Immuno-modulatory Properties of Proanthocyanidins and Implications during Helminth-induced Inflammation in the Gut

PROJECT DESCRIPTION
Proanthocyanidins (PAC) are specialized plant metabolites, more commonly known as a type of anti-oxidant, and they are part of the larger phytochemical group of polyphenols. Interestingly, several studies have demonstrated important anti-oxidant and anti-inflammatory properties of PAC both in cellular and animal models.

However, the complexity of their diverse chemical structures challenges the study of these promising molecules, and their potential application during infectious diseases remains to be comprehensively determined. Especially within the field of gut inflammation, little is known on the potential immune-modulatory effects of PAC on type 2 immune responses, which can be induced by helminth infections. In other words, investigating how the immune response towards intestinal helminth infections can be modulated by bioactive compounds may offer new insights into novel treatment options of dysregulated immune function. Thus, the trilateral inter-relationship between PAC, helminths and immune function brings together three important research fields with relevance to human and animal health.

Therefore, this research project investigated the structure-activity interplay and cellular mechanisms leading to the immuno-modulatory effects of purified PAC in vitro. Furthermore, we aimed at exploring the effect of PAC on helminth-induced type 2 immune response in vivo, and thus investigating the trilateral interactions between PAC, parasites and the immune system.

PROJECT PURPOSE

The overall aim of this project was to investigate the relationship between chemical structure and bioactivity of purified PAC molecules. We investigated their modulatory effects on immune cells, and elucidated the effects of PAC on helminth-induced inflammation in the gut of mice and pigs. 

The primary objectives were as follows: 

  • Extract, purify and determine the structural characteristics of PAC from selected natural sources (In collaboration with the University of Turku, Finland)
  • Conduct in vitro screening of purified PAC samples and mechanistic studies to evaluate bioactivity and immuno-modulatory effects
  • Assess the effect of PAC on gut inflammation and immune response in helminth-infected mice and pigs
  • Investigate the implications of PAC bioactivity on the gut-lung axis in helminth-infected pigs

PROJECT RESULTS

Overall, our studies demonstrated that PAC purified from natural sources using chemical techniques such as UPLC-MS/MS and semi-preparative liquid chromatography, provided a large variety of diverse PAC molecules with distinct bioactivities. For example, we found that IL-6 secretion in LPS-activated macrophages was strongly inhibited by PAC in a molecular structure-dependent manner.

We also showed that PAC supplementation was able to significantly modulate immune responses in helminth-infected animal models. These studies indicated that PAC enhanced susceptibility to infection by modulating the Th1/Th2 balance in two different mouse models of helminth infection. On the other hand, PAC improved anti-oxidant status in helminth-infected pigs with a limited effect on the gut-lung axis. Interestingly, PAC significantly modulated the gut microbiota in both mice and pigs regardless of infection status, with varying effect on the abundance of beneficial bacteria.
Taken together, our studies demonstrate an effect of chemical structure on bioactivity, and a complex interplay between dietary PAC, the immune system and helminth infections. PAC demonstrated a broad-spectrum of activities, and strong immune-modulating properties, which were context-dependent.

Finally, by continuously uncovering various modes of action of PAC and identifying potent immune-modulating molecules, they may potentially benefit infectious inflammatory diseases, as well as diseases linked to  dysregulated type 1 or type 2 immune responses.

For more information contact Audrey Andersen-Civil: audrey.andersen-civil@hotmail.com