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. 2021 Apr;35(4):e21435.
doi: 10.1096/fj.202002215R.

Lack of peptide YY signaling in mice disturbs gut microbiome composition in response to high-fat diet

Aitak Farzi  1   2 , Chi Kin Ip  1   3 , Felicia Reed  1 , Ronaldo Enriquez  1 , Geraldine Zenz  2 , Marija Durdevic  4   5   6 , Lei Zhang  1   3 , Peter Holzer  2 , Herbert Herzog  1   3
Affiliations

Lack of peptide YY signaling in mice disturbs gut microbiome composition in response to high-fat diet

Aitak Farzi et al. FASEB J. 2021 Apr.

Abstract

Peptide YY (PYY), produced by endocrine L cells in the gut, is known for its critical role in regulating gastrointestinal functions as well as satiety. However, how these processes are integrated with maintaining a healthy gut microbiome composition is unknown. Here, we show that lack of PYY in mice leads to distinct changes in gut microbiome composition that are diet-dependent. While under chow diet only slight differences in gut microbiome composition could be observed, high-fat diet (HFD) aggravated these differences. Specifically an increased abundance of the Bacteroidetes phylum with a corresponding decrease of the Firmicutes/Bacteroidetes ratio could be detected in Pyy-knockout (KO) mice in response to HFD. Detailed analysis of the Bacteroidetes phylum further revealed that the Alistipes genus belonging to the Rikenellaceae family, the Parabacteroides belonging to the Tannerellaceae family, as well as Muribaculum were increased in Pyy-KO mice. In order to investigate whether these changes are associated with changed markers of gut barrier and immunity, we analyzed the colonic expression of various pro-inflammatory cytokines, as well as tight junction proteins and mucin 2, and identified increased mRNA expression of the tight junction proteins Cldn2 and Ocel1 in Pyy-KO mice, while pro-inflammatory cytokine expression was not significantly altered. Together these results highlight a critical gene-environment interaction between diet and the gut microbiome and its impact on homeostasis of the intestinal epithelium under conditions of reduced PYY signaling which is commonly seen under obese conditions.

Keywords: food intake; gut hormones; intestinal barrier; intestinal microbiota; obesity.

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Conflict of interest statement

No potential conflicts of interest associated with this article were reported and there has been no significant financial support for this work that could have influenced its outcome.

Figures

FIGURE 1
FIGURE 1
High‐fat diet has a bigger influence on microbiome composition as compared to PYY‐deficiency. Bacterial alpha diversity as assessed by Simpson, Shannon and operational taxonomic units (OTUs) (A). Bacterial communities of controls and Pyy‐KO mice under chow‐fed conditions as well as after 4‐week HFD feeding were clustered using Bray Curtis distance‐based principal coordinates analysis (PCoA). The percentage variation in the plotted principal coordinate (PC) is indicated on the axes (B). Pie charts of the average relative abundances of the bacterial phyla in controls and Pyy‐KO mice on standard chow as well as HFD (C). Most differentially abundant taxa selected by Linear discriminant analysis Effect Size (LEfSe) for diet (D). Green taxa with positive LDA scores enriched in response to HFD. Red taxa with negative LDA scores enriched in response to standard chow diet (D). n = 8‐10
FIGURE 2
FIGURE 2
PYY‐deficiency has an impact on fecal microbiome composition in response to high‐fat diet. Abundance (total sum normalization combined with square root transformation) of the bacterial phyla Firmicutes (A) and Bacteroidetes (B), and Firmicutes/Bacteroidetes ratio (C). Bacterial taxa belonging to Firmicutes that are differentially affected by Pyy‐KO in response to HFD (D, E, F). Bacterial taxa belonging to Bacteroidetes that are differentially affected by Pyy‐KO in response to HFD (G, H). Most differentially abundant taxa selected by Linear discriminant analysis Effect Size (LEfSe) for genotype in response to HFD (I). Green taxa with positive LDA scores enriched in control mice in response to HFD. Red taxa with negative LDA scores enriched in Pyy‐KO mice in response to HFD (I). Data are means ± SEM. + P ≤.1; *P ≤.05; **P ≤.01; ***P ≤.001 for Pyy‐KO versus controls on the same diet or as indicated. n = 8‐10
FIGURE 3
FIGURE 3
Pyy‐knockout increases food intake without affecting fat mass in response to high‐fat diet. Daily spontaneous/basal food intake during fed state expressed as kcal d‐1 in control and Pyy‐KO mice under standard chow and HFD (A). Absolute bodyweight measured weekly in controls and Pyy‐KO mice (B). Whole body fat mass determined by DXA under standard chow and HFD (C). Data are means ± SEM. *P ≤.05; ***P ≤.001 for Pyy‐KO versus controls on the same diet or as indicated. n = 8‐10
FIGURE 4
FIGURE 4
PYY‐deficiency increases Cldn2, Ocel1, and Y‐receptor mRNA expression. mRNA expression of Muc2 and tight junction proteins (A), pro‐inflammatory cytokines (B), and Y‐receptors (C). Correlations of abundance of bacterial taxa with Ocel1 (D), Ifn‐ɣ (E), and Il‐18 (F). Data are means ± SEM. + P ≤.1; *P ≤.05 for Pyy‐KO versus controls. n = 8‐10
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