Polyphenols and the Microbiota
In Part 1 we discussed a bit about what polyphenols are, how they are classified, and then discussed their health effects and some of the mechanisms of these. Now, we delve deeper into one mechanism of action — that is, their effect on the microbiota. Enjoy!
Following consumption of polyphenols, only a small percentage of polyphenols are absorbed in the stomach and small intestine. The vast majority — around 90–95% — proceed to the large intestine where they become subject to the enzymatic reactions of the residential bacteria there (Cardona et al., 2013). In this way, polyphenols affect bacterial populations of the large intestine and the metabolites released by the microbiota, both of which have implications for health. These two points — low bioavailability and manipulation of the microbiota — have led researchers to hypothesise that much of the beneficial health effects previously ascribed to the polyphenol substances themselves may actually be owed to their effect on the microbiota, which in turn then leads to the observed health effects (Fernando F. Anhê et al., 2016). To the first point, the low bioavailability can be explained in part by the modifications that polyphenols undergo before and after being absorbed, meaning they assume different forms in systemic circulation or the tissues than in the foods (Cardona et al., 2013; Pandey & Rizvi, 2009). The latter point, however, has much research supporting it that we will now take a closer look at.
Firstly, there are various mechanisms by which polyphenols are capable of manipulating microbiota composition. Seemingly paradoxically, one such is by having an antibacterial effect, which consists of inhibiting nucleic acid synthesis, membrane and cell wall disruption, interfering with cell metabolism, chelation of ions essential for the bacteria (such as copper, zinc, and iron) and interfering bacterial cell communication (quorum sensing) (Rodríguez-Daza et al., 2021). Antibacterial effects on a broad spectrum are not good for microbiota health (which is why antibiotics have a bad reputation with those concerned about the microbiota (Langdon et al., 2016)). Fortunately for us, the antimicrobial effects of polyphenols appear biased to favour inhibition of the growth of pathogenic bacteria. Additionally, however, polyphenols have a growth-promoting effect on beneficial bacteria, which further enhances the beneficial effect that polyphenols have on our microbiota and therefore health. Polyphenols have been shown to promote bacterial genera such as Lactobacilli, Bifidobacteria, and Akkermansia, whilst inhibiting pathogenic bacteria such as E. coli, Bacteroides, and Enterobacter cloacae (Cardona et al., 2013; Rodríguez-Daza et al., 2021). These dual-action effects shown in the figure below lead to population alterations that impact health outcomes.
Much literature exists in both animal and human studies that demonstrate that polyphenols alter microbiota composition and that these lead to (or at least correlate with) positive health outcomes.
A 2020 systematic literature review looked for evidence of a prebiotic effect of polyphenols on certain microbial species (Alves-Santos et al., 2020). Twenty-two animal studies were identified which, taken together, showed that various polyphenols (particularly catechins, anthocyanins and proanthocyanidins) had a prebiotic effect on various microbial genera, including Lactobacillus, Bifidobacterium, Akkermansia, Roseburia, and Faecalibacterium spp (“spp” means various species — so in this case, various species in the genus of Faecalibacterium). Only two clinical human trials were found but showed similar results: increased Lactobacillus, Bifidobacterium and Faecalibacterium. In one of these two studies (a randomized cross-over trial that consisted of pomegranate extract administration in overweight/obese subjects), lipopolysaccharide-binding protein was also measured and was lower (González-Sarrías et al., 2018). Lipopolysaccharide-binding protein is used as an estimate for gut barrier integrity. If this protein is higher, then more bacterial products (like LPS) are leaking from the gut to the body, which causes an immune response, inflammation, and ultimately ill-health.
The same study also found enhanced short-chain fatty acid (SCFA) production with polyphenol consumption. For those unfamiliar, SCFAs (acetate, propionate and butyrate) are produced when bacteria in the large intestine ferment the polysaccharides that we cannot digest in our small intestine (i.e., fibre). Fortunately for us, these SCFAs have a bunch of positive health outcomes, which you can see in the infographics below that I’ve made previously about these fascinating substances.
