Akkermansia muciniphila in Inflammatory Bowel Disease and Colorectal Cancer
Akkermansia muciniphila (A. muciniphila) is a Gram-negative anaerobic bacterium first isolated and identified from the feces of a healthy Caucasian woman at Wageningen University in 2004. This bacterium stably colonizes the human gut approximately one year after birth and constitutes 1% to 4% of the total gut microbiota. A. muciniphila specializes in the degradation of mucin, a glycoprotein found in mucus, which it uses as its sole source of carbon and nitrogen. The bacterium is predominantly found in the host’s intestinal mucosal layer, with the highest abundance in the cecum, where mucin production is most active. Although mucin degradation is typically a pathogen-like behavior, A. muciniphila does not exhibit pathogenicity. It resides only in the outer mucosal layer and does not penetrate the inner mucosal layer. Recent studies have revealed that A. muciniphila plays a significant role in maintaining gut homeostasis.
A. muciniphila and Gut Microbiota Dysbiosis
Dysbiosis, or imbalance, of the gut microbiota has been closely linked to the development and progression of inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD). Colorectal cancer (CRC), particularly colitis-associated colorectal cancer (CAC), is also intricately associated with IBD, which is a significant risk factor for CRC. Interestingly, the abundance of A. muciniphila is inversely correlated with metabolic disorders, which are known to increase the risk of CRC. Supplementation with A. muciniphila, specific proteins from its outer membrane (Amuc_1100), secreted proteins (such as glucagon-like peptide-1-inducing protein), or extracellular vesicles has been shown to alleviate metabolic diseases in both humans and mice. These findings suggest that A. muciniphila is a beneficial member of the gut microbiota, capable of modulating various disorders. However, the role of A. muciniphila in IBD and CRC remains inconclusive, as environmental factors such as diet, probiotics, and medications significantly influence the composition of the gut microbiome.
A. muciniphila in Intestinal Inflammation and Tumorigenesis
Lower colonization and abundance of A. muciniphila have been observed in patients with UC and CD. Similarly, experimental colitis induced by dextran sulfate sodium (DSS) or 2,4,6 trinitrobenzenesulfonic acid (TNBS) in animal models also showed a decreased abundance of A. muciniphila. In azoxymethane (AOM)/DSS-induced CAC, a disruption of the gut microbiota was noted, characterized by a higher abundance of harmful bacteria (such as Desulfovibrio and Helicobacter) and a lower abundance of beneficial bacteria (including Lactobacillus, Bifidobacterium, A. muciniphila, and Faecalibaculum). Furthermore, the abundance of A. muciniphila in colon biopsies was modestly and inversely correlated with baseline trimethylamine N-oxide content, a known risk factor for CRC. Previous studies have shown that A. muciniphila could distinguish CRC and AOM/DSS-induced CAC from healthy controls due to its reduced abundance. However, some studies have reported contradictory findings, with an increased abundance of A. muciniphila observed in patients with CRC. Additionally, the abundance of A. muciniphila was found to be significantly increased in colitis-prone mice with certain gene mutations (such as muc2) or knockouts, such as interleukin (IL)-10. These discrepancies may be partly explained by differences in health state, disease activity, and gene functions. Therefore, large-scale human studies, animal studies, and clinical trials are needed to establish the causality between A. muciniphila and IBD and CRC.
Dietary Interventions Targeting A. muciniphila
Diet plays a crucial role in modulating the gut microbiota, metabolome, and gut immunity. Ketogenic diets have been found to alleviate colitis by reducing the number of colonic group 3 innate lymphoid cells through alterations in the gut microbiome, with a reproducible increase in A. muciniphila abundance. Fermented foods have been shown to protect against colitis induced by pathogenic bacteria or DSS by increasing the abundance of A. muciniphila. Extracts from various fruits, vegetables, and meats exhibit inhibitory effects on colitis and augment the abundance of A. muciniphila. Phytochemicals such as caffeic acid derivatives, myricetin, resveratrol, teasaponin, and polysaccharides have been observed to enrich A. muciniphila and provide beneficial effects in colitis mice. Conversely, barley leaf insoluble dietary fiber and egg white peptides ameliorated colitis while inhibiting the expansion of A. muciniphila. Host-derived substances, including primary bile acids, secondary bile acids, vitamin D, and α-ketoglutarate, have been shown to boost the abundance of A. muciniphila. These substances protect against DSS-induced colitis or inhibit the occurrence and development of CRC by regulating A. muciniphila-mediated colon barrier integrity and immunomodulatory effects.
