Mechanistic insights into the attenuation of intestinal inflammation and modulation of the gut microbiome by krill oil using in vitro and in vivo models

Authors: LIU, FANG - Ocean University Of China; Smith, Allen; Solano-Aguilar, Gloria; Wang, Thomas - Tom; Pham, Quynhchi; TANG, QINGJUAN - Ocean University Of China; Urban, Joseph; XUE, CHANGHU - Ocean University Of China; Li, Robert

Submitted to: Microbiome
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/17/2020
Publication Date: 6/4/2020
Citation: Liu, F., Smith, A.D., Solano Aguilar, G., Wang, T.T., Pham, Q., Tang, Q., Urban Jr, J.F., Xue, C., Li, R.W. 2020. Mechanistic insights into the attenuation of intestinal inflammation and modulation of the gut microbiome by krill oil using in vitro and in vivo models. Microbiome. 8:83. https://doi.org/10.1186/s40168-020-00843-8.
DOI: https://doi.org/10.1186/s40168-020-00843-8

Interpretive Summary: Parasitic infection is one of the key factors negatively affecting food animal production. The infection can result in mucosal damage, disrupt lipid metabolism in the host tissue and affect gut permeability and intestinal inflammation. In this study, we investigated the effect of krill oil, a natural product rich in omega 3 polyunsaturated fatty acids and a potent antioxidant astaxanthin, on the gut microbiome and its potential to mitigate the tissue damage induced by parasitic infection. We identified biological pathways through which krill oil ameliorates intestinal inflammation and provided novel insight into the mechanisms via which krill oil improves gut microbial dysbiosis. Our findings will facilitate the development of novel dietary supplements able to improve gut health.

Technical Abstract: Background: The anti-inflammatory property of '-3 polyunsaturated fatty acids (PUFA) has been exploited in the prevention and management of inflammatory bowel diseases (IBD) with promising results. However, it remains unclear if PUFA play a significant role in the resolution of inflammation and promote mucosal healing. Krill oil (KO) is a natural product rich in PUFA and the potent antioxidant, astaxanthin. In this study, we attempted to understand the mechanisms through which KO modulates the gut microbiome and metabolome using in vitro and in vivo colitis models and a multi-omics based approach. Results: KO significantly decreased LPS-induced IL1ß and TNFa expression in human macrophages in vitro in a dose-dependent manner by regulating a broad spectrum of signaling pathways, such as NF-'B and NOD-like receptor signaling. KO displayed a synergistic effect with COX2 and IKK2 inhibitors in attenuating inflammation. Moreover, KO was also involved in the proper resolution of inflammation by promoting M2 polarization and enhancing macrophage mediated intracellular bacterial killing. KO supplementation mitigated intestinal mucosal damage induced by helminth infection and partially restored microbial dysbiosis. KO supplementation reduced the abundance of Rickettsiales and several species of Lactobacillus, which were among the important features identified by Random Forests analysis contributing to classification accuracy for KO supplement. Several microbial signatures with strong predictive power for the status of both infection and supplementation were identified. The inhibitory effect of KO on histidine metabolism was identified using untargeted metabolomics. KO supplementation significantly reduced several key metabolites related to histamine metabolism by suppressing the expression of a gene encoding the rate-limiting L-histidine decarboxylase in colon mucosa and reducing histamine biosynthesis of microbial origin. Moreover, the pro-resolving properties of KO were validated using a Th1-inducing Citrobacter rodentium colitis murine model. Further, microbial signatures with high prediction accuracy for colitis related pathophysiological traits were identified in mice. Conclusion: The findings from this study provided a mechanistic basis for optimizing microbiome-inspired alternative therapeutics in the management of IBD. The microbial signatures identified, particularly those with strong predictive accuracy for colitis phenotypes, may facilitate the development of biomarkers for dietary intervention in colitis models.