Exactly how polyphenols lead to enhanced SCFA production is not entirely clear, but there are various mechanisms. For example, by promoting more SCFA producing bacteria (such as Lactobacillus), there are more entities that can ferment fibres and produce SCFAs. Another explanation is that polyphenols may inhibit digestive enzymes of the small intestine, meaning more polysaccharides arrive in the large intestine to be fermented, as may occur with green and black tea. Polyphenols may also stimulate metabolic functions, leading to enhanced SCFA production (Van Hul & Cani, 2019)
In any case, some of the various health benefits that these studies found (likely through a combination of bacterial population alterations and SCFA production) included reduced LDL cholesterol and improved glucose and insulin regulation; decreased inflammation (prevention of NFκB gene induction); and increased hepatic AMPK. AMPK is a master sensor of energy status in the cell. When it is active, catabolism is favoured, so fatty acids are oxidized and their storage inhibited. Gluconeogenesis is also inhibited, whereas glucose is shuttled into energy production pathways (such as glycolysis) (Garcia & Shaw, 2017). Thus, in tissues like the liver, this means less fatty acid deposition, which leads to problems such as non-alcoholic fatty liver disease.
Other beneficial effects observed included strengthening of the gut barrier. For example, a catechin from green tea, epigallocatechin gallate (conveniently abbreviated EGCG), prevented a compromise of barrier integrity induced by high-fat diet feeding. Isoflavones of soy also induce various proteins that keep the gut barrier tight (ZO-1, occludin and Muc-2). Mucin-producing goblet cells are also positively affected (but more on this later…). In addition to these specific and technical effects, it’s also worth keeping in mind the intrinsic antioxidant effect that polyphenols possess. Excess oxidative stress in the intestine can compromise barrier integrity by damaging cell membranes and tight junctions (Alves-Santos et al., 2020). Berries represent a rich and diverse source of polyphenols and so are suitable for studying the interaction between polyphenols, the microbiota, and health. Fortunately for us, Lavefve et al. did exactly that in their review, and concluded, as with other studies, that the majority of polyphenols make their way to the gut as opposed to directly entering systemic circulation (Lavefve et al., 2020). Various examples of microbiota modulation are described in their review.
One pertinent finding is a decrease in the ratio of Firmicutes to Bacteroidetes. The ratio of these phyla is interesting because of their relationship to obesity and health. Obesity usually comes with an increase in this ratio, and the ratio decreases when weight is lost. Although causality is not confirmed, colonisation of bacteria from obese mice to germ-free mice (mice without intestinal bacteria) leads to weight gain, which is evidence that the bacteria of the large intestine are impacting obesity status and are not just by-standers (Stojanov et al., 2020). Blueberry, blackberry, honeyberry and cranberry all favourably influenced this ratio in animal models. In humans, blackcurrants decreased Bacteroides and Clostridium (a pathogenic genus) and magnolia berry increases various favourable bacteria, including Bifidobacterium (though this study also observed an increase in Bacteroides, showing that these changes are not always black and white). Other encouraging findings were increases of Lactobacillus and Bifidobacterium in various animal and human studies with various different types of berries. These changes have various health effects, from increased SCFA production to protection against carcinogenesis. Inflammatory bowel disease (IBD) markers are decreased following berry consumption, which is unsurprising given that these polyphenols show an inhibitory effect on NF-κB expression (Lavefve et al., 2020).
Red wine has a reputation for having health benefits, even in spite of its alcohol content. Morano-Indias et al. proved that some of these health claims actually hold up by using a randomized crossover trial that involved ten healthy and ten obese subjects (with metabolic syndrome) consuming red wine (272 mL per day), with and without alcohol, for 30 days (with a 15-day washout period) (Moreno-Indias et al., 2016). Before the trial began, the MetS (metabolic syndrome) patients had a distinct microbiota, which included species enrichment of “bad” bacteria and vice-versa for beneficial bacteria. Incredibly, after the intervention, the microbiota between the groups did not differ. Intestinal barrier protectors Bifidobacteria and Lactobacillus, as well as Faecalibacterium prausnitzii and Roseburia, bacteria with butyrate (the SCFA with the most impressive health profile) production capacity, were all enriched.
