Gut microbiota and its implications in small bowel transplantation

Abstract

The gut microbiota is mainly composed of a diverse population of commensal bacterial species and plays a pivotal role in the maintenance of intestinal homeostasis, immune modulation and metabolism. The influence of the gut microbiota on solid organ transplantation has recently been recognized. In fact, several studies indicated that acute and chronic allograft rejection in small bowel transplantation (SBT) is closely associated with the alterations in microbial patterns in the gut. In this review, we focused on the recent findings regarding alterations in the microbiota following SBT and the potential roles of these alterations in the development of acute and chronic allograft rejection. We also reviewed important advances with respect to the interplays between the microbiota and host immune systems in SBT. Furthermore, we explored the potential of the gut microbiota as a microbial marker and/or therapeutic target for the predication and intervention of allograft rejection and chronic dysfunction. Given that current research on the gut microbiota has become increasingly sophisticated and comprehensive, large cohort studies employing metagenomic analysis and multivariate linkage should be designed for the characterization of host–microbe interaction and causality between microbiota alterations and clinical outcomes in SBT. The findings are expected to provide valuable insights into the role of gut microbiota in the development of allograft rejection and other transplant-related complications and introduce novel therapeutic targets and treatment approaches in clinical practice.

Keywords

gut microbiota / small bowel transplantation / acute rejection / chronic rejection / mucosal immunity / biomarker / microbiota-targeted therapy

Introduction

The gastrointestinal tract harbors an organized and highly specialized microbial community, termed the gut microbiota, which is mostly composed of bacteria, fungi, parasites, and viruses [¹]. Recently, the gut microbiota has been considered a unique organ that has coevolved with humans for thousands of years, establishing a symbiotic relationship with the host [²]. The abundant and diverse members of the microbiota play critical roles in the maintenance of gut homeostasis, development of host immune system, resistance against pathogen colonization, and modulation of metabolism [²]. Despite its special importance, the gut microbiota has been poorly characterized owing to its compositional complexity and the limitation of culture-based methodology. In the last few decades, breakthroughs in large-scale DNA sequencing and bioinformatics have enabled the comprehensive characterization of the gut microbiota, including commensal and pathological bacterial species [³]. The relative abundance of individual species in the gut and its functional and metabolic signatures can now be further determined by genomic and metagenomic sequencing [⁴]. Owing to these advances, our knowledge of the role of the gut microbiota in human health and disease has been greatly enriched. The alterations (dysbiosis) of the gut microbiota have been linked with chronic diseases, such as inflammatory bowel disease (IBD) [⁵], diabetes mellitus [⁶], obesity [⁷], and metabolic disorders [⁸]. Unfortunately, the precise pathophysiological mechanism by which microbiota dysbiosis, commonly characterized by a loss of the microbiota diversity, a reduced abundance of commensals and outgrowth of pathogenic organisms, increases susceptibility to diseases remains under investigation.

Small bowel transplantation (SBT) is a life-preserving treatment for patients who suffer intestinal failure and severe complications from total parenteral nutrition [⁹]. According to the data from the International Intestinal Transplant Registry (ITR), the number of patients receiving intestinal transplantation has increased annually since 1990 [¹⁰]. The long-term survival rate of SBT remains unsatisfactory in contrast to those of liver, kidney, and heart transplantation because of severe transplantation rejection [¹¹,¹²]. The intestine is a unique organ containing a dense microbial population that promotes the development and maturation of the immune system of a host [¹³]. Microbiota dysbiosis is associated with a variety of local and systemic immunological disorders, such as IBD, allergies, and rheumatoid arthritis [¹⁴,¹⁵]. Thus, the gut microbiota possibly affects alloimmune responses to transplanted organ. Recently, some studies have demonstrated that the compositions of the gut microbiotas in patients receiving SBT are profoundly altered likely because of surgical procedures, immunosuppressive treatments, and antibiotic agents [¹⁶]. Given the close connection of the gut microbiota with host immune system, characterizing these alterations following SBT might provide novel mechanistic insights into the development of allograft rejection and transplant-related complications (e.g., infection and sepsis). Furthermore, the identification of some specific bacterial signatures may be critical to the production of potential diagnostic markers of allograft rejection or characterization of therapeutic targets for protection against post-transplant infections.

