Probiotics Decrease Mortality from Stem Cell Transplantation

Probiotics Decrease Mortality from Stem Cell Transplantation

by Jeffrey Dach MD

We are continually surprised by new studies showing the importance of the microbiome, or “friendly bacteria” colonizing the gut.  One such study was done  by Dr Ying Taur published in the hematology oncology journal, Blood, in 2014.(1)

Dr Ying Taur studied the “effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation.”  He obtained fecal specimens from 80 allogeneic transplant recipients, at time of engraftment.  He used bacterial 16S rRNA gene sequencing to characterize microbial diversity classified into high, intermediate, and low diversity.   Surprisingly, after three years, over all survival was only 36% for the patients with low diversity, compared to 67% over-all survival for patients with higher microbial diversity. Dr Taur’s conclusion:

In conclusion, the diversity of the intestinal microbiota at engraftment is an independent predictor of mortality in allo-HSCT recipients. These results indicate that the intestinal microbiota may be an important factor in the success or failure in allo-HSCT. (1) (note allo-HSCT =allogeneic stem cell transplant”

What is allogeneic hematopoetic stem cell transplantation?

This is a common treatment for leukemia or lymphoma in which the patient’s bone marrow stem cells are destroyed by an intensive chemotherapy regimen.  Bone marrow stem cells are essential for the immune system and  necessary for life. To restore them, stem cells from a matching sibling are drawn off. and then infused into the cancer patient, called engraftment, this  restores bone marrow cellularity.   The new bone marrow cells from the matched sibling mounts an immune response to the cancer cells, thus accounting for the curative effects of the allogeneic stem cell transplant procedure.

Conclusion:  Probiotics increase microbial diversity and reduce mortality associated with allogeneic stem cell transplantation.

This article is part two, for part one click here.

Articles with related interest:

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Depression and Leaky Gut Michael Maes

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Links and References

header image human stem cell courtesy of  Microbiology Spring 2011

1) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4133489/

Taur, Ying, et al. “The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation.” Blood 124.7 (2014): 1174-1182.

Highly diverse bacterial populations inhabit the gastrointestinal tract and modulate host inflammation and promote immune tolerance. In allogeneic hematopoietic stem cell transplantation (allo-HSCT), the gastrointestinal mucosa is damaged, and colonizing bacteria are impacted, leading to an impaired intestinal microbiota with reduced diversity. We examined the impact of intestinal diversity on subsequent mortality outcomes following transplantation. Fecal specimens were collected from 80 recipients of allo-HSCT at the time of stem cell engraftment. Bacterial 16S rRNA gene sequences were characterized, and microbial diversity was estimated using the inverse Simpson index. Subjects were classified into high, intermediate, and low diversity groups and assessed for differences in outcomes. Mortality outcomes were significantly worse in patients with lower intestinal diversity; overall survival at 3 years was 36%, 60%, and 67% for low, intermediate, and high diversity groups, respectively (P = .019, log-rank test). Low diversity showed a strong effect on mortality after multivariate adjustment for other clinical predictors (transplant related mortality: adjusted hazard ratio, 5.25; P = .014). In conclusion, the diversity of the intestinal microbiota at engraftment is an independent predictor of mortality in allo-HSCT recipients. These results indicate that the intestinal microbiota may be an important factor in the success or failure in allo-HSCT.

http://www.bloodjournal.org/content/126/14/1723.long?sso-checked=true

Blood. 2015 Oct 1;126(14):1723-8. doi: 10.1182/blood-2015-04-638858. Epub 2015 Jul 24.

Low urinary indoxyl sulfate levels early after transplantation reflect a disrupted microbiome and are associated with poor outcome.

Weber D1, Oefner PJ2, Hiergeist A3, Koestler J3, Gessner A3, Weber M4, Hahn J1, Wolff D1, Stämmler F5, Spang R5, Herr W1, Dettmer K2, Holler E1.

