Review of oral and gut microbiome signatures in allo-HSCT-associated aGvHD

Hematopoietic stem cell transplantation (HSCT) can induce cure in many acute leukemias but may be associated with acute graft-versus-host disease (aGvHD) which comes with longer hospital stays, increased medical costs, and individuals with Grade 3–4 aGvHD only have a 40% survival rate.¹ HSCT conditioning and antibiotic treatment can damage the gut mucosa and create an imbalance in gut microbiota. It is believed that this imbalance and mucosa damage may lead to an increased immune response to the graft, causing aGvHD.¹

Micaela Beckman and team, in their systematic review published in Supportive Care in Cancer, using conventional literature search and computational approaches, provide an overview of the oral and gut bacteria associated with aGvHD following allogeneic HSCT (allo-HSCT), and how bacterial metabolic pathways might be involved in protecting from aGvHD.¹

Methods

Beckman and colleagues used a combination of methods to identify studies of microbiome profiling with or without aGvHD (traditional search methods) and bacterial taxa associated with aGvHD, and drug interaction analysis (text-mining methods). The methodology used is detailed in Figure 1.

Figure 1. Flowchart of different methods used for literature search¹ 

KEGG, Kyoto Encyclopedia of Genes and Genomes database; MACADAM, metabolic pathways database for microbial taxonomic groups; STRING, program for modeling molecular interaction networks. 

 Results

The team found several oral bacteria to be positively associated with aGvHD, and gut bacterial taxa to be both positively and negatively associated with aGvHD (Table 1), with a relative abundance (RA) gradient of bacteria in stools being indicative of severe aGvHD. Several oral genera, Rothia, Solobacterium, and Veillonella, were identified in the stool of HSCT patients and associated with aGvHD. The team found that a change in the microbiome post allo-HSCT was associated with gut aGvHD, and that this was particularly apparent in patients receiving antibiotics for neutropenic infections. Indeed, several of the studies found that dysbiosis of the gut microbiome preceding or during allo-HSCT was associated with a higher risk of aGvHD or a higher morbidity, and that a lower gut microbial diversity in the recipients was associated with higher aGvHD incidence. In studies of pediatric patients, Beckman and team found an association of aGvHD with an RA increase in fecal Enterococcus and Clostridiales, and an RA decrease in fecal Faecalibacterium and Ruminococcus. There was also an association between a higher RA of pathogenic-associated bacteria, such as Staphylococcus and Streptococcus, and an inability to maintain stability of both the oral and gut microbiomes, whereas Akkermansia, Subdoligranulum, and Pseudobutyrivibrio were found to be linked to an increase in stability of microbiome diversity.

Table 1. Oral and gut bacterial taxa identified as potentially associated with aGvHD¹

 Lipopolysaccharide (LPS) is a bacterial surface protein that can bind to the toll-like receptor 4 (TLR4), leading to activation of the NFkB pathway and release of proinflammatory cytokines. In a small pilot study, higher levels of oral Capnocytophaga spp. were found in allo-HSCT patients who did not develop aGvHD, which was believed to be due to the production of a specific LPS that inhibits TLR4. Using the metabolic pathways database for microbial taxonomic groups (MACADAM), the team found that phyla previously identified as positively associated with GvHD using BioReader mostly contained metabolic pathways with links to LPS biosynthesis. When looking at the target genes of drugs used in the treatment and prevention of GvHD, STRING networks highlighted the molecular pathways around TLR4, signaling as drug targets. According to the authors, there are currently no clinical trials on GvHD targeting TLR4. However, an anti-TLR4 drug has been recently assessed for rheumatoid arthritis, which was able to reduce symptoms in more than half of patients.

Conclusion

Beckman and team highlight the importance of the oral and gut microbiomes in aGvHD development, with dysbiosis of the microbiota before or after HSCT being strongly associated with aGvHD. They found that oral bacterial species may, in addition to the gut microbiome, be important factors in the development of aGvHD, and that changes in the diversity of these bacteria need to be better understood in the context of aGvHD. Finally, trials in patients with GvHD targeting TLR4 seem warranted given the link between TLR4 inhibition and lower rates of GvHD.