Predictive and Prognostic Roles of Gut Microbial Variation in Liver Transplant

Wong, Hon Jen; Lim, Wen Hui; Ng, Cheng Han; Tan, Darren Jun Hao; Bonney, Glenn Kunnath; Kow, Alfred Wei Chieh; Huang, Daniel Q.; Siddiqui, Mohammad Shadab; Noureddin, Mazen; Syn, Nicholas; Muthiah, Mark

doi:10.3389/fmed.2022.873523

Cited by 5 publications

(7 citation statements)

References 64 publications

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“…19 It was previously observed that KTR and LTR have a lower abundance of butyrate producing bacteria compared with controls and that a lower abundance of butyrate producing bacteria is associated with a lower health related quality of life in KTR. 11,[20][21][22] We now find a higher mortality risk for SOTR with a lower abundance of butyrate producing bacteria. These results suggest that reduced butyrate levels could potentially have a direct role in mortality for SOTR.…”

Section: Discussionmentioning

confidence: 56%

Multiple indicators of gut dysbiosis predict all-cause and cause-specific mortality in solid organ transplant recipients

Swarte,

Zhang,

Nieuwenhuis

et al. 2023

Preprint

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ObjectiveGut microbiome composition is associated with multiple diseases, but relatively little is known about its relationship with long-term outcome measures. While gut dysbiosis has been linked to mortality risk in the general population, the relation with overall survival in specific diseases has not been extensively studied. In the current study, we present in-depth analyses regarding the relationship between gut dysbiosis and all-cause and cause-specific mortality in the setting of solid organ transplant recipients (SOTR).DesignWe analyzed 1,337 metagenomes derived from fecal samples of 766 kidney, 334 liver, 170 lung and 67 heart transplant recipients from the TransplantLines Biobank and Cohort; a prospective cohort study including extensive phenotype data with 6.5 years of follow up. To quantify gut dysbiosis, we included additional 8,208 metagenomic samples from a general population from the same geographical location. Multivariable Cox regression and a machine learning algorithm were used to analyze the association of indicators of gut dysbiosis and species abundances, with all-cause and cause-specific mortality.ResultsWe identified two patterns representing overall microbiome community variation that were associated with both all-cause and cause specific mortality. Gut microbial distance to the average of the general population was associated with all-cause mortality and infection-, malignancy- and cardiovascular disease related mortality. Using multivariable Cox regression, we identified 23 species that were associated with all-cause mortality. By using a machine learning algorithm, we identified a log-ratio of 19 species predictive of all-cause mortality, all of which were also independently associated in the multivariable Cox-regression analysis.ConclusionGut dysbiosis is consistently associated with mortality in SOTR. Our results support the observations that gut dysbiosis is predictive of long-term survival. Since our data do not provide causative evidence, further research needs to be done to see determine whether gut-microbiome targeting therapies might improve long term outcomesSummary boxSignificance of this studyWhat is already known on this subject?Current literature suggests that the gut microbiome signature might be associated with mortality risk in the general population.Higher diversity of gut microbiota is associated with lower mortality in allogeneic hematopoietic-cell transplantation recipients.Liver and kidney transplant recipients suffer from gut dysbiosis and an analysis with a relatively low number of events showed that dysbiosis is associated with mortality.What are the new findings?Across kidney, liver, heart and lung transplant recipients, we identified two overall microbial community variation patterns that are associated with all-cause mortality independent of the organ transplant and specifically to death from malignancy and infection.We find that multiple indicators of gut dysbiosis predict all-cause mortality and death by cardiovascular diseases, malignancy and infection.We find multiple microbial species associated with all-cause and cause-specific mortality. Using three different methods, we identify multiple bacterial species (shared between different analytical approaches) that are associated with an increased or decreased risk of mortality following solid organ transplantation.Using a machine learning algorithm, we identify a log-ratio of 19 bacterial species that was associated with all-cause mortality.

