prebiotic used here is a resistant starch.
It is common to read that up to 50% of patients develop GVHD symptoms.
These starches are a subgroup of the larger grouping of fermentable fibers, which includes such things as cellulose, lignins, fructans, betaglucans, and pectin. Starches can be divided into 3 categories based on how fast they are broken down during digestion. Some starches are digested slowly (slowly digestible starch, SDS), and some are so resistant (RS) to digestion that they reach the large intestine intact and are then broken down by bacterial fermentation. Most modern foods consist of easily and rapidly digestible starches (RDS). In fact, the modern diet tends to avoid resistant starches and rely almost exclusively on rapidly digestible starches. This may, in part, be due to greater flatus production as the resistant starches are fermented.5 The most common dietary starches include white bread, cakes, and pasta, all of which are composed of rapidly digested starch. Current belief among researchers is that these rapidly digested starches contribute to chronic disease.6
Fermentation of resistant starches favors butyrate production. Dietary intake of resistant starch and fecal butyrate levels are higher in populations at low risk of diet-related large bowel disease. Conversely, RS intake and fecal butyrate levels are low in high-risk groups.7 Potato starch may have the highest concentrations of RS of any starch. Thus, it is not surprising to read that consumption of potato starch is more effective at increasing fecal butyrate than other starches, such as corn or inulin from chicory root.8 Resistant potato starch, used as a prebiotic, is more effective at increasing butyrogenic bacteria and intestinal butyrate than other RS tested. Nielson Baxter reported in 2019 that potato starch was the most effective substrate for increasing fecal butyrate levels. Baxter had compared butyrate production in 174 adults who were fed daily doses of different resistant starches for 2 weeks. Potato starch produced greater amounts of butyrate than starches from maize or inulin from chicory root.9
The Mediterranean diet is relatively high in resistant starch, which may be largely why it seems to improve health.10 This may also explain why ultra-processed foods have such a deleterious impact on health. Current thinking is that resistant starches, because they are resistant to digestive enzymes, will stimulate bacterial growth and diversity and result in higher levels of essential metabolites. The study currently under review monitored bacterial butyrate production since this short-chain fatty acid is thought to be key to tracking health benefits from the microbiome.11 It is estimated that Americans eat approximately 5 grams of RS per day, while it is believed that triple that amount, about 6 grams per meal, is required to maintain good health.12,13 Potato starch by weight is 80% resistant starch.14
The results of this study by Mary Riwes and colleagues demonstrate that an easy-to-consume and inexpensive, low-tech, nonproprietary form of resistant starch, specifically Bob’s Red Mill potato starch, is capable of shifting gut microbiome populations enough to significantly increase butyrate production, a response that is widely predicted to improve a wide range of health conditions. Murine data have demonstrated that butyrate is inversely associated with GVHD and adverse effects of stem-cell transplants, so this ongoing trial should be of specific interest to oncologists.15
Patients undergoing stem-cell transplants undergo a brutally rigorous pre- and post-treatment regime that aims to eradicate the initial cancer, create “space” in the bone marrow for the donor stem cells to engraft, and suppress the immune system to decrease the risk of the host rejecting the donor cells.16
This combination of chemotherapy, radiation, immunosuppressants, antibacterial agents, antifungals, and antivirals leave the gut microbiome in a sorry state. This creates a problem, as a healthy gut biome greatly lowers the risk of developing GVHD. A paper by Riccardo Masetti et al notes, “Higher gut microbiota diversity before transplantation correlates with better overall survival and lower acute GVHD incidence.” Higher pretransplant diversity is associated with higher abundance of short-chain fatty acid–producing taxa.17 Yet unfortunately, microbiome diversity decreases rapidly during these treatments and is associated with poor outcomes.
We should mention a 2020 study by Yoshifuji et al, in which 49 allogenic stem-cell transplant patients were treated with a combination of resistant starches and probiotics along with standard treatments. Investigators then compared the incidence and intensity of GVHD with that of 142 previous patients who served as a control group. The treated patients exhibited significantly fewer GVHD symptoms.18
Butyrate, the SCFA metabolite produced by the gut microbiome, is believed to have an immunomodulatory role associated with lower risk of GVHD, based on preclinical studies. Butyrate is an energy source for colonocytes and helps maintain epithelial hypoxia ideal for anaerobic commensals. Butyrate, along with some of the other SCFAs, is a histone deacetylase inhibitor, which promotes the upregulation and nudges immune function toward greater tolerance to commensal bacteria and helps reduce gut inflammation.19,20
The authors of the current study have successfully demonstrated that their prebiotic treatment with resistant starch maintains microbiome diversity and maintains SCFA production, particularly butyrate. Whether this will alter overall survival and lower GVHD still remains to be determined in their larger follow-up study. In this small trial, only 1 of their 10 patients (10%) experienced GVHD. It is common to read that up to 50% of patients develop GVHD symptoms.21,22
With its low cost, low risk of adverse effects, and possible efficacy in preventing GVHD, the Riwes study protocol seems reasonable for allogenic stem-cell transplant patients to follow. We may also want to consider a similar plan for patients suffering from conditions in which we desire to favorably impact the gut microbiome—in particular, conditions in which increased butyrate levels are associated with improvement.