Perspective on the Coevolutionary Role of Host and Gut Microbiota in Polyphenol Health Effects: Metabotypes and Precision Health

Abstract

"Personalized nutrition" aims to establish nutritional strategies to improve health outcomes for non-responders. However, it is utopian since most people share similar nutritional requirements. "Precision health," encompassing lifestyles, may be more fitting. Dietary (poly)phenols are "healthy" but non-nutritional molecules (thus, we can live without them). The gut microbiota influences (poly)phenol effects, producing metabolites with different activity than their precursors. Furthermore, producing distinctive metabolites, like urolithins, lunularin, and equol, leads to the term "polyphenol-related gut microbiota metabotypes," grouping individuals based on a genuine microbial metabolism of ellagic acid, resveratrol, and isoflavones, respectively. Additionally, (poly)phenols exert prebiotic-like effects through their antimicrobial activities, typically reducing microbial diversity and modulating microbiota functionality by impacting its composition and transcriptomics. Since the gut microbiota perceives (poly)phenols as a threat, (poly)phenol effects are mostly a consequence of microbiota adaptation through differential (poly)phenol metabolism (e.g., distinctive reductions, dehydroxylations, etc.). This viewpoint is less prosaic than considering (poly)phenols as essential nutritional players in human health, yet underscores their health significance in a coevolutionary partnership with the gut microbiota. In the perspective on the gut microbiota and (poly)phenols interplay, microbiota metabotypes could arbiter health effects. An innovative aspect is also emphasized: modulating the interacting microbial networks without altering the composition.

Keywords: gut microbiota; metabolite; metabotype; personalized nutrition; polyphenol.

Figure 1

Catabolism of ellagitannins and ellagic acid to urolithins. Green circle: urolithin metabotype A (UMA); Orange circle: urolithin metabotype B (UMB). “R” urolithins are highlighted in purple. The different dehydroxylase activities required in each metabolic step are shown. ¹ Gordonibacter species; ² Ellagibacter species; ³ Enterocloster species; *Unknown.^{[ 12} , ^{73 ]}

Figure 2

Catabolism of the isoflavones daidzein and genistein. Sequential saturation of the C‐ring of isoflavones is marked in pink to highlight the equol producer metabotype (EP). Pink circle: equol producer metabotype (EP). Pink metabolites are only present in EP. The rest of the metabolites can be present in both EP and ENP. C‐ring cleavage to produce O‐DMA is marked in purple. D(G)R, daidzein(genistein) reductase; DH(G)R, dihydrodaidzein(genistein) reductase; THD(G)R, tetrahydrodaizein(genistein) reductase; CYP450, mammalian cytochrome P450; 4‐HPPA, 4‐hydroxyphenyl propanoic acid.^1,2,3 Slackia isoflavoniconvertens strain HE8, Eggerthella sp. strain YY7918, Lactococcus garvieae (among others); ⁴ Eubacterium ramulus, Clostridium sp. strain HGH 136, among others; ⁵Unknown.^{[ 70} , ^{161 ]}

Figure 3

Catabolism of trans‐resveratrol (RSV) by the human gut microbiota. Green circle: Lunularin (LUNU) non‐producer metabotype (LNP); Blue circle: LUNU‐producer metabotype (LP); Green compounds are metabolites found in all the individuals (LP+LNP); Blue compounds are metabolites only found in LP. Red compounds are not produced in humans. The numbers in the RSV structure designate the position of the carbon atoms. *4HST is not detected in vivo but rapidly reduced to 4HDB when incubated in vitro, impeding 4HST detection even in the eventual case it was produced. Thicker arrows designate more favored catabolic steps.^{[ 162 ] a}Slackia equolifaciens; ^bAdlercreutzia equolifaciens; ^cUnknown.^{[ 244 ]}