Abstract
Akkermansia muciniphila is widely considered a next-generation beneficial microbe. This bacterium resides in the mucus layer of its host and regulates intestinal homeostasis and intestinal barrier integrity by affecting host signaling pathways. However, it remains unknown how the expression of genes encoding extracellular proteins is regulated in response to dynamic mucosal environments. In this study, we elucidated the effect of mucin on the gene expression and probiotic traits of A. muciniphila. Transcriptome analysis showed that the genes encoding most mucin-degrading enzymes were significantly upregulated in the presence of mucin. By contrast, most genes involved in glycolysis and energy metabolic pathways were upregulated under mucin-depleted conditions. Interestingly, the absence of mucin resulted in the upregulation of 79 genes encoding secreted protein candidates, including Amuc-1100 as well as members of major protein secretion systems. These transcript level changes were consistent with the fact that administration of A. muciniphila grown under mucin-depleted conditions to high-fat diet-induced diabetic mice reduced obesity and improved intestinal barrier integrity more efficiently than administration of A. muciniphila grown under mucin-containing conditions. In conclusion, mucin content in the growth medium plays a critical role in the improvement by A. muciniphila of high-fat diet-induced obesity, intestinal inflammation, and compromised intestinal barrier integrity related to a decrease in goblet cell density. Our findings suggest the depletion of animal-derived mucin in growth medium as a novel principle for the development of A. muciniphila for human therapeutics.
Highlights
The gastrointestinal (GI) tract harbors complex and diverse microorganisms, termed the gut microbiota, establishing symbiotic interactions between the gut microbiota and the host (Hooper et al, 2012)
Among the 1,126 Differentially expressed genes (DEGs) between the mucin (+) and (−) conditions (Supplementary Table S2), 583 genes were downregulated and 543 genes were upregulated in mucin (−) conditions compared to mucin (+) conditions; the DEGs exhibited a considerable dynamic range of gene expression, with fold changes ranging from 0.03-to 41.01-fold (Figure 1D)
Considering that mucin is composed of heavily O-glycosylated glycoproteins, these results indicate that genes involved in mucin-degrading processes were overexpressed under mucin (+) conditions
Summary
The gastrointestinal (GI) tract harbors complex and diverse microorganisms, termed the gut microbiota, establishing symbiotic interactions between the gut microbiota and the host (Hooper et al, 2012). Gut microbes affect mucus composition by degrading mucin and releasing bioactive factors that can alter the gene expression of mucin-producing host cells (Deplancke and Gaskins, 2001; Johansson et al, 2011; Ottman et al, 2012). Due to these significant mucus–microbiota interactions, the mucus layer plays an essential role in shaping the mucus barrier and composition of the gut microbiota (Johansson et al, 2015). Substantial evidence has demonstrated that the host–microbiota interaction has a critical role in obesity and other disorders by affecting several homeostatic (Cani et al, 2012; Everard et al, 2013), metabolic (Cani et al, 2007, 2008), and other physiological interactions with the hosts (Sommer and Bäckhed, 2013)
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