Protocatechuic Acid, a Gut Bacterial Metabolite of Black Raspberries, Inhibits Adenoma Development and Alters Gut Microbiome Profiles in Apc^Min/+ Mice

Abstract

Administration of black raspberries (BRBs) and their anthocyanin metabolites, including protocatechuic acid (PCA), has been demonstrated to exert chemopreventive effects against colorectal cancer through alteration of innate immune cell trafficking, modulation of metabolic and inflammatory pathways, etc. Previous research has shown that the gut microbiome is important in the effectiveness of chemoprevention of colorectal cancer. This study aimed to assess the potency of PCA versus BRB dietary administration for colorectal cancer prevention using an Apc Min /+ mouse model and determine how bacterial profiles change in response to PCA and BRBs. A control AIN-76A diet supplemented with 5% BRBs, 500 ppm PCA, or 1,000 ppm PCA was administered to Apc Min /+ mice. Changes in incidence, polyp number, and polyp size regarding adenomas of the small intestine and colon were assessed after completion of the diet regimen. There were significant decreases in adenoma development by dietary administration of PCA and BRBs in the small intestine and the 5% BRB-supplemented diet in the colon. Pro-inflammatory bacterial profiles were replaced with anti-inflammatory bacteria in all treatments, with the greatest effects in the 5% BRB and 500 ppm PCA-supplemented diets accompanied by decreased COX-2 and prostaglandin E 2 levels in colonic mucosa. We further showed that 500 ppm PCA, but not 1,000 ppm PCA, increased IFN-γ and SMAD4 levels in primary cultured human natural killer cells. These results suggest that both BRBs and a lower dose PCA can benefit colorectal cancer patients by inhibiting the growth and proliferation of adenomas and promoting a more favorable gut microbiome condition.

The Role of Anthocyanins in Alleviating Intestinal Diseases: A Mini Review

“…CRC is a complex pathology that originates from intestinal stem cells (ISC) and is caused by multiple factors, , depending on the environment and internal individual factors, such as diet, lifestyle, genetics, and epigenetics . As an important public health problem, CRC accounts for roughly 1.2 million new cases and 0.6 million deaths each year and is caused by malignant transformation of the large intestine epithelium, with an increased incidence in young people. ,, Currently, the treatment of CRC is commonly adopted by a combination of surgery and chemoradiotherapy. Serious adverse reactions and toxicity to normal cells caused by chemotherapeutic agents are the main flaws .…”

“…Moreover, the administration of BRBs and their anthocyanin metabolites, such as protocatechuic acid (PCA), has already been confirmed to play a chemoprophylactic role in CRC by altering innate immune cell transport and modulating metabolic and inflammatory pathways. Also, the role of BRBs and their metabolites requires the participation of gut bacteria . Simultaneously, the exposure of BRBs reduces ISC gene expression and tumorigenicity of CRC organoid cells in the gut using 3D-grown ISO50, ISO48, and Caco-2 cells, and the impact of BRB on the characteristics of human gut stem cells was demonstrated .…”

“…41 As an important public health problem, CRC accounts for roughly 1.2 million new cases and 0.6 million deaths each year and is caused by malignant transformation of the large intestine epithelium, with an increased incidence in young people. 11,63,64 Currently, the treatment of CRC is commonly adopted by a combination of surgery and chemoradiotherapy. Serious adverse reactions and toxicity to normal cells caused by chemotherapeutic agents are the main flaws.…”

“…10 Presently, millions of people all over the world suffer from intestinal diseases, including inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), and colorectal cancer (CRC). 7,8,11 However, the objective of managing IBD is to minimize distressing symptoms in order to achieve sustained remission, instead of curing it completedly. 12,13 CRC patients have experienced significant adverse effects from chemotherapy or radiotherapy.…”

“…The intestinal tract, known as “the second brain”, is the largest digestive and absorption organ in the body, colonized with many microorganisms that come into direct contact with nutrients, therapeutic drugs, and toxic food contaminants. , Thus, the intestine is not only vital for absorbing nutrition but also a major barrier against pathogenic microorganisms, and pathologies of the intestinal tract are closely related to the collapse of the defense system . Presently, millions of people all over the world suffer from intestinal diseases, including inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), and colorectal cancer (CRC). ,, However, the objective of managing IBD is to minimize distressing symptoms in order to achieve sustained remission, instead of curing it completedly. , CRC patients have experienced significant adverse effects from chemotherapy or radiotherapy . In addition, the pathogenesis of IBS is still unclear, and the treatment for IBS is currently limited to symptomatic management .…”