In this review, we highlighted advances regarding the characterization of the gut microbiota alterations following SBT and the mechanisms by which the aberrant interplay between the microbiota and host immune system shapes allograft acute rejection and chronic dysfunction. Furthermore, we explored the potential of the gut microbiota as a microbial marker and/or a therapeutic target for the predication and intervention of allograft rejection and transplant-related complications.

Shifts of gut microbiota and its involvement in acute allograft rejection following SBT

Over the last two decades, the incidence of acute rejection in intestinal transplantation has been largely reduced owing to the advancement of immunosuppressive strategies [¹⁷]. Acute rejection now occurs in less than 20%–30% of recipients in several large transplantation centers [¹⁸,¹⁹]. However, severe allograft rejection remains one of the major reasons for post-transplant mortality [²⁰]. Owing to complete mucosal sloughing and the use of high-dose immunosuppressive agents, infection and sepsis have been frequently observed in patients with acute allograft rejection, leading to multiple organ dysfunction and death [²¹]. The mechanism underlying intestinal allograft rejection may differ from those underlying solid organ transplantation owing to the existence of diverse microbial community in the gut [²²]. Some certain members of the gut microbiota and their metabolites may elicit signals that promote a proinflammatory or tolerogenic immune response [²³], which probably affect the development of acute allograft rejection in SBT. However, the characteristics of the gut microbiota during acute allograft rejection and its potentially clinical implications are rarely studied. Until recently, Oh and his colleagues systematically characterized the composition of the ileal microbiota in the duration of nonrejection (NR), pre-rejection (PR), and active rejection (AR) for patients with SBT [²⁴]. Their findings showed that the phylum Proteobacteria, particularly the family Enterobacteriaceae, was strikingly expanded in patients with active rejection, whereas the commensal Firmicutes (especially Lactobacillales) was dramatically decreased relative to nonrejecting recipients. Despite no significant difference between NR and PR has been observed for most taxa, bacterial taxa showing significant variations during active rejection displayed the same changing trend during prerejection (Fig. 1). This finding suggests that acute rejection is closely associated with the changes in the ileal microbial populations in recipients with SBT. At the genus level, the most significant change in the ileal microbiota is the significant expansion of the relative abundance of the genera Escherichia and Klebsiella during acute rejection [²⁴]. Basing on the previous observations in Toll-like receptor 4 (TLR4) knockout mice [²⁵], we speculated that the outgrowth of the pathpoints in the ileal microbiota, particularly Escherichia coli and Klebsiella sp., is involved in alloimmune responses and the mechanism underlying this effect is the activation of the TLR4 pathway during the acute rejection of SBT. Although significant microbial shifts associated with acute rejection have been identified, studies including a larger number of patients are still necessary for the characterization of rejection-related microbiota alterations. Whether the alterations are a cause or consequence of allograft rejection in SBT can be determined through such studies. The findings are expected to lay the groundwork for the identification of microbiota signatures that can be used as diagnostic markers for organ transplantation and the development of microbiota-targeted therapeutic strategies that can improve the long-term outcome of intestinal transplantation.