Indole, which is produced from l-tryptophan by commensal bacteria expressing tryptophanase, not only is an important intercellular signal in microbial communities, but also modulates mucosal barrier function and expression of pro- and anti-inflammatory genes by intestinal epithelial cells. Here, we hypothesized that decreased urinary excretion of 3-indoxyl sulfate (3-IS), the major conjugate of indole found in humans, may be a marker of gut microbiota disruption and increased risk of developing gastrointestinal (GI) graft-versus-host-disease. Using liquid chromatography/tandem mass spectrometry, 3-IS was determined in urine specimens collected weekly within the first 28 days after allogeneic stem cell transplantation (ASCT) in 131 patients. Low 3-IS levels within the first 10 days after ASCT were associated with significantly higher transplant-related mortality (P = .017) and worse overall survival (P = .05) 1 year after ASCT. Least absolute shrinkage and selection operator regression models trained on log-normalized counts of 763 operational taxonomic units derived from next-generation sequencing of the hypervariable V3 region of the 16S ribosomal RNA gene showed members of the families of Lachnospiraceae and Ruminococcaceae of the class of Clostridia to be associated with high urinary 3-IS levels, whereas members of the class of Bacilli were associated with low 3-IS levels. Risk factors of early suppression of 3-IS levels were the type of GI decontamination (P = .01), early onset of antibiotic treatment (P = .001), and recipient NOD2/CARD15 genotype (P = .04). In conclusion, our findings underscore the relevance of microbiota-derived indole and metabolites thereof in mucosal integrity and protection from inflammation.

A significantly higher transplant -related mortality (TRM) was observed in patients with low intestinal microbiome diversity, whereas patients with a microbiome dominated by commensal bacteria showed a better overall survival (OS) within 3 years after transplantation.8

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4991773/

Sci Transl Med. 2016 May 18;8(339):339ra71. doi: 10.1126/scitranslmed.aaf2311.

Increased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice.

Shono Y1, Docampo MD2, Peled JU3, Perobelli SM2, Velardi E4, Tsai JJ2, Slingerland AE2, Smith OM2, Young LF2, Gupta J2, Lieberman SR2, Jay HV2, Ahr KF2, Porosnicu Rodriguez KA2, Xu K2, Calarfiore M2, Poeck H2, Caballero S2, Devlin SM5, Rapaport F6, Dudakov JA7, Hanash AM8, Gyurkocza B8, Murphy GF9, Gomes C9, Liu C10, Moss EL11, Falconer SB11, Bhatt AS11, Taur Y12, Pamer EG13, van den Brink MR14, Jenq RR15.

Intestinal bacteria may modulate the risk of infection and graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Allo-HSCT recipients often develop neutropenic fever, which is treated with antibiotics that may target anaerobic bacteria in the gut. We retrospectively examined 857 allo-HSCT recipients and found that treatment of neutropenic fever with imipenem-cilastatin and piperacillin-tazobactam antibiotics was associated with increased GVHD-related mortality at 5 years (21.5% for imipenem-cilastatin-treated patients versus 13.1% for untreated patients, P = 0.025; 19.8% for piperacillin-tazobactam-treated patients versus 11.9% for untreated patients, P = 0.007). However, two other antibiotics also used to treat neutropenic fever, aztreonam and cefepime, were not associated with GVHD-related mortality (P = 0.78 and P = 0.98, respectively). Analysis of stool specimens from allo-HSCT recipients showed that piperacillin-tazobactam administration was associated with perturbation of gut microbial composition. Studies in mice demonstrated aggravated GVHD mortality with imipenem-cilastatin or piperacillin-tazobactam compared to aztreonam (P < 0.01 and P < 0.05, respectively). We found pathological evidence for increased GVHD in the colon of imipenem-cilastatin-treated mice (P < 0.05), but no difference in the concentration of short-chain fatty acids or numbers of regulatory T cells. Notably, imipenem-cilastatin treatment of mice with GVHD led to loss of the protective mucus lining of the colon (P < 0.01) and the compromising of intestinal barrier function (P < 0.05). Sequencing of mouse stool specimens showed an increase in Akkermansia muciniphila (P < 0.001), a commensal bacterium with mucus-degrading capabilities, raising the possibility that mucus degradation may contribute to murine GVHD. We demonstrate an underappreciated risk for the treatment of allo-HSCT recipients with antibiotics that may exacerbate GVHD in the colon.

http://www.ncbi.nlm.nih.gov/pubmed/26900084

Biol Blood Marrow Transplant. 2016 Jun;22(6):1087-93. doi: 10.1016/j.bbmt.2016.02.009. Epub 2016 Feb 18.

Impact of Gut Colonization by Antibiotic-Resistant Bacteria on the Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation: A Retrospective, Single-Center Study.