In contrast, pathogenic bacteria Escherichia coli and Enterobacter cloacae were decreased. These species are notorious producers of LPS, which, as you’ll recall from above, is bad news for systemic health. This shows a multi-faceted effect of red wine consumption: not only is gut barrier integrity and SCFA production higher but LPS production is also lower. Considering the short duration of the trial (60 days) and the mild nature of the intervention (simply 272ml of red wine/day) this is quite remarkable. And unsurprisingly, these microbiota alterations were predictive of improved lipid profile, plasma cholesterol and glucose, insulin sensitivity, C-reactive protein, and blood pressure, as shown in the figure below.
Other studies with similar contributions include a grape seed polyphenol extract enriching Bifidobacteria in healthy adults in only 2 weeks; polyphenols of chocolate, green tea and blackcurrant promoting Lactobacillus whilst also inhibiting Clostridium; flavanols increasing Lactobacillus and Bifidobacterium in humans, with a co-occurring plasma decrease in CRP; daily dark flavonoid consumption modulating microbiota composition and metabolism in human subjects; and cacao decreasing Bacteroides, Clostridium and Staphylococcus in a rat model, amongst various other findings of different foods and different polyphenols (Cardona et al., 2013).
A recent systematic review explored the prebiotic effect of polyphenols for the management of obesity in animals on a high-fat diet and found some promising findings (Moorthy et al., 2021). Of the 45 studies included, 98% (all but one) of the studies showed that polyphenols were protective against high-fat diet-induced metabolic derangements. These derangements were weight gain (polyphenols were protective against weight gain in 83% of the studies), visceral adipose tissue, measures relating glucose homeostasis and lipid profile, and LPS and inflammatory markers. And in 93% of these studies, significant changes were found in microbiota composition. The most notable alterations were a beta-diversity that more closely resembled a normal diet (i.e., the polyphenols protected against high-fat diet-induced beta diversity alterations); reduced Firmicutes: Bacteroidetes ratio; and enrichment of beneficial bacteria. The authors conclude their discussion by suggesting that these microbiota alterations ultimately reduce LPS, and this is what leads to the beneficial changes. Indeed, improved barrier integrity is a common feature of studies that report beneficial effects of polyphenol supplementation. A discussion on the topic of gut barrier integrity would be incomplete without the mention of a bacterium that has a famous role to play in this area: Akkermansia muciniphila, to which we will now focus our attention.
Akkermansia and Gut Barrier Integrity
Many of the above studies also mention Akkermansia as part of their results showing a beneficial effect of polyphenols on microbiota composition and health in general. In fact, it’s quite hard not to given the importance that Akkermansia has in barrier integrity and therefore overall health. However, I wanted to give it a section all on its own since it may in fact underpin many of the beneficial effects observed with polyphenol consumption. The reason for this will hopefully be clear towards the end of this section.
Akkermansia muciniphila was named on the genus level after the Dutch microbiologist Anton Akkermans, and on the species level for its love for mucus (the microbe, not the biologist). Since A. muciniphila is the only microbe of this genus relevant for human health, it is sometimes referred to only by its genus name. This is the approach I take here. It constitutes about 1–5% of a health microbiota and resides on the outer mucus layer of the large intestine, using mucus as its sole energy source (Anonye, 2017). Akkermansia has gained a great reputation in recent years for its association with heath. Many studies exist showing improved health with approaches that increase Akkermansia (Fernando F. Anhê et al., 2016; Van Hul & Cani, 2019). Supplementation in obese and overweight individuals leads to improvement in health markers such as fat mass, insulin sensitivity, plasma cholesterol, liver function markers, and inflammatory markers (Depommier et al., 2019). In obese adults, higher Akkermansia abundance led to more favourable improvements of clinical markers after a calorie restricting diet, and those with a greater abundance of Akkermansia had a healthier metabolic status (Dao et al., 2016). Interestingly, some of the beneficial effects that metformin has on metabolic outcomes appear to come via modulation of Akkermansia levels, too (Naito et al., 2018). Although Akkermansia has other potential health benefits such as cancer and inflammatory bowel disease (Bian et al., 2019; Jayachandran et al., 2019; Naito et al., 2018), it is particularly renowned for its metabolic functions, which it appears to possess via its barrier strengthening properties (more on this later).