Potential contribution of the gut microbiota to the development of chronic allograft rejection after SBT

Chronic rejection (CR), characterized by graft vasculopathy, parenchymal fibrosis, and inflammatory cell infiltration, is a leading cause of late dysfunction and eventual loss of allograft in SBT [²⁶]. Despite the successful application of new potent immunosuppressive agents, CR remains a major challenge to the long-term survival of grafts in SBT patients [²⁷]. The pathophysiological mechanism of CR is far more complex than that of AR [²⁸] and is rarely investigated. Previous studies suggested that chronic inflammatory response plays a critical role in the development of CR [26, 29]. In addition to alloantigen-dependent immune reaction, the innate and adaptive immune response against intestinal microbes may be another source of allograft inflammatory response during SBT [³⁰]. However, information regarding the composition of the gut microbiota and its possible involvement in CR is currently limited. Using the 16S rDNA-based fingerprinting technique (PCR-DGGE), we attempted to characterize the composition of the gut microbiota during CR in a rat model with SBT [³¹]. Significant shifts in the ileal microbiota were observed in the rats with CR and were mainly characterized by remarkable expansion in the genera Bacteroides and Clostridium, along with severe depletion of Lactobacillales [³¹]. Recently, we have applied a next-generation sequencing technique to define ileal microbiota variations in an animal model. We were able to provide detailed information on microbiota configurations during the CR. Basing on the linear discriminant analysis (LDA) effect size (LEfSe), we identified 69 specific bacterial taxa enriched or depleted in the ileal microbiota of the CR rats (Fig. 2), suggesting that chronic rejection is related to the compositional changes in the microbiota. Interestingly, the microbiota alterations in CR were accompanied by chronic inflammation in the allograft intestine and vessel, implying a potential link between immunological alterations and gut microbiota. Then, we examined the influence of fish oil (FO) enriched with n-3 polyunstatured fatty acids on gut microbiota composition and chronic graft inflammation in the CR model [³¹]. Furthermore, FO treatment promoted the recovery of the microbiota toward normal community composition and simultaneously alleviated inflammatory disorders, thereby enhancing the long-term survival of the allograft. The beneficial changes following FO treatment provided indicated the potential connection between the gut microbiota and CR in intestinal transplantation. To the best of our knowledge, this is the first observational study that profiled the microbial landscape in a grafted intestine during CR. As microbiota composition changes during CR in human recipients with SBT has not been reported, the characterization of CR-related microbiota changes in a cohort of SBT patients and validation of the contribution of these changes to the development of CR are necessary. The potential causative role of specific gut bacteria on CR in SBT presents exciting opportunities for the development of novel therapeutic interventions against graft vasculopathy and improvement of the long-term survivals of grafts.

