Dietary antigens reduce small intestine cancer by boosting immune T-cells

By Pooja Toshniwal PahariaReviewed by Benedette Cuffari, M.Sc.Sep 22 2024

New research reveals how common dietary proteins like bovine serum albumin (BSA) or ovalbumin (OVA) may stimulate the body’s immune response and reduce small intestine cancer.

Study: Food antigens suppress small intestinal tumorigenesis. Image Credit: Sinhyu Photographer / Shutterstock.com

In a recent study published in the journal Frontiers in Immunology, researchers investigate the impact of dietary antigens in regulating small intestinal tumors.

How does diet affect cancer of the small intestine?

Despite being the most common type of cancer to affect individuals throughout the world, there remains a lack of non-invasive diagnostic technologies for monitoring the growth of gastrointestinal (GI) tumors.

Although rare, tumors in the small intestine can arise. Many of these remain undetected for extended periods due to the delayed onset of symptoms, which can worsen treatment outcomes. Thus, identifying dietary components that prevent or inhibit small intestine carcinogenesis is critical.

It remains unclear which dietary components can reduce small intestine carcinogenesis, as this type of tumor is much more rare than colorectal malignancies. However, given the crucial role of the immune system in tumor control, researchers hypothesize that food components and bacteria, both of which can impact immune responses in the GI tract, may be involved in the development of small intestine tumors.

About the study

The researchers of the present study used Apc^min/+ mice, a mouse model for intestinal tumorigenesis with a loss-of-function mutation in the tumor-suppression gene adenomatous polyposis coli (Apc).

All mice consumed antigen-free diets (AFD) in specific-pathogen-free (SPF) settings for six weeks to study tumors. Ovalbumin (OVA) or bovine serum albumin (BSA) was incorporated into AFDs to determine how the addition of these food antigens may affect tumor proliferation and immune responses.

To generate Peyer's patches (PP)-null wild-type (WT) mice, antibodies against interleukin-7 receptor alpha (IL-7Rα) were injected into WT animals. The offspring of these mice were fed AFDs or regular chow diets (NCD) for five weeks. At E14.5, WT dams crossed with Apc^min/+ male mice were injected with A7R34 antibodies to produce Peyer’s patches-null Apc^min/+ animals.

Stereomicroscopy was used to measure tumor size and number, whereas flow cytometry and fluorescence-activated cell sorting (FACS) allowed the researchers to assess immune cell populations. Single-cell ribonucleic acid sequencing (scRNA-seq) was used to investigate immune cell induction in PPs in response to dietary antigens.

The researchers were also interested in examining PP involvement in triggering small intestine lamina propria T-cells with food antigens, as this may be the location where dietary antigens transfer from the intestinal lumen. To this end, fluorescein isothiocyanate (FITC)-conjugated OVA was injected into ligated loops of the small bowel in mice, which allowed for immunohistochemistry (IHC) analysis to confirm this hypothesis.

Microfold (M) cells are a specialized subset of epithelial cells present within PPs that transport large luminal molecules or microorganisms across the cell membrane. The current study investigated the involvement of M cells in transporting dietary antigens to dendritic cells in PPs. The amount of small intestine lamina propria T-cells in M cell-deficient mice was also determined, in addition to assessing the food-antigen-regulated actions of dendritic cells, which may influence T-cell development in PPs.

Study findings

The scRNA-seq results revealed that dietary antigens influence the activation of T- and dendritic cells to present antigens. T-cells within the small intestine lamina propria, particularly T helper 1 (Th1) cells, prevent the development of cancer in the small intestine.

Lower T-cell counts were observed among AFD-fed mice under SPF and germ-free conditions, thus indicating that dietary antigens contribute to T-cell induction and, as a result, carcinogenic processes. The incorporation of BSA into the diet reduced small intestinal cancers to levels comparable to NCD-fed animals. In wild-type mice consuming AFD, cluster of differentiation 4 (CD4)-expressing helper and CD8-expressing cytotoxic T-cells within PPs were reduced but recovered after the addition of BSA into the diet. Adding OVA to antigen-free diets restored T-cell quantities in PPs, suggesting that this effect is not specific to a particular antigen.

M cells were found to transport dietary antigens from the lumen to dendritic cells, thereby inducing T-cell activity. Dendritic cells were reduced in AFD animals; however, adding BSA into the diet under germ-free and SPF conditions confirms that dietary antigens regulate dendritic cell function.

Conclusions

Dietary antigens suppress carcinogenesis in the small intestine by stimulating T-cells through PPs in response to food antigens. Cytotoxic T-cell activity is a crucial aspect of antitumor responses, with their efficacy dependent on the presence of Th1 cells. In the current study, reduced cytotoxic T-cell levels were observed in small intestinal cancer among AFD-fed APC^min/+ animals; however, these levels partially recovered following the incorporation of BSA into the antigen-free diet.

The study findings have clinical implications, as the AFD ingredients used in the current study are similar to enteral nutritional components that are often used as adjunctive treatment in gastrointestinal cancers, particularly in individuals suffering from familial adenomatous polyposis and inflammatory bowel disease (IBD).