Gut Microbiome – The Role in Haematological Cancers and Impact on Response to Immunotherapy and Car-T Cell Therapy

The microbes in our gut, including bacteria, viruses, protozoa and fungi, exist in a state of ecological balance, influenced by various environmental factors such as geographical location, lifestyle choices, antibiotic use, and dietary habits. This delicate balance is known as the gut microbiome. It is estimated that there are over 40 trillion intestinal microorganisms, bringing the ratio closer to 1:1 to the total number of cells in our human body (around 30 trillion). ¹

The vital roles of these microbes include breaking down foods in our diet through the fermentation of non-digestible substrates like dietary fibres, to generate vitamins, essential amino acids, and short-chain fatty acids like butyrate, propionate, and acetate, which are critical in regulating local and systemic immune response. The complex interplay between the gut microbiome and the human host has garnered significant attention in recent years, with growing evidence suggesting that the gut microbial community plays a crucial role in the maintenance of human health, including immunity, the occurrence of cancer (oncogenesis) and response to anticancer therapies such as immunotherapies and CAR-T cell therapies.^2-6

The gut microbiota is initially populated through vertical transmission from the mothers’ birth canal at birth. A child delivered through caesarean section has a different microbiome than that of a child delivered via vaginal delivery.^7,8  Then, diet, environmental factors such as household exposures, geographical locations and genetics continuously influence and shape the composition of this microbial community throughout an individual’s life. ²

Ecological disturbances in the normal gut microbiota, called dysbiosis, have been linked to immune dysregulation and the development of many diseases. Dysbiosis contributes to autoimmune disorders, including arthritis and inflammatory bowel disease, allergic and metabolic diseases, such as obesity and diabetes and malignancy, including blood cancers. ^2,3,5,10-16 Emerging research suggests that gut microbiota plays a crucial role in influencing the effectiveness of cancer therapies and the severity of their side effects.⁵ All these studies provide strong evidence for a close and complex interplay between the gut microbiome, tumour development, and anti-tumour immunotherapies.^2,3,5

Cancer treatment, which includes chemo, radio, and immunotherapy, can have significant and far-reaching impacts on the human body, including the delicate balance of the gut microbiome, leading to decreased beneficial bacteria and increased pathogenic microbes. A growing body of research suggests that by actively managing the gut microbiome during chemotherapy, patients may be able to mitigate some of the adverse side effects and potentially improve the overall efficacy of cancer treatment.

Clinical studies on the role of the microbiota in patients on CAR-T  therapy suggest that the gut microbiota influences the response and toxicity to CAR-T  therapy. ²⁵ A high abundance of obligate anaerobes such as Ruminococcus, Bacteroides, Faecalibacterium, and Akkermansia was associated with complete response at day 100. ²⁶ Similar observations were demonstrated in studies on immune checkpoint inhibitors, where a favourable gut microbiota (high diversity and abundance of Ruminococcaceae and Faecalibacterium) promoted antigen presentation and improved effector T cell function in patients treated with check-point inhibitor.^27-29

Antibiotics profoundly affect microbiota composition and are commonly used in haematological patients for infection prevention (prophylaxis) and treatment. Broad-spectrum antibiotics significantly reduce obligate anaerobes and gut microbe metabolites, which can diminish the effectiveness of immunotherapy and CAR-T cell therapy, increase related toxicities and have been associated with high mortality after allogeneic transplantation, reduce antitumor efficacy of immunotherapy, and more recently, reduced survival in CAR-T treated patients.

Amongst the patients with lymphoma receiving CAR T cell therapy, individuals exposed to antibiotics before CART infusion exhibited a higher incidence of immune effector cell-associated neurotoxicity syndrome. ²⁵

Similar findings were observed in the transplant realm. The effects of high-dose chemotherapy on faecal diversity have been studied in a cohort of autologous hematopoietic cell transplantation (auto-HCT) recipients, in which a low gut microbiota diversity has been associated with decreased progression-free survival. In allogeneic hematopoietic cell transplantation (allo-HCT), intense conditioning regimens using chemotherapy and high-dose radiation significantly decrease the diversity of gut bacteria. This reduction in diversity, particularly in the types and proportions of bacteria present, is strongly linked to survival rates and the risk of disease recurrence after allo-HCT. ²⁵

Judicious use of a pathogen-directed treatment instead of the empiric broad-spectrum could minimise dysbiosis. More research is needed to examine the effects of different antibiotics on the microbiota composition to help clinicians with microbiota-sparing strategy. While antibiotics are known to have the most significant impact on the composition of gut microbiota, other medications, such as antimetabolites, antipsychotics, and calcium channel blockers, have also been shown to affect the human microbiome. ⁹
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Foods that promote healthy microbiome – fibres and fermented foods

Many therapeutic strategies have been developed to modulate the microbiota activity and bolster the antitumor effects of immunotherapies, such as faecal microbiota transplantation, probiotics, prebiotics, diet, and adjustments in antimicrobial therapy.

