The effect of bile acids on the growth and global gene expression profiles in Akkermansia muciniphila

Abstract

Akkermansia muciniphila is a prominent member of the gut microbiota and the organism gets exposed to bile acids within this niche. Several gut bacteria have bile response genes to metabolize bile acids or an ability to change their membrane structure to prevent membrane damage from bile acids. To understand the response to bile acids and how A. muciniphila can persist in the gut, we studied the effect of bile acids and individual bile salts on growth. In addition, the change in gene expression under ox-bile condition was studied. The growth of A. muciniphila was inhibited by ox-bile and the bile salts mixture. Individual bile salts have differential effects on the growth. Although most bile salts inhibited the growth of A. muciniphila, an increased growth was observed under culture conditions with sodium deoxycholate. Zaragozic acid A, which is a squalene synthase inhibitor leading to changes in the membrane structure, increased the susceptibility of A. muciniphila to bile acids. Transcriptome analysis showed that gene clusters associated with an ABC transporter and RND transporter were upregulated in the presence of ox-bile. In contrast, a gene cluster containing a potassium transporter was downregulated. Membrane transporter inhibitors also decreased the tolerance to bile acids of A. muciniphila. Our results indicated that membrane transporters and the squalene-associated membrane structure could be major bile response systems required for bile tolerance in A. muciniphila. Key points • The growth of Akkermansia muciniphila was inhibited by most bile salts. • Sodium deoxycholate increased the growth of A. muciniphila. • The genes encoding transporters and hopanoid synthesis were upregulated by ox-bile. • The inhibitors of transporters and hopanoid synthesis reduced ox-bile tolerance.

The interaction of Akkermansia muciniphila with host-derived substances, bacteria and diets

“…As described above in this review, UDCA treatment can increase the abundance of A. muciniphila in mice (Van den Bossche et al 2017). Our group showed that DCA increased the growth of A. muciniphila in vitro and its bile acid-resistant metabolism (Hagi et al 2020). These studies indicate that the change in bile acids, especially UDCA, by the treatment of camu camu could increase the abundance of A. muciniphila, and the interaction between secondary bile acids and A. muciniphila might affect the host bile acid metabolism.…”

“…Bile metabolism is strongly associated with gut microbiota because primary bile acids secreted by the host are converted to secondary bile acids by gut bacteria-harbouring bile modification enzymes associated with bile hydroxylation and deconjugation (Wahlström et al 2016). The growth of A. muciniphila is increased by a secondary bile acid (deoxycholic acid (DCA)) (Hagi et al 2020). DCA also increases the expression of MUC2 in human colon carcinoma cells (Song et al 2005).…”

“…Secondary bile acid may be a key bile acid for A. muciniphila to survive in the gut. A part of the bile acid-resistant mechanism in A. muciniphila has been clear (Hagi et al 2020). Transcriptomic analysis showed that the treatment of ox-bile upregulated the expression of genes encoding HlyD (membrane fusion protein)-ABC and RND (resistance-nodulation-cell division protein family) type transporters.…”

The antioxidant tempol transforms gut microbiome to resist obesity in female C3H mice fed a high fat diet

“…We also found a very interesting association between Akkermansia muciniphila and the secondary bile acid DCA. It has been reported that DCA increases the growth of Akkermansia muciniphila and helps in its survival in the gut [ 70 ]. In our experiments, DCA in Tempol treated animals was found to be substantially increased.…”

Bacterial succession and specialization within the poultry gastrointestinal tract

“…7α/β-dehydroxylation can also serve as an electronaccepting reaction for these bacteria, producing an NADPH molecule (101,173). Both DCA and LCA act as chemical signals for certain bacteria, leading to the upregulation of genes involved in colonization and growth, as well as triggering biofilm formation and leading to conformational changes to promote gut colonization and persistence (258)(259)(260)(261)(262)(263)(264). While 7α/β-dehydroxylation may be beneficial for some bacterial species, the minimum inhibitory concentration range for LCA and DCA is much lower than for conjugated and unconjugated primary BAs, likely due to the increased hydrophobicity, allowing for a more rapid transit of the secondary BA into the cell and the induction of similar stressors to bacteria (147,150,173,265).…”