Bacterial folate biosynthesis and colorectal cancer risk: more than just a gut feeling

Abstract

Folate is a B-vitamin with an important role in health and disease. The optimal folate status with regard to human health remains controversial. A low intake of natural folate as well as excessive intake of synthetic folic acid, were previously linked to an increased risk of colorectal cancer or with aberrant molecular pathways related to carcinogenesis in some studies. Importantly, most studies conducted so far, solely focused on dietary intake or circulating levels of folate in relation to cancer risk. Notably, diet or dietary supplements are not the only sources of folate. Several bacteria in the gastrointestinal tract can synthesize B-vitamins, including folate, in quantities that resemble dietary intake. The impact of bacterial folate biosynthesis concerning human health and disease remains unexplored. This review highlights current insights into folate biosynthesis by intestinal bacteria and its implications for processes relevant to cancer development, such as epigenetic DNA modifications and DNA synthesis. Moreover, we will reflect on the emerging question whether food-grade or intestinal bacteria can be considered a potential target to ensure sufficient levels of folate in the gastrointestinal tract and, hence the relevance of bacterial folate biosynthesis for disease prevention or treatment.

Postbiotics—A Step Beyond Pre- and Probiotics

“…Citizens of countries with mandatory folate food fortification were reported to have lower risk of stroke compared to the controls (RR, 0.85; p = 0.004) [63]. However, the impact of on colorectal cancer risk takes the form of a U-shaped relationship, and the optimum folate status has not been defined [64]. Nevertheless, the issue of intestinal bacteria producing folate and their potential clinical application in maintaining optimal folate status deserves further consideration.…”

Folate Receptor β (FRβ) Expression in Tissue-Resident and Tumor-Associated Macrophages Associates with and Depends on the Expression of PU.1

“…FRβ has a very high affinity for folic acid and folates (Kd~0.1-1nM), but mammals do not synthesize folate and are dependent on other sources. Diet or dietary supplements are not the only sources of folate, as several bacteria in the gastrointestinal tract can synthesize B vitamins, including folates (e.g., Lactococcus lactis, Bifidobacterium adolescentis) [96,97]. The macrophage-specific expression of FRβ described in this report, and the fact that folic acid is produced by numerous bacterial species [96,97], have led us to hypothesize that FRβ acts as a receptor or co-receptor for recognition of bacterial microbiota.…”

“…Diet or dietary supplements are not the only sources of folate, as several bacteria in the gastrointestinal tract can synthesize B vitamins, including folates (e.g., Lactococcus lactis, Bifidobacterium adolescentis) [96,97]. The macrophage-specific expression of FRβ described in this report, and the fact that folic acid is produced by numerous bacterial species [96,97], have led us to hypothesize that FRβ acts as a receptor or co-receptor for recognition of bacterial microbiota. If so, gut macrophages could detect high concentrations of folate through FRβ as a mechanism to control bacterial overgrowth through signaling or by phagocytosis, which would allow the microbiota homeostasis to be restored/maintained by a folate-dependent quorum sensing-like mechanism.…”

Bacteria increase host micronutrient availability: mechanisms revealed by studies in C. elegans

“…A third possibility is the impact of folic acid on microbial metabolism. It is surprising how little is known about how folic acid and how other micronutrient supplements influence bacterial metabolism in the microbiota [24]. Other micronutrient supplements also have reported negative health consequences.…”