Manipulating the gut microbiome to produce 'beneficial' commensal microbes, which protect the host from pathogens and can boost immune responses, among other things, could potentially help patients respond better to cancer drugs called immune checkpoint inhibitors, a type of immunotherapy.
Researchers at the University of Michigan have developed a new dietary fibre formulation that improves the potency of immunotherapies against colorectal cancer (CRC) by modulating the gut microbiome. In the future, cancer patients treated with immune checkpoint blockers may benefit from consuming this inulin gel dietary fibre, explained James Moon, the John G Searle Associate Professor of Pharmaceutical Sciences in the College of Pharmacy. The findings appear in the paper, ‘Generation of systemic antitumour immunity via the in situ modulation of the gut microbiome by an orally administered inulin gel’, published in Nature Biomedical Engineering.
Inulin, a dietary fibre found in chicory root, Jerusalem artichoke and other plants, is a prebiotic that helps produce colon-residing commensal bacteria. By formulating inulin into a more colon-targeted inulin gel formulation, the team was able to provide a rich source of nutrients to allow beneficial gut microbes to expand more in the gastrointestinal tract.
The inulin gel improved immune checkpoint inhibitor therapy in rodents with colon carcinoma as well as melanoma. For instance, when inulin gel was combined with an immune checkpoint inhibitor in a colon carcinoma rodent model, the rate of tumour eradication doubled (100% improvement), compared with the immune checkpoint inhibitor therapy alone.
"Consumption of the inulin gel expanded and increased the number of beneficial microbes in tumour-bearing mice," said Kai Han, postdoctoral fellow and first author of the study. "These are beneficial commensal microbes that are found in cancer patients who respond well to immune checkpoint inhibitors. The current approaches to restoring a healthy gut microbiome include oral ingestion of defined probiotics or faecal microbiota transplantation. However, it would be very challenging to develop these as pharmaceutical products due to scale-up manufacturing and quality control."
The human microbiome has recently emerged as the next frontier in drug development. Intense research interest in the microbiome is driven by evidence linking the potential health benefits of modulating gut microbiota to treating various diseases, including cancer, diabetes, obesity and neurodegenerative diseases. In particular, a series of recent studies showed that the gut microbiome plays a crucial role in cancer patients' response rate to immune checkpoint inhibitors, Moon said.
"We and others have shown that the gut microbiome has a crucial role in our immune responses," added Han. "Close to 70% of lymph nodes in our bodies are located in the gastrointestinal tract and therefore, microbes residing in the gastrointestinal tract closely interact with our immune cells. Maintaining a healthy gut microbiome nurtures our immune system so that our immune cells can effectively fight against cancer."
The group chose inulin because it wanted something that could be readily translated to the clinic. Inulin is a dietary fibre that is widely consumed by the public and is present in many plants. It is used as a sugar substitute and in candies and butter. By making inulin into inulin gel, researchers found that inulin gel coats the gastrointestinal tract much better, leaving more nutrients to the commensal microbes.
The inulin gel also works with anti-PD-1 plus anti-CTLA-4 combo-therapy, (widely used immune checkpoint inhibitors) that treat many types of cancer, Han said.
Roughly 10-30% of cancer patients respond to immune checkpoint inhibitors, depending on the types of cancer, and there is risk of serious immune-related complications and side-effects, Moon said. For instance, inflammation in the gastrointestinal tract and skin are common. Previous studies have shown that inulin consumption may alleviate gastrointestinal inflammation, such as colitis and IBD.
"So, inulin gel may alleviate gastrointestinal inflammation induced by immune checkpoint inhibitors and we are testing this idea now," concluded Moon. "Generation of systemic anti-tumour immunity via the in situ modulation of the gut microbiome by an orally administered inulin gel."