Probiotics and A. muciniphila
An increasing number of probiotics are being used to improve IBD and CRC by regulating the immune response and altering the gut microbiota. Single probiotic treatments, such as Lactobacillus pentosus, have been shown to alleviate colitis symptoms by modulating the immune response, accompanied by increased A. muciniphila abundance and short-chain fatty acid (SCFA) production. Probiotic mixtures containing Bifidobacterium infantis, Lactobacillus acidophilus, Enterococcus faecalis, and Bacillus cereus have been found to improve DSS-induced colitis by rebuilding the structure of the gut microbiota, particularly by increasing the abundances of Bifidobacterium, Akkermansia, and Lactobacillus. Additionally, probiotics alone or in combination with therapeutic proteins or plant extracts have been shown to reduce tumor volume, inhibit tumor growth, and increase the abundance of A. muciniphila in CAC mice. However, some probiotics exert anti-inflammatory activities while significantly decreasing the abundance of A. muciniphila, indicating that probiotic effectiveness can be species- and disease-specific. The underlying mechanisms involve direct interactions with intestinal epithelial cells and immune cells, as well as interactions with other gut microbiota constituents, such as A. muciniphila, to support gut homeostasis by producing beneficial metabolites.
Pharmaceutical Interventions Targeting A. muciniphila
Exposure to antibiotics is a major stressor of the intestinal microbiota and significantly modulates the relative abundance of A. muciniphila. The interaction between gut microbes and commonly used non-antibiotic drugs is complex and bidirectional. Enrichment of A. muciniphila following metformin treatment has been found to coincide with alleviated colonic inflammation in colitis mice. TAK-242 (resatorvid), an inhibitor of Toll-like receptor 4 (TLR4), has been reported to exhibit therapeutic potential in UC by regulating the gut microbiota and promoting the growth of A. muciniphila. Hyaluronic acid-bilirubin nanomedicine has been associated with the enrichment of A. muciniphila, regulation of innate immune responses, and potent therapeutic efficacy against colitis. Inhibition of human antigen R (HuR) by MS-444 has been shown to increase the abundance of A. muciniphila and attenuate tumorigenesis in APC^Min/+ mice, a model of familial adenomatosis polyposis and CRC. Expansion of A. muciniphila is also associated with the anti-inflammatory and anti-tumor effects of various traditional Chinese medicines. However, some medications, such as berberine and alisol B 23-acetate, prevent the development of CAC while decreasing the relative abundance of A. muciniphila. These results suggest that A. muciniphila can serve as an intermediary for pharmaceutical interventions in IBD and CRC.
Intervention of A. muciniphila in IBD and CRC
Emerging evidence indicates that A. muciniphila may be a potential probiotic agent for ameliorating colitis and CRC. Gavage of A. muciniphila (strain DSM 22959) has been shown to accelerate recovery from colitis in mice fed a casein diet by decreasing the disease activity index and increasing mucus thickness and muc2 mRNA levels. The A. muciniphila type strain ATCC BAA-835 has been reported to alleviate DSS-induced colitis through microbe-host interactions and improving the microbial community. Both the murine A. muciniphila strain (designated 139) and the type strain ATCC BAA-835 have been shown to exert anti-inflammatory effects on chronic colitis, with the latter exhibiting stronger effects. Oral administration of A. muciniphila to low-cellulose diet-fed mice elevated crypt length, increased goblet cell numbers, and ameliorated DSS-induced colitis. A. muciniphila-derived extracellular vesicles, Amuc_1100, and pasteurized bacteria (strain ATCC BAA-835) have been shown to improve colitis by regulating intestinal barrier integrity and the immune response. Oral administration of A. muciniphila elevated systemic anti-aging and anti-cancer metabolite levels, such as SCFAs, polyamines, and multiple bile acids, with more pronounced effects observed after pasteurized A. muciniphila treatment than after live bacterium treatment. Pasteurized A. muciniphila and Amuc_1100 have been shown to blunt AOM/DSS-induced CAC by expanding CD8+ T cells and enhancing their cytotoxic effects. However, A. muciniphila (strain ATCC BAA-835) failed to promote short-term intestinal inflammation in gnotobiotic IL10-deficient mice, and repeated oral gavage of A. muciniphila induced spontaneous colitis in germ-free IL10-deficient mice, suggesting that A. muciniphila can act as a pathobiont to promote colitis in genetically susceptible hosts. Therefore, genotypes and disease states should be considered when evaluating the validity and feasibility of microbiota-based therapies for IBD or CRC.
Conclusions and Outlook
Dysbiosis of the gut microbiota is a hallmark of intestinal disorders, and the symbiotic equilibrium between the host and A. muciniphila is disrupted in IBD and CRC. Increased levels of A. muciniphila are associated with the prevention and protection against IBD and CRC following dietary ingredients, nutrients, probiotics, and medication intervention. Despite these therapeutic advantages, a negative correlation between their beneficial effects and A. muciniphila has also been observed in some animal studies. Thus, it would be best to propose A. muciniphila as both a “friend and foe” until additional research and clinical data emerge. However, the application of A. muciniphila, A. muciniphila-derived extracellular vesicles, and the therapeutic protein Amuc_1100 has been shown to effectively protect against IBD and CRC, and the cellular and molecular mechanisms need further investigation. The discovery of new strains or derivatives of A. muciniphila will reveal new approaches for biomolecule-isolated probiotics to treat intestinal disorders. Overall, A. muciniphila has brought new hope for the use of probiotics in the prevention and treatment of intestinal diseases.
doi.org/10.1097/CM9.0000000000001829
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