Bilinski J1, Robak K1, Peric Z2, Marchel H3, Karakulska-Prystupiuk E1, Halaburda K1, Rusicka P1, Swoboda-Kopec E3, Wroblewska M4, Wiktor-Jedrzejczak W1, Basak GW5.

Gut colonization by antibiotic-resistant bacteria may underlie hard-to-treat systemic infections. There is also accumulating evidence on the immunomodulatory function of gut microbiota after allogeneic stem cell transplantation (alloSCT) and its impact on graft-versus-host disease (GVHD). We investigated the epidemiology and clinical impact of gut colonization after alloSCT and retrospectively analyzed data on 107 alloSCTs performed at a single transplant center. Pretransplant microbiology screening identified colonization in 31% of cases. Colonization had a negative impact on overall survival after alloSCT in univariate (34% versus 74% at 24 months, P < .001) and multivariate (hazard ratio, 3.53; 95% confidence interval, 1.71 to 7.28; P < .001) analyses. Nonrelapse mortality was significantly higher in colonized than in noncolonized patients (42% versus 11% at 24 months, P = .001). Colonized patients more frequently experienced bacteremia (48% versus 24%, P = .01), and more deaths were attributable to infectious causes in the colonized group (42% versus 11% of patients and 67% versus 29% of deaths, P < .05). We observed a significantly higher incidence of grades II to IV acute GVHD in colonized than in noncolonized patients (42% versus 23%, P < .05), especially involving the gastrointestinal system (33% versus 13.5%, P = .07). In summary, we determined that gut colonization by antibiotic-resistant bacteria decreases the overall survival of patients undergoing alloSCT by increasing nonrelapse mortality and the incidences of systemic infection and acute GVHD.

Khoruts, Alexander, et al. “Toward revision of antimicrobial therapies in hematopoietic stem cell transplantation: target the pathogens, but protect the indigenous microbiota.” Translational Research (2016).

Host microbiota plays important roles in providing colonization resistance to pathogens and instructing development and function of the immune system. Antibiotic treatments intended to target pathogens further weaken the host defenses and may paradoxically increase the risk of systemic infections. This consequence is especially problematic in patients undergoing hematopoietic stem cell transplantation, where the mucosal defenses are already weakened by the conditioning regimens. This review discusses the roles that indigenous microbiota plays in protecting the host and maintaining immune homeostasis. In addition, we highlight possible strategies that are being developed to allow targeted antimicrobial therapy against pathogens, while minimizing the harm to indigenous microbiota.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4996265/

Andermann, T. M., A. Rezvani, and A. S. Bhatt. “Microbiota Manipulation With Prebiotics and Probiotics in Patients Undergoing Stem Cell Transplantation.” Current hematologic malignancy reports 11.1 (2016): 19.

Hematopoietic stem cell transplantation (HSCT) is a potentially life-saving therapy that often comes at the cost of complications such as graft-versus-host disease and post-transplant infections. With improved technology to understand the ecosystem of microorganisms (viruses, bacteria, fungi, and microeukaryotes) that make up the gut microbiota, there is increasing evidence of the microbiota’s contribution to the development of post-transplant complications. Antibiotics have traditionally been the mainstay of microbiota-altering therapies available to physicians. Recently, interest is increasing in the use of prebiotics and probiotics to support the development and sustainability of a healthier microbiota. In this review, we will describe the evidence for the use of prebiotics and probiotics in combating microbiota dysbiosis and explore the ways in which they may be used in future research to potentially improve clinical outcomes and decrease rates of graft-versus-host disease (GVHD) and post-transplant infection.

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0105706#abstract0

Vossen, Jaak M., et al. “Complete suppression of the gut microbiome prevents acute graft-versus-host disease following allogeneic bone marrow transplantation.” PloS one 9.9 (2014): e105706.