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Section: Discussionmentioning

confidence: 56%

Multiple indicators of gut dysbiosis predict all-cause and cause-specific mortality in solid organ transplant recipients

Swarte,

Zhang,

Nieuwenhuis

et al. 2023

Preprint

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“…This pathway is reported in Figure 4B. Although the increase in tolerance of the transplanted organ is a welcome effect, the excessive suppression of the immune system produced by these processes brings the patient more susceptible to further inflammatory processes caused by the translocated microbiota or by MDR bacteria that have colonized the graft site after surgery, increasing the mortality risk [58].…”

Section: Beneficial Effects Of Gut Microbiota On Liver Transplantationmentioning

confidence: 97%

“…The translocation of microbiota to the liver following cirrhosis triggers the immune response, causing worsening of tissue damage or promoting the onset of further infectious foci [58,59]. Specifically, bacteria activate various PRR receptors in myeloid cells within the liver, resulting in an increased production of Interferon I (IFN), which in turn causes the overproduction of IL-10.…”

Section: Gut Microbiota and Liver Cirrhosismentioning

confidence: 99%

“…An important role is played by Treg cells that release inhibitory cytokines that interact with CD80/CD86 receptors and inhibit the action of T cells through the Cytotoxic T-Lymphocyte-associated Antigen 4 (CTLA-4) immune checkpoint [63]. In this way, Tregs would help the tolerance of the transplanted organ [58]. Another mechanism recalls the anti-inflammatory activity of IL-10.…”

Section: Beneficial Effects Of Gut Microbiota On Liver Transplantationmentioning

confidence: 99%

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Gut Microbiota and Liver Transplantation: Immune Mechanisms behind the Rejection

et al. 2023

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Liver transplantation (LT) is the treatment of choice for patients with cirrhosis, decompensated disease, acute liver failure, and hepatocellular carcinoma (HCC). In 3–25% of cases, an alarming problem is acute and chronic cellular rejection after LT, and this event can lead to the need for new transplantation or the death of the patient. On the other hand, gut microbiota is involved in several mechanisms sustaining the model of the “gut–liver axis”. These include modulation of the immune response, which is altered in case of gut dysbiosis, possibly resulting in acute graft rejection. Some studies have evaluated the composition of the gut microbiota in cirrhotic patients before and after LT, but few of them have assessed its impact on liver rejection. This review underlines the changes in gut microbiota composition before and after liver transplantation, hypothesizing possible immune mechanisms linking dysbiosis to transplantation rejection. Evaluation of changes in the gut microbiota composition in these patients is therefore essential in order to monitor the success of LT and eventually adopt appropriate preventive measures.

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“…Several studies have found that specific microbiome profiles are associated with worsened cirrhosis and higher MELD scores [38][39][40]. Donor microbiome likely transfers to the recipient through the liver graft and influences the evolution of the microbiome after liver transplant [41]. Decreased microbiome diversity before liver transplant makes patients more susceptible to colonization from multidrug-resistant organisms [38], a leading cause of morbidity and mortality after liver transplant.…”

Section: Other Molecular Omicsmentioning

confidence: 99%

Improving liver transplant outcomes with transplant-omics and network biology

Scarpa

2023

Current Opinion in Organ Transplantation

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Purpose of review Molecular omics data is increasingly ubiquitous throughout medicine. In organ transplantation, recent large-scale research efforts are generating the ‘transplant-ome’ – the entire set of molecular omics data, including the genome, transcriptome, proteome, and metabolome. Importantly, early studies in anesthesiology have demonstrated how perioperative interventions alter molecular profiles in various patient populations. The next step for anesthesiologists and intensivists will be to tailor perioperative care to the transplant-ome of individual liver transplant patients. Recent findings In liver transplant patients, elements of the transplant-ome predict complications and point to novel interventions. Importantly, molecular profiles of both the donor organ and recipient contribute to this risk, and interventions like normothermic machine perfusion influence these profiles. As we can now measure various omics molecules simultaneously, we can begin to understand how these molecules interact to form molecular networks and emerging technologies offer noninvasive and continuous ways to measure these networks throughout the perioperative period. Molecules that regulate these networks are likely mediators of complications and actionable clinical targets throughout the perioperative period. Summary The transplant-ome can be used to tailor perioperative care to the individual liver transplant patient. Monitoring molecular networks continuously and noninvasively would provide new opportunities to optimize perioperative management.

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Predictive and Prognostic Roles of Gut Microbial Variation in Liver Transplant

Cited by 5 publications

References 64 publications

Multiple indicators of gut dysbiosis predict all-cause and cause-specific mortality in solid organ transplant recipients

Multiple indicators of gut dysbiosis predict all-cause and cause-specific mortality in solid organ transplant recipients

Gut Microbiota and Liver Transplantation: Immune Mechanisms behind the Rejection

Improving liver transplant outcomes with transplant-omics and network biology

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