Currently, a growing body of scientific evidence shows that flavonoids could exert a protective role against obesity-related pathologies by modulating intestinal inflammation, barrier integrity and gut microbiota composition and functionality.

The MoBioFood (Molecular Bioactivity of Foods) Research Group from the Biochemistry and Biotechnology Department at the Rovira i Virgili University in Tarragona (Spain) focuses on the interaction of flavonoids with the enteroendocrine system, and the role of these compounds in maintaining intestinal barrier integrity and/or inducing anti-inflammatory effects in the gastrointestinal tract.

Dr. Mayte Blay and Dr. Ximena Terra, senior researchers at the MoBioFood Research Group, and Katherine Gil, PhD student in the same group, corresponded with GMFH editors about emerging knowledge about the role of flavonoids in obesity-related pathologies.


What’s the role of the gut microbiome in obesity and metabolic disease?

The intestine is essential for the digestion and extraction of nutrients, such as lipids, carbohydrates and proteins, but its role in metabolic diseases has been [seldom] investigated over the years. Recently, the gastrointestinal tract has been described as another potential source of inflammation that is associated with diet- and/or obesity-related pathologies. Increased attention has been paid to the link between the gut microbial composition and obesity. The gut microbiota is a source of endotoxins [which, when increased in plasma, are] related to obesity and insulin resistance through increased intestinal permeability in animal models and [through] triggering systemic inflammation. However, this relationship still needs to be confirmed in humans. More studies are needed to precisely define how intestinal inflammation favours obesity and insulin resistance, but the mechanisms likely include altered epithelial permeability, translocation of bacterial products, up-regulation of pro-inflammatory cytokines and hormones produced from gut endocrine cells and the modulation of neural signalling between the gut and brain that impacts appetite or satiety.

Consequently, defining the sources, causes and mechanisms underlying the development of intestinal alterations during progressive increases in body weight and adiposity is a powerful tool for developing strategies and therapies that prevent or limit the adverse effects of obesity on health.


What is the specific role of flavonoids in modulating the intestinal inflammatory response, barrier integrity and changes in gut microbiota? At which levels do they act?

Flavonoids could exert a protective role against obesity-associated pathologies [by] reducing the intestinal inflammatory processes, protecting the barrier integrity and modulating the composition of the microbiota.

In mammals, the NF-kB family [plays] a key role in the intestinal inflammation. In response to an inflammatory stimulus, the classical NF-kB activation pathway activates IkB kinase, triggering the NF-kB inhibitory protein phosphorylation, IkB-a, to subsequent proteasomal degradation. Upon activation, NF-κB regulates the transcriptional activation of many genes involved in the immune and inflammatory responses, such as pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) and inducible enzymes (inducible nitric oxide synthase, iNOS, and cyclooxygenase 2, COX2) among others. In this sense, flavonoids have demonstrated [effects on] NF-κB inflammatory response at different levels in the intestine. For example, luteolin and complex forms of flavonoids are able to inhibit the NF-κB translocation to the nucleus, preventing pro-inflammatory gene transcription by suppressing IkB-a activity. Moreover, the beneficial effect of other flavonoids, like catechins, on intestinal inflammation has directly been related to the suppression of pro-inflammatory enzyme expression, such as COX2 and iNOS.

During inflammation, persistent high circulating levels of inflammatory cytokines, which are often observed in obese patients, may cause impairment of intestinal barrier function by altering the structure and localization of tight junctions, a cluster of junctional proteins that selectively regulate the transport of molecules from the lumen to the intestinal mucosa and bloodstream. Altogether, this induces an increase in intestinal permeability. Surprisingly, flavonoids such as genistein and quercetin exert protective and promoting effects on intestinal barrier integrity. In particular, these metabolites interact with intracellular signalling molecules, such as tyrosine kinases and PKCδ, resulting in the regulation of tight [junction] protein expression and assembly. More specifically, it has been demonstrated that oxidative stress-induced tight [junction] dysfunction is related to the tyrosine phosphorylation of occludin, ZO-1 and E-cadherin in colorectal cells, and flavonoids act against this oxidative stress in the intestinal barrier by suppressing c-Src kinase activation, which inactivates tyrosine phosphorylation of the tight junctions.

Flavonoids reach the gastrointestinal tract, where they can directly interact with the intestinal cells, but also with the gut microbiota. Both dietary flavonoids, which are the substrates of intestinal bacteria, and the metabolites produced during flavonoid degradation in the colon can modulate and induce oscillations in the composition of the microbiota populations. In fact, some flavonoids such as quercetin or isoflavones [have a] significant impact on different taxonomic [categories] of the gut microbiota composition in both animal and human studies. In addition, flavonoids like catechin and epicatechin and their metabolites are able to influence [the] growth pattern of common pathogenic, commensal and probiotic intestinal bacteria as representative intestinal microflora. All together, these facts suggest that flavonoids may modulate the microbiota composition by means of prebiotic and antimicrobial properties. However, the mechanisms involved are still poorly understood and more studies are needed.


Based on your research, what kind of potential interventions do you suggest to combat the current pandemic of obesity-related pathologies via targeting the gastrointestinal ecosystem?

Obesity and related pathologies are characterized by gut dysbiosis. That is, imbalance in the gut microbiome populations.

[The first potential intervention is diet.] The ingestion of proanthocyanidins at specific amounts that have to be still specified, can be a recommendation in the current diets of the population of industrialized countries, aiming to prevent or ameliorate [dysbiosis] in the gut of the obese individuals or [those] at risk of obesity and related pathologies as a result of a high-fat refined-carbohydrate diet ingestion. Proanthocyanidins have a prebiotic role in some circumstances. Moreover, proanthocyanidins because of [their] anti-inflammatory effects could reduce local and systemic inflammation associated [with] obesity, thus ameliorating not only gut performance but the systemic [health]. [This needs further study to be made concrete.] Human diets rid of some types of industrial food additives that can promote dysbiosis, such as some [kinds] of emulsifiers, in the general and affected population, [is] also a recommendation.

[The second potential] intervention is avoiding antibiotics when not strictly necessary. And when necessary, they have to be combined with prebiotic/probiotics in the diet.

Other more direct interventions could be performed, such as gut microbiota transplantation from healthy donors to obese individuals with the aim of restoring the homeostasis of gut ecosystem, but this is [still] under investigation.


What’s the next step in finding out whether flavonoids could improve human metabolic health over the long term?

The study of flavonoid [effects] in human metabolic health is a topic of intense research and taking into consideration the diversity of [the] flavonoid family of natural compounds and of their specific effects, the amount of work [to be done] is huge. However, because of [emerging information about] the importance of [proper] gut performance in metabolic health our opinion is that the effect of flavonoids in modulating microbiome and gut barrier maintenance and prevention of inflammation is a hot topic.

The next step is assessing the influence of flavonoids included in diet [on] gut microbiome and general metabolic parameters in animal models and humans for long-term time periods.