Modifying the microbiome through diet is the safest, most accessible, and least invasive approach. Adding essential foods to a diet will help restore gut health and regulate the gut microbiome. Probiotics are live microorganisms found in fermented foods, like bacteria and yeasts. These live microorganisms maintain intestinal microbial balance by interacting with the host’s microbiota, regulating immune function, and supporting the integrity of the gut barrier. They are often called “good” or “helpful” bacteria because they help maintain a healthy balance in your gut microbiome. Also, a high-fibre diet can significantly alter the gut microbiota composition, enriching beneficial bacteria such as Bifidobacterium and Lactobacillus spp.

By incorporating probiotics from fermented foods and a high-fibre diet into a cancer treatment regimen, patients may be able to improve their gut microbiome, enhance their response to chemotherapy, and potentially mitigate some of the adverse side effects of the treatment

You can find probiotics in supplements like pills or powders, and they are also naturally present in some fermented foods, such as Yogurt, Kefir, Suan Tsai (Chinese Sauerkraut, a type of fermented cabbage), Kimchi (a spicy fermented Korean dish made from vegetables), Miso (fermented soybean paste used in Japanese cuisine), sourdough bread, Kombucha (a fermented, lightly effervescent, sweetened black tea)

A prospective study involving healthy adults discovered that consuming fermented foods was linked to greater gut microbiota diversity and reduced systemic inflammation, similar to the benefits observed in patients who respond well to immunotherapy. ^23
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Current thinking about low microbial diet in patients with blood cancers

What patients eat is a big concern, and conversations about food are a regular part of caring for people with cancer. However, we don’t have enough research to confidently recommend specific dietary interventions or even an overall optimal diet during cancer treatment and recovery. This lack of knowledge is reflected in how things were done in the early days of transplantation (1960s-1970s). Back then, patients were given sterilised food and kept in extremely clean environments to minimise contact with bacteria. A low microbial or neutropenic diet has gained prominence as a strategy to reduce the risk of food-borne infections by limiting the introduction of potentially harmful bacteria into the gut. The neutropenic diet generally limits foods that are more likely to be contaminated, such as uncooked fruits and vegetables, raw fish and meat, and soft cheeses. Patients are encouraged to choose thoroughly cooked foods, pasteurised dairy products, and commercially processed items that have undergone rigorous safety checks. But, the neutropenic diet recommendations for patients with cancer have fallen from favour, with both the American Society of Clinical Oncology (ASCO) and the Infectious Diseases Society of America (IDSA) citing a lack of evidence that these restrictions reduce risks of infection or all-cause mortality. ^19,20

Stella and colleagues published a multicenter trial that randomly assigned patients undergoing hematopoietic stem cell transplantation (HCT) to a traditional restrictive neutropenic diet or a liberalised diet.¹⁷  More than 200 patients who underwent auto- and allo-HCT and underwent treatment at three transplant centres in Italy were included in the study, and the authors found that restricting posttransplant dietary options conferred no benefit with regards to the incidence of severe infections or any of the secondary outcomes studied.

The results of this study is practice-changing for our patients. After chemotherapy and transplantation, many patients experience loss of appetite, digestive issues, and taste disturbances, making it difficult to eat. Having to follow a restricted diet on top of these challenges can be incredibly frustrating and may even lead to malnutrition when the body needs more calories for recovery.

Figure 1. Comparison between neutropenic diet and liberalised diet in the clinical trial conducted by Stella et al. Adapted from Jonathan U et al.

This trial also paves the way for future research on another possible advantage of a varied diet: could dietary diversity support a healthy and diverse intestinal microbiome? Since damage to the microbiome is linked to poor outcomes after transplantation, it might be beneficial to explore the role of a diverse diet in maintaining optimal microbiome health in the context of HCT.¹⁸

Looking at a bigger data, two published systematic literature reviews showed that a low bacteria diet did not reduce infection and mortality rates compared to an unrestricted diet in patients with haematological malignancy and in the stem cell transplant setting.^21,22 Similar findings were found in a paediatric haematopoietic stem cell transplant setting; an additional observational before-and-after analysis of 102 paediatric patients undergoing allo-HCT at a single centre did not reveal any association between the liberalised diet and infectious risk after transplantation. ^24
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Conclusion:

Modulating the gut microbiome shows promise in enhancing the effectiveness of treatments for blood cancers, particularly in preventing severe side effects associated with these therapies. While we don’t fully understand why, studies suggest that eating fermented foods and plenty of fibre can positively impact the gut microbiome. These dietary changes seem to increase the diversity and activity of gut bacteria, which can influence the immune system and reduce inflammation. This chain reaction may ultimately lead to a better response to cancer treatment.
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References

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– Contributed by Dr Lee Chun Tsu