Interaction between gut microbiota and immune system in allograft rejection

The complex and dynamic interplay between the gut microbiota and the immune system has been broadly appreciated [³²,³³]. Overall, host–microbe interactions contribute to a mutually beneficial symbiosis in the gut [³⁴]. The colonization of the commensal organisms in the intestinal tract can stimulate the development of the mucosal immune system. Meanwhile, the immune system has evolved with the resident microbiota, thereby enhancing the tolerance of hosts to such “normal” organisms [³⁵]. In recent studies on IBD, disruptions in the symbiotic relationship between the gut microbiota and mucosal immune cells were observed and demonstrated to lead to the pathogenesis of chronic intestinal inflammation [³⁶]. The delicate balance between the microbiota and host immune system might be perturbed in the process of allograft rejection following SBT. However, the mechanisms by which the changes of bacterial microbiota in the gut interconnect locally with immune cells for the initiation and perpetuation of rejection remains unclear. Jenq and his group found that the intestinal inflammation induced by graft-versus-host disease (GvHD) in bone marrow transplant recipients is closely associated with a remarkable shift in the gut microbiome, as revealed by the reduction and expansion in the abundances of Clostridiales and Lactobacillales, respectively [³⁷]. Recent studies with 16S rDNA sequencing of gut microbiota and metabolomics of microbial metabolites revealed a dramatic association between the loss of gut microbial diversity and GvHD-related mortality after allogeneic hematopoietic cell transplant in human patients and mice [³⁸–⁴¹]. The role of the gut microorganisms initiating alloimmune reactivity and intestinal inflammation was usually mediated via the stimulation of Ag-presenting cells (APCs), including dendritic cells (DCs), macrophages, and natural killer cells (NK cells); this mediation is supported by observations in pediatric allogeneic bone marrow transplantation [⁴²,⁴³]. Furthermore, the host immune system controls intestinal microbiota and prevents the outgrowth of pathogenic species through a variety of mechanisms. For example, Eriguchi and colleagues reported that the elimination of Paneth cells in GvHD potentially leads to a striking decrease of a-defensins, thereby altering the normal composition of the gut microbiota and favoring pathologic over commensal microbiota [⁴⁴]. This finding is consistent with our previous findings in cynomolgus monkeys treated with alemtuzumab [⁴⁵]. This mechanism partly explains the aforementioned dysbiotic shifts toward a pathologic microbial composition in GvHD and allograft rejection in SBT. More recently, we used a nonhuman primate model to unravel the interaction between intestinal microbiotas and mucosal lymphocytes [⁴⁶]. We showed that the depletion of mucosal lymphocytes following administration of alemtuzumab considerably increases the species richness of the ileal mucosa-associated microbiota and the proportions of Prevotella and Enterobacteriales and reduces the proportion of Lactobacillaes. The dysbiosis of the fungal microbiota was also observed during mucosal lymphocyte depletion [⁴⁷]. Notably, the gut microbiota subsequently shifted toward normal community composition with the recovery of mucosal lymphocytes. The data provide strong evidence of the interrelationship between the gut microbiota and mucosal immune system under an immunosuppressive state. Basing on these observations, we proposed a hypothesis that addresses the questions of how the gut microbiota interacts with mucosal immune system and how the interaction affects the pathogenesis of allograft rejection in small bowel transplant (Fig. 3). Despite the available information on microbiota changes associated with allograft rejection, the exact interplay between the gut microbiome and host immune system in the development of allograft rejection and GvHD requires further elucidation. The mechanistic insights into the influence of individual gut organism or microbial communities on the regional or systemic immune system might be helpful for the design of novel therapeutic strategies that can diminish alloimmune response and graft injury or promote allograft survival.

Microbiota as a diagnostic marker for allograft rejection

Monitoring of allograft rejection in SBT has historically been performed by serial endoscopic biopsies. The majority of recipients requires endoscopy with biopsy at least once a week until several months after SBT for the identification of allograft rejection [¹⁹]. Given the high cost of endoscopy and its potentially adverse effect on mucosal healing [⁴⁸], several noninvasive markers, such as plasma citrulline and fecal calprotectin, have been developed for the evaluation of allograft function and have been shown to exhibit some potential clinical utility [⁴⁹,⁵⁰]. However, the low sensitivity of these markers limits their applications and novel noninvasive tests are urgently needed for the measurement of allograft function. In recent years, the potential of gut microbiota as a diagnostic marker of diseases has gained interests [⁵¹,⁵²]. Qin and his colleagues identified a combination of 15 gut microbial genes that can discriminate patients with liver cirrhosis from healthy individuals and showed high sensitivity and specificity, indicating that microbial markers are powerful tools for the diagnosis of diseases [⁵³]. In addition, microbiota can also be used as diagnostic markers for kidney and liver transplantation [²³,⁵⁴]. Furthermore, AR and CR in intestinal transplant are closely associated with specific shifts of the gut microbiota [²⁴,³¹], suggesting that the intestinal microbiota may be a potential marker for the monitoring of graft rejection. Using receiver operating characteristic (ROC) analysis, Oh et al. [²⁴] showed that specific variations in the relative proportions of several bacterial taxa in ileal effluents, especially those of Firmicutes, Proteobacteria and Enterobacteriaceae, can be used for discriminating nonrejection from active rejection in recipients with SBT with excellent accuracy. The ratio between the orders Lactobacillales and Enterobacteriales can be used for distinguishing acute rejection from nonrejection samples. Basing on these findings, we observed that the microbial profile of the ileal effluents is a potential diagnostic marker for allograft rejection and can thus be used with existing diagnostic tools for SBT monitoring. Furthermore, noninvasive assessment of microbiota changes can be used for the detection of allograft function prior to the occurrence of histopathological and pathophysiological changes. The present study may represent the first step toward the development of novel diagnostic marker for allograft rejection in small bowel transplant. As these microbial makers are not currently used in clinical practice, further studies of the gut microbiota in a large cohort of patients involved with allograft rejection are needed to validate the efficacy of microbiome profiling as diagnostic and monitoring tools.

