Dietary proanthocyanidins promote localized antioxidant responses in porcine pulmonary and gastrointestinal tissues during Ascaris suum-induced type 2 inflammation

Authors: ANDERSEN-CIVIL, AUDREY INGE - University Of Copenhagen; MYHILL, LAURA - University Of Copenhagen; GOKGOZ, NILAY - University Of Copenhagen; ENGSTROM, MARICA - University Of Turku; MEJER, HELENA - University Of Copenhagen; ZHU, LING - University Of Copenhagen; Zeller, Wayne; SALMINEN, JUHA-PEKKA - University Of Turku; KRYCH, LUKASZ - University Of Copenhagen; LAURIDSEN, CHARLOTTE - Aarhus University; NIELSEN, DENNIS - University Of Copenhagen; THAMSBORG, STIG - University Of Copenhagen; WILLIAMS, ANDREW - University Of Copenhagen

Submitted to: Journal of Federation of American Societies for Experimental Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/7/2022
Publication Date: 3/25/2022
Citation: Andersen-Civil, A.S., Myhill, L.J., Gokgoz, N.B., Engstrom, M., Mejer, H., Zhu, L., Zeller, W.E., Salminen, J., Krych, L., Lauridsen, C., Nielsen, D.S., Thamsborg, S.M., Williams, A.R. 2022. Dietary proanthocyanidins promote localized antioxidant responses in porcine pulmonary and gastrointestinal tissues during Ascaris suum-induced type 2 inflammation. Journal of Federation of American Societies for Experimental Biology. 36(4). Article e22256. https://doi.org/10.1096/fj.202101603RR.
DOI: https://doi.org/10.1096/fj.202101603RR

Interpretive Summary: Proanthocyanidins (PAC) are a class of secondary plant metabolites found in several plants and are composed of oligomers and polymers of flavan-3-ol subunits. Beneficial attributes of the consumption of plant material containing PAC by mammals includes use as natural anthelminthic (deworming) agents. In this study, pigs were infected with the parasite Ascaris suum then treated with grapeseed PAC supplementation to study the effect of PAC on pathogens that induce a strong, a strong immune response in lung and intestinal tissues. Both A. suum infection and grapeseed PAC supplementation had similar activity modifying pathways related to B-cell (antibody generation) function. Grapeseed PAC also affected pathways related to oxidative stress. The limited effects of dietary grapeseed PAC observed in the lungs is in line with a previous study demonstrating no effect of PAC on proper lung function on A. suum infected pigs. Thus, in contrast to some rodent studies suggesting beneficial effects of dietary PAC on asthma, our results in the pig model suggest a limited influence on asthmatic diseases in the respiratory tract in pigs. However, PAC had a significant modulatory effect on pig intestinal gene expression suggesting a primarily gut-localized effect of PAC. Thus, PAC may play a role in maintaining gut health during enteric infection in pigs and humans. These results shed further light on the mechanisms underlying the health-promoting properties of PAC-rich foods, and may aid in the design of novel dietary supplements to regulate mucosal inflammatory responses in the gastrointestinal tract.

Technical Abstract: Proanthocyanidins (PAC) are dietary polyphenols with putative anti-inflammatory and immunomodulatory effects. However, whether dietary PAC can regulate type-2 immune function and inflammation at mucosal surfaces remains unclear. Here, we investigated if diets supplemented with purified PAC modulated pulmonary and intestinal mucosal immune responses during infection with the helminth parasite Ascaris suum in pigs. A. suum infection induced a type-2 biased immune response in lung and intestinal tissues, characterized by pulmonary granulocytosis, increased Th2/Th1 T cell ratios in tracheal-bronchial lymph nodes, intestinal eosinophilia, and modulation of genes involved in mucosal barrier function and immunity. Whilst PAC had only minor effects on pulmonary immune responses, RNA-sequencing of intestinal tissues revealed that dietary PAC significantly enhanced transcriptional responses related to immune function and antioxidant responses in the gut of both naïve and A. suum-infected animals. A. suum infection and dietary PAC induced distinct changes in gut microbiota composition, primarily in the jejunum and colon, respectively. Notably, PAC consumption substantially increased the abundance of Limosilactobacillus reuteri. In vitro experiments with porcine macrophages and intestinal epithelial cells supported a role for both PAC polymers and PAC-derived microbial metabolites in regulating oxidative stress responses in host tissues. Thus, dietary PAC may have distinct beneficial effects on intestinal health during infection with mucosal pathogens, while having a limited activity to modulate naturally-induced type-2 pulmonary inflammation. Our results shed further light on the mechanisms underlying the health-promoting properties of PAC-richfoods, and may aid in the design of novel dietary supplements to regulate mucosal inflammatory responses in the gastrointestinal tract.