Microbiota-Derived Short-Chain Fatty Acids: New Road in Colorectal Cancer Therapy

Abstract

The colon microbiota is an important player in colorectal cancer (CRC) development, which is responsible for most of the cancer-related deaths worldwide. During carcinogenesis, the colon microbiota composition changes from a normobiosis profile to dysbiosis, interfering with the production of short-chain fatty acids (SCFAs). Each SCFA is known to play a role in several biological processes but, despite their reported individual effects, colon cells are exposed to these compounds simultaneously and the combined effect of SCFAs in colon cells is still unknown. Our aim was to explore the effects of SCFAs, alone or in combination, unveiling their biological impact on CRC cell phenotypes. We used a mathematical model for the prediction of the expected SCFA mixture effects and found that, when in mixture, SCFAs exhibit a concentration addition behavior. All SCFAs, alone or combined at the physiological proportions founded in the human colon, revealed to have a selective and anticancer effect by inhibiting colony formation and cell proliferation, increasing apoptosis, disturbing the energetic metabolism, inducing lysosomal membrane permeabilization, and decreasing cytosolic pH. We showed for the first time that SCFAs are specific towards colon cancer cells, showing promising therapeutic effects. These findings open a new road for the development of alternatives for CRC therapy based on the increase in SCFA levels through the modulation of the colon microbiota composition.

Modulation of the Tumor Microenvironment by Microbiota-Derived Short-Chain Fatty Acids: Impact in Colorectal Cancer Therapy

“…Despite being known that each SCFA plays a role in several biological processes, it is also important to understand the combined effects of the three SCFAs, since colon cells are exposed to these compounds simultaneously [ 44 ]. Recently, our group reported that all three SCFAs, alone or combined at the physiological proportions found in the human colon (60 acetate: 15 butyrate: 25 propionate), revealed to have a selective and anticancer effect by inhibiting colony formation and cell proliferation, increasing apoptosis, disturbing the energetic metabolism, inducing lysosomal membrane permeabilization, and decreasing cytosolic pH [ 44 ]. Additionally, this study showed for the first time that SCFAs are specific towards colon cancer cells, showing promising therapeutic effects [ 44 ].…”

“…Recently, our group reported that all three SCFAs, alone or combined at the physiological proportions found in the human colon (60 acetate: 15 butyrate: 25 propionate), revealed to have a selective and anticancer effect by inhibiting colony formation and cell proliferation, increasing apoptosis, disturbing the energetic metabolism, inducing lysosomal membrane permeabilization, and decreasing cytosolic pH [ 44 ]. Additionally, this study showed for the first time that SCFAs are specific towards colon cancer cells, showing promising therapeutic effects [ 44 ]. All the current evidence concerning the effects of acetate, butyrate, and propionate on CRC cells, alone or in combination, clearly supports the potential use of SCFAs in cancer prevention and treatment [ 2 ].…”

Enhancement of Acetate-Induced Apoptosis of Colorectal Cancer Cells by Cathepsin D Inhibition Depends on Oligomycin A-Sensitive Respiration

“…Despite the advances in CRC treatment options, classical chemotherapy with 5-Fluorouracil (5-FU) is still a clinical problem due to resistance, presenting response rates of less than 10% in metastatic CRC patients [2]. The intestinal microbiota, composed of a large population of microorganisms modulated by dietary patterns, has been increasingly linked with CRC [3,4]. Differences in intestinal microbiota composition have been reported between patients with CRC and healthy individuals, and the reduced production of microbiota-derived short-chain fatty acids (SCFAs), namely acetate, butyrate, and propionate, is linked to a high CRC risk [5,6].…”

“…However, the effectiveness of this approach would likely vary according to individual intestinal flora and dietary compliance. In the search for new alternatives for CRC treatment capable of overcoming some of the limitations associated with the currently available approaches in the clinic, SCFA administration has been also been considered [3,7,8,[10][11][12]. This possibility was advanced due to their described role in several biological processes against CRC cells [13][14][15].…”

“…We also showed that acetate interferes with energetic metabolism through the modulation of monocarboxylate transporter (MCT) expression [15]. More recently, we demonstrated that a mixture of SCFAs in physiological proportions can modulate several biological processes in CRC cells, namely cell survival, proliferation, apoptosis, energetic metabolism, cytosolic pH, and lysosomal membrane permeabilization (LMP) [3]. These results highlight the possibility of applying SCFAs in the clinic as potentiators of classical chemotherapy, thus promoting the quality of life of patients by decreasing its associated side effects.…”