The role of the gut microbiome in lymphoma outcomes

The gut microbiome is a collective term for the various microorganisms that colonize the gastrointestinal tract, including bacteria, fungi, protists, and viruses. It is a key immunologic environment in the body, with substantial links to the host immune system, and is increasingly recognized as an important element in maintaining host health.^1,2

Aberrations to the equilibrium of this ecosystem is termed microbial dysbiosis, defined as a loss of commensal microbes in the gut or the presence of more harmful pathogenic ones. Microbial dysbiosis has been shown to be associated with a multitude of conditions, including chronic inflammatory conditions such as inflammatory bowel diseases, infections, and immune dysregulations.¹ These outcomes can result in a myriad of immune-mediated diseases and neoplastic conditions, including hematological malignancies. Dysbiosis has also been associated with many cancers, including lymphoma, with research ongoing to fully elucidate its impact on cancer treatment.^1–3

Gut microbiome composition varies greatly between individuals and populations. Key factors to consider when interpreting the results of gut microbiome studies in cancer patients include previous therapies, co-existing malignancies, disease status, race/ethnicity, gender, age, lifestyle factors, diet, and body composition; all of which can significantly impact on gut microbial composition. ¹

The Lymphoma Hub is happy to provide a brief overview of this complex topic, highlighting key aspects that relate to lymphoma pathogenesis and treatment outcomes.

The microbiome and lymphomagenesis

Lymphomagenesis, the complex process of the growth and development of lymphomas, can be impacted by the microbiome. Research has demonstrated that the eradication of specific microorganisms, such as Staphylococcus aureus, from the gut microbiome leads to improved outcomes in in animal models of cutaneous T-cell lymphoma; S.aureus has also demonstrated increased microbial dominance in microbiome analysis compared to healthy controls. Furthermore, gastric mucosa-associated lymphoid tissue lymphoma, a lymphoma that commonly arises in the stomach, has been shown to be closely associated with infection by Helicobacter pylori.¹

The gut microbiome can affect lymphomagenesis indirectly via immune system alterations, also known as aberrant immune responses. Recent analysis has demonstrated a relationship between the timing of exposure to microbiomes in the lifetimes of young adults and the development of Hodgkin’s lymphoma (HL). The results showed that early oral exposure to microbiomes can lead to a reduction in the occurrence of HL. Examples of these exposures included smoking, appendectomy, eczema, and behaviors associated with increased oral-oral and fecal-oral exposures.¹

Clinical implications for diagnosis and therapy

Current research is ongoing to identify specific bacterial species that contribute to the tumorigenesis and proliferation of chronic lymphocytic leukemia (CLL) B cells. Studies have found a lower overall diversity and increased abundance of the Bacteroides and Proteobacteria species in patients with CLL, along with a lower abundance of bacteria responsible for producing short chain fatty acids. These findings may lead to uses in diagnostic guidance and a means of early CLL identification.¹

The microbiome environment of patients prior to chemo-immunotherapy has been identified as a key predictor of treatment outcomes across multiple lymphoma subtypes, including diffuse large B-cell lymphoma (DLBCL), marginal zone lymphoma, and follicular lymphoma. Studies have found that higher pretreatment microbial diversity and overall distinct microbial composition is more common in patients who achieve a response compared with those who do not.¹

A study which utilized machine learning to develop a bloodstream infection risk index for patients with non-Hodgkin lymphoma, who were undergoing hematopoietic stem cell transplantation (HSCT), was able to accurately predict a patients risk of developing posttransplant infection with a specificity and selectivity of approximately 90%. This implies that the pretransplant gut microbiome could provide an important predictor of posttransplant infection risk.¹

Previous or ongoing antibiotic use has been shown to decrease the efficacy of immune checkpoint inhibitor therapy, suggesting that aberrations to the host microbiome can impact treatment efficacy. Similarly, patients undergoing autologous HSCT (auto-HSCT) and allogenic HSCT (auto-HSCT) are likely to be subjected to gut microbial dysbiosis via mechanisms such as exposure to anti-microbial therapy, nutritional modifications, and intestinal mucosal injuries from high-dose chemotherapy regimens.¹

A recent study by Yoon et al. examined the influence of microbial dysbiosis on chemo-immunotherapy treatment outcomes in patients with DLBCL. Samples from newly diagnosed patients were sequenced and compared with healthy controls. A lower level of alpha diversity among patients with DLBCL was observed, along with a significantly different microbial composition between the groups.⁵ Additionally, a loss of intestinal microbial diversity, resulting from the use of antibiotics at engraftment, was independently correlated with increased mortality over the 3 years following allo-HSCT. Patients exhibiting a lower microbial diversity had higher mortality from infection or graft-versus-host disease than patients with a higher microbial diversity.¹

The role of the microbiome has also been evaluated in respect to chimeric antigen receptor (CAR) T-cell therapy outcomes and toxicities. Prior exposure to broad-spectrum antibiotics such as piperacillin/tazobactam, meropenem, and imipenem/cilastatin in the 4 weeks leading up to CAR T-cell therapy was shown to result in unfavorable survival outcomes and an increased incidence of cytokine related toxicities, such as immune effector cell-associated neurologic syndrome. In particular, the increased correlation of CAR T-cell therapy with immune effector cell-associated neurologic syndrome may be due to gut microbiome factors affecting the permeability of the blood-brain barrier, also known as the gut-brain axis.¹

Microbiome focused treatment interventions

One established method of successful microbial intervention is fecal microbial transplant, which involves the transplant of fecal material from a healthy donor into the lower colon of a patient. It is often used in cases of chronic Clostridium difficile infection, where it has been highly effective.⁴ Another intervention involves the use of dietary modifications to enhance gut microbiota. This involves the use of prebiotics; nutritional supplements that support the proliferation of beneficial microbial species within the gut microbiome.¹

Table 1 provides a selection of ongoing microbiome-related clinical trials in connection with hematologic malignancies.

Table 1. Ongoing microbiome-related clinical trials in lymphoma/hematological malignancies*

Conclusion  

The gut microbiome is deeply complex and many important questions regarding its relation to pathogenesis and treatment outcomes are yet to be answered. Considerable progress has been made in our understanding of the symbiotic interactions within the gut microbiome, while our understanding of its functions at a mechanistic level is still lacking.

Many analytical challenges present obstacles to research in this area. Key challenges include small sample sizes in many studies and the high cost of next-generation sequencing technologies, which are vital to generating a high-degree of specificity in analytical results. Despite these challenges, our understanding of the role of the gut microbiome in human health and disease is growing significantly.

Acknowledgement of the role of the gut microbiome as an effective cancer hallmark has grown in parallel with our increased knowledge of its role in various types of hematological malignancy, including lymphoma. Our collective understanding of this important topic is starting to impact treatment decisions. Of note, it is now clear that consideration of the microbiome is important when initiating antibiotic therapy in cancer patients, particularly around the time of malignancy-related therapy administration.

The role of the gut microbiome may be a valuable future target for personalized treatment approaches for patients with lymphoma. In the meantime, gut microbiome research represents a promising new frontier for ongoing clinical investigation.