Potential of microbiota as a therapeutic target in SBT

Recent studies have indicated that microbiota-targeted interventions have become a therapeutic alternative for a range of chronic disorders, such as refractory Clostridium difficile infection [⁵⁵], IBD [⁵⁶], and metabolic syndrome [⁵⁷]. Although our knowledge of the causality between the microbiome change and specific disease is limited, preventive or therapeutic approaches against allograft rejection and intestinal inflammatory disorders in SBT can be developed by targeting this axis. With the use of the understanding of the relationships between the gut microbiota and alloimmune response, efficient interventions can be designed for the manipulation of the microbiota and corresponding maintenance and/or reshaping of intestinal homeostasis against transplant-related complications. Fecal microbiota transplantation (FMT), that is, the transfer of gut microbial community from a healthy donor to a patient, has been successfully utilized for the treatment of relapsing Clostridium difficile colitis in solid organ transplant recipients [⁵⁸]. The changes of the microbiota following healthy fecal infusion are linked dramatically to the improvement of gut condition and increase of peripheral effector regulatory T cells in patients receiving stem cell transplantation; thus, FMT is a potential therapeutic option for acute GvHD [⁵⁹]. Emerging evidence has supported the use of probiotics and prebiotics in combating microbiota dysbiosis and their potential roles for the improvement of the clinical outcomes of GvHD and post-transplant infection [⁶⁰]. The transfer of faces infusion from a healthy donor to sepsis patients is sufficient to correct the microbiota dysbiosis and promote the recovery of systemic immune equilibrium, leading to the improvement of clinical outcomes [⁶¹,⁶²]. Apart from FMT, the development of engineered-genetically microorganisms that combine the beneficial properties of multiple bacterial strains or enable the targeting of a particular metabolic pathway may represent a novel direction for researches of microbiota-targeted therapeutics in SBT and others diseases. These approaches based on gut microbiota offer a novel preventive or treatment option for transplant-related complications, including AR, CR and enteric/systemic infections (Fig. 4). Although the implementation of gut microbiota engineering as a tool for the prevention or treatment of inflammatory diseases is at its early stages, it nevertheless provides an exciting prospect that may have a great impact on the clinical outcomes of SBT.

Concluding remarks

Complex interaction exists between an allograft microbiome and immune system. Emerging evidence has also demonstrated that shifts in the post-transplant microbiome are involved in allograft rejection and result in poor clinical outcomes in SBT recipients. Despite this evidence, studies wherein the influence of the gut microorganisms and their products on host immunity and graft function were examined are rare. The comprehensive characterization of the gut microbiota in a large cohort of SBT patients represents the first but the most critical step for the exploration of the interconnection between the gut microbiota and host immune system under specific pathological conditions. For the identification of the specific pathophysiological pathways of the microbiota involved in allograft immune response and identification of microbial biomarkers (target) for diagnosis and/or therapy, moving beyond the current microbial taxonomy and shifting the focus toward gene catalogs and functional analyses in SBT recipients are necessary. Furthermore, the critical question of whether alterations of the microbiota are causally or consequently associated with pathological episodes in SBT remains unanswered. Metagenomic analyses of the gut microbiota and microbiome-wide association studies may lead to new discoveries and validation of biological networks relevant to transplant-related pathophysiology, development of novel tools for evaluation of allograft function, and identification of novel therapeutic targets and intervention/prevention strategies in clinical practice.

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