Complete Suppression of the Gut Microbiome Prevents Acute Graft-Versus-Host Disease following Allogeneic Bone Marrow Transplantation

The hypothesis that elimination of facultative and strict anaerobic microorganisms from the gastro-intestinal tract by antimicrobial drugs in the period of time around allogeneic bone marrow transplantation (BMT) prevents acute graft-versus-host disease (GVHD), was examined in a cohort of 112 children grafted between 1989 and 2002 for hematological malignancies. All patients received T-cell replete marrow from human leukocyte antigens (HLA) matched sibling donors under identical transplantation conditions. To eliminate microorganisms from the gastro-intestinal tract, total gastro-intestinal decontamination (GID) was applied by high doses of non-absorbable antimicrobial drugs while the graft recipient was maintained in strict protective isolation. About half of the children (51%) proved to be successfully decontaminated, and about half (49%) unsuccessfully. One recipient got acute GVHD in the first group and 8 in the second group (p = 0.013). The degree of success of total GID was decisive for the occurrence of acute GVHD, irrespective of the presence of other risk factors such as higher age of recipient and/or donor, female donor for male recipient and carriership or reactivation of herpesviruses. Our results demonstrate that successful total GID of the graft recipient prevents moderate to severe acute GVHD. We suppose that substantial translocation of gastro-intestinal microorganisms or parts of these, functioning as microbial-associated molecular patterns (MAMP’s), triggering macrophages/dendritic cells via pattern recognizing receptors (PRR’s) is prohibited. As a consequence the initiation and progression of an inflammatory process leading to acute GVHD is inhibited.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4973578/

Biol Blood Marrow Transplant. 2014 May;20(5):640-5. doi: 10.1016/j.bbmt.2014.01.030. Epub 2014 Jan 31.

Metagenomic analysis of the stool microbiome in patients receiving allogeneic stem cell transplantation: loss of diversity is associated with use of systemic antibiotics and more pronounced in gastrointestinal graft-versus-host disease.

Holler E1, Butzhammer P2, Schmid K3, Hundsrucker C2, Koestler J4, Peter K3, Zhu W2, Sporrer D3, Hehlgans T5, Kreutz M3, Holler B3, Wolff D3, Edinger M3, Andreesen R3, Levine JE6, Ferrara JL6, Gessner A4, Spang R2, Oefner PJ2.

next-generation sequencing of the hypervariable V3 region of the 16s rRNA gene isolated from serial stool specimens collected from 31 patients receiving allogeneic stem cell transplantation (SCT) was performed to elucidate variations in the composition of the intestinal microbiome in the course of allogeneic SCT. Metagenomic analysis was complemented by strain-specific enterococcal PCR and indirect assessment of bacterial load by liquid chromatography-tandem mass spectrometry of urinary indoxyl sulfate. At the time of admission, patients showed a predominance of commensal bacteria. After transplantation, a relative shift toward enterococci was observed, which was more pronounced under antibiotic prophylaxis and treatment of neutropenic infections. The shift was particularly prominent in patients that developed subsequently or suffered from active gastrointestinal (GI) graft-versus-host disease (GVHD). The mean proportion of enterococci in post-transplant stool specimens was 21% in patients who did not develop GI GVHD as compared with 46% in those that subsequently developed GI GVHD and 74% at the time of active GVHD. Enterococcal PCR confirmed predominance of Enterococcus faecium or both E. faecium and Enterococcus faecalis in these specimens. As a consequence of the loss of bacterial diversity, mean urinary indoxyl sulfate levels dropped from 42.5 ± 11 μmol/L to 11.8 ± 2.8 μmol/L in all post-transplant samples and to 3.5 ± 3 μmol/L in samples from patients with active GVHD. Our study reveals major microbiome shifts in the course of allogeneic SCT that occur in the period of antibiotic treatment but are more prominent in association with GI GVHD. Our data indicate early microbiome shifts and a loss of diversity of the intestinal microbiome that may affect intestinal inflammation in the setting of allogeneic SCT.

http://www.ncbi.nlm.nih.gov/pubmed/25708215

Biol Blood Marrow Transplant. 2015 Aug;21(8):1360-6. doi: 10.1016/j.bbmt.2015.02.016. Epub 2015 Feb 21.

Emerging Influence of the Intestinal Microbiota during Allogeneic Hematopoietic Cell Transplantation: Control the Gut and the Body Will Follow.

Docampo MD1, Auletta JJ2, Jenq RR3.

The intestinal microbiota has many critical roles in maintaining gastrointestinal epithelial and gastrointestinal systemic immune homeostasis. This review provides insight into how allogeneic hematopoietic cell transplantation (HCT) and its associated complications and supportive care therapies affect the microbiota. Additionally, the review discusses how preservation and restoration of the microbiota might be advantageous in decreasing HCT-related morbidity and mortality.

Jeffrey Dach MD

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