Fortunately, Akkermansia abundance seems to be positively influenced by polyphenol intake. Indeed, a highly cited 2016 study showed that cranberry extract was protective against high fat/sugar-induced obesity in mice, and this occurred despite calorie intake being the same between the groups (Fernando F. Anhê et al., 2015). Other markers of metabolic health such as visceral fat, hepatic, intestinal and plasma triglyceride accumulation, insulin sensitivity, plasma LPS, oxidative stress and inflammation were all improved in the group of mice consumption cranberry extract. Although causality could not be proven, weaker barrier integrity is known to lead to leakage of contents of the lumen of the large intestine to the plasma, causing inflammation and insulin resistance. By strengthening the integrity of the gut barrier by preserving mucus thickness, there is a strong rationale for Akkermansia being causal in improving inflammation, insulin resistance, triglyceride accumulation, and metabolic status (Fernando F. Anhê et al., 2015). Other studies show pterostilbene (found in almonds, berries and grapes), capsaicin (found in chilis), and proanthocyanidin (of grape) polyphenol extract also promoted Akkermansia growth, and that this was protective against obesity and metabolic derangements (Anonye, 2017; Zhang et al., 2018).
In the systematic literature review of Alves-Santos mentioned above that investigated bacterial population changes following polyphenol consumption, Akkermansia enrichment was observed in multiple studies. It is elaborated that the improved barrier function that occurs due to polyphenol consumption creates a niche that favours Akkermansia growth (Alves-Santos et al., 2020). Various polyphenols have been shown to increase tight junctions, which prevent gaps from appearing between the cells of the epithelium of the gut. Additionally, goblet cells, cells that produce mucin in the body, increase in number, and their mucin-production capacity is augmented following polyphenol consumption (Alves-Santos et al., 2020; Fernando F. Anhê et al., 2016; Rodríguez-Daza et al., 2021). This in of itself is beneficial by increasing barrier integrity, but an additional benefit of this phenomenon is the extra mucin provides a substrate for Akkermansia, which exerts a prebiotic effect and encourages its growth. With mucus as a substrate, Akkermansia can now produce SCFAs (Anonye, 2017). And I hope, by now, you’re clear on what is so great about this.
Separating causation from correlation when investigating Akkermansia has been important over the last few years. That is, is there actually a positive effect to be had with Akkermansia, or does a healthier gut barrier mean there is more mucus to feed on, meaning Akkermansia increases or decreases with health status rather than causing changes in health status? Evidence exists that show it has a causal role to play. We mentioned above that Akkermansia uses mucin to produce SCFAs, and we know SCFAs exert positive impacts on health. In a fortunate positive feedback cycle, the SCFAs released by Akkermansia in the outer mucus layer in the large intestine support the health of goblet cells, causing the release of more mucus which Akkermansia can continue to feed on. Imagine having a three-course meal waiting for you every time you finished your business on the toilet? Additionally, though, a protein on the outer membrane of Akkermansia (Amuc-1100) interacts with epithelial cells (via TLR-2) which strengthens barrier functions and directly leads to improvements in the metabolic status of obese and diabetic mice (Plovier et al., 2017). It is suggested that this protein is crucial to the beneficial health actions of Akkermansia (Fernando Forato Anhê & Marette, 2017). Akkermansia also interacts with the immune system around the gut and favours anti-inflammatory cytokine expression, namely via IL-10 induction. Other research that suggests causal roles for Akkermansia include studies that have used faecal transplants or administration of live culture to demonstrate beneficial effects are dependent on microbiota composition (Naito et al., 2018). Delivery of Akkermansia as a probiotic improves glucose intolerance, insulin resistance and hepatic steatosis in rodents and improve cardiometabolic risk factors in obese and overweight subjects (Van Hul et al., 2020). Other examples of Akkermansia administration improving health markers in humans are also known (Moorthy et al., 2021)
A recent study from Lu et al. produced a few interesting findings (Lu et al., 2021). Exposure to polyphenols early in life may be important for the health effects of polyphenols and Akkermansia to be relevant. Grape polyphenol supplementation in baby — but not adult mice — promoted Akkermansia growth. This finding must be reconciled with other studies that have found Akkermansia growth-promoting effects in adults (both in animals and humans), it may suggest these beneficial effects are more pronounced with younger age. It should be kept in mind, however, that mice in this study were kept in pathogen-free conditions, reducing translatability to humans. (Though, other groups have also found correlation evidence for the association between the beneficial health effects of Akkermansia to be lost with age (Q. Zhou et al., 2020)). Lu et al. also investigated mechanisms by which (grape) polyphenols lead to positive health outcomes. Early-life polyphenol supplementation led to long-lasting architectural changes of the colon and the barrier. And as with the results described just above, goblet cells and their mucin-producing capacity were augmented, facilitating the Akkermansia bloom. Preceding all of this, though, they hypothesise a potential role for Lactobacillus via lactate production modulating growth pathways (BMP, Wnt3, Notch, for the nerds), thus stimulating goblet cell growth (Lu et al., 2021). This suggests a synergistic role for the two bacteria. Future work is required to investigate this further. For now, let’s just say your baby should be drinking red wine regularly.
The powerful antioxidant properties of polyphenols have been described. Although it seems they may have unduly taken the credit for the beneficial health effects observed with polyphenol intake in the early days, it may still be appropriate to give polyphenols their credit for utilising this property not in the host system directly but to the advantage of the microbiota in the gut. Grape polyphenols reduced oxidative stress in the gut of mice fed a high-fat diet to levels comparable to mice fed a low-fat diet, whilst other antioxidants such as vitamin C and vitamin E did not, since their bioavailability is higher and therefore are absorbed earlier in the gastrointestinal tract leaving less for the microbes of the gut. By scavenging reactive oxygen species (ROS) in the intestinal lumen, polyphenols appear to protect Akkermansia from oxidative stress, promoting their survival (Kuhn et al., 2018). Akkermansia is part of the group of organisms known as obligate anaerobes, which are without antioxidant systems meaning they are highly intolerant to oxygen (Imlay, 2013). In my opinion, this is a very interesting finding. We (rightly) emphasise the importance of the dietary acquisition of dietary constituents like vitamin C and E due to their relevance to health, but in this aspect, these essential vitamins are of little use, whereas polyphenols — which are without dietary intake recommendations — are. In sum, the antioxidant function of polyphenols (in the case of Kuhn et al., grape polyphenols) represents yet another mechanism by which polyphenols exert positive effects on Akkermansia populations.
Thus, it seems that among the various health benefits of polyphenols, a large portion can be ascribed to modulation of the microbiota, and a significant portion of these effects can be ascribed to improved gut barrier integrity and increased Akkermansia abundance. Now, if you’re anything like me, you’re probably wondering what you can do to promote Akkermansia growth in your own large intestine. Multiple polyphenols and food sources have been scattered throughout the last few passages, but I will list a few here. Various foods promote Akkermansia growth, particularly those of apple, green grape, green tea (ECGC), blueberry, black raspberry, and cranberry. Rhubarb extract is also reported to have a positive effect on Akkermansia numbers but, since it is low in both fibre and polyphenol content, the mechanisms are currently unclear (K. Zhou, 2017). In terms of specific polyphenolic compounds, chlorogenic acid and caffeic acid (both of coffee), quercetin (found ubiquitously), resveratrol (of red wine and red grape), and malvidin-3-galactoside (of bilberry, blueberry, and red wine) are noted (Rodríguez-Daza et al., 2021), though others are also capable of promoting Akkermansia growth. Additionally, other things you can do to prevent Akkermansia population decline include avoiding a high-fat, Western-style diet and limiting alcohol intake (K. Zhou, 2017).
To find out more about practical applications, possible adverse effects, and other points of interest on polyphenols, keep an eye out for our final instalment of this series coming soon.
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