The role of Akkermansia muciniphila in the regulation of inflammatory bowel disease: intestinal immunity and metabolism.

Although there has been extensive research on the utilization of A. muciniphila in animal models, the assessment of its safety in the clinic is limited ( 121 , 122 ). In 2019, Depommier et al. conducted the initial utilization of A. muciniphila in humans through a randomized, double-blind, placebo-controlled trial with overweight/obese and insulin-resistant volunteers. Their findings indicated that the daily oral supplementation of 10 10 A . muciniphila bacteria for three months, whether in live or pasteurized form, was both safe, well-received and improved several metabolic parameters ( 123 ). In 2021, the EFSA Panel on Nutrition, Novel Foods, and Food Allergens issued a scientific opinion on the safety of pasteurized A. muciniphila (strain ATCC BAA-835T) as a novel food. The Panel determined that the pasteurized A. muciniphila at a daily intake of 3.4ake 10 cells is safe for the target population as long as the quantity of viable A. muciniphila remains under 10 cells/g in the novel food, which opened doors for its application into food supplements and medical nutrition ( 124 ). An analysis of the WHO International Clinical Trials Registry Platform and relevant literature indicates that research on A. muciniphila has predominantly focused on the effects of its live and pasteurized forms on metabolic disorders, including overweight, obesity, and insulin resistance ( 125 – 127 ). A smaller number of clinical studies have explored its impact on muscle strength and respiratory symptoms ( 128 , 129 ). However, the clinical trials assessing the gastrointestinal inflammation are presently restricted to the impact of A. muciniphila on irritable bowel syndrome ( 130 ). There are few experiments to demonstrate its safety in the treatment of IBD. Hence, further clinical research is essential to confirm the potential and safety of A. muciniphila in mitigating intestinal inflammatory diseases.

The IBD, including Crohn’s disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disease driven by inappropriate intestinal immune activation. The etiology of IBD is complex and multifactorial, primarily involving genetic and environmental factors, which perturb the homeostasis between the gut microbiome and the host immune system ( Figure 1 ) ( 1 , 2 ). The burden of IBD across the globe is still considerable ( 3 ). Patients with IBD have an increased risk of colorectal cancer, which is the third most common cancer in the world (9.6% of all cancers globally) ( 4 – 6 ). Conventional IBD treatment methods involve medication therapy, e.g., aminosalicylates, corticosteroids, antibiotics, biological agents, small molecule drugs, and surgical treatment if necessary ( 7 ). Researchers have identified that patients with IBD exhibit altered bacterial diversity and abundance compared to healthy individuals. In addition, the Gram-negative bacteria exhibit the main difference in fecal microbiota between UC patients and healthy individuals ( 8 ). The precise mechanisms of host-microbiota crosstalk in IBD remain incompletely elucidated. To address this, multi-omics approaches are being leveraged to systematically decode these complex cross-talk networks ( 9 – 13 ). Consequently, modulating the gut microbiota has emerged as a promising strategy for restoring homeostasis and advancing novel therapeutic interventions for IBD ( 8 , 14 , 15 ). The factors involved in the pathogenesis of IBD. A. muciniphila is a species of the genus Akkermansia , which belongs to the family Akkermansiaceae in the phylum Verrucomicrobiota . It was initially isolated from healthy female feces in 2004 and cultivated in a specific medium containing mucin as the sole carbon and nitrogen source ( 16 , 17 ). A. muciniphila is a Gram-negative commensal bacterium that is dominantly distributed in the intestinal mucus layer and fecal samples of both human and animals. Its relative abundance is approximately 1-4% (10 6– 10 8 CFU/g) of total bacteria in feces of healthy adults ( 18 , 19 ). A. muciniphila in the intestinal tract is known as a mucolytic specialist, primarily degrading mucins ( 20 , 21 ). This process not only leads to the renewal of mucins but also results in the release of oligosaccharides and short-chain fatty acids (SCFAs), which all play an important role in microbial community and host health ( 16 , 22 – 27 ). Several studies have demonstrated that the abundance of A. muciniphila is significantly altered in both IBD patients and model mice compared with healthy controls ( 28 – 30 ). Recent studies have demonstrated that the gut microbiota composition in UC patients during long-term remission closely resembles that of healthy individuals. Notably, the abundance of A. muciniphila increases significantly during the remission phase compared to the active phase of CD ( 31 , 32 ). The live and pasteurized A. muciniphila , as well as its components, e.g., outer membrane proteins, extracellular vesicles, have been evidenced to be relevant to IBD, which predominantly influence the immune responses, gut microbiota, metabolism, and the integrity of the intestinal barrier ( 30 , 33 – 37 ). However, the role of A. muciniphila in IBD remains contentious, as it may exert pro-inflammatory effects under specific conditions. These include bacterial strain differences; host species disparities (e.g., human, mouse); the presence of pathogen-induced inflammation (such as Salmonella Typhimurium infection); reconstitution of the gut microbiota following antibiotic treatment; and increased susceptibility in certain hosts. Such susceptible individuals may include those with polycystic ovary syndrome (PCOS), endometriosis, disrupted gastrointestinal motility, as well as people carrying genetic defects (e.g., IL-10 or HNF4A deficiency) ( 38 – 42 ). Although A. muciniphila has shown promise in the intervention of IBD, its specific mechanisms of action remain complex and unexplained. In this review, we outline the interaction of A. muciniphila in IBD with intestinal immunity and gut metabolism. These interactions are crucial for modulating intestinal immune responses, the integrity of the intestinal barrier, the homeostasis of intestinal microbiota, and metabolism.

The pathways of A. muciniphila in mitigating IBD are mainly represented by the regulation of the immune response, gut microbiota homeostasis, and intestinal barrier integrity. The majority of these pathways involve the participation of intestinal cells and microbial metabolism. In the future, more research efforts should be devoted to explore the mechanisms of various components or different forms of A. muciniphila in regulating intestinal cells and metabolism by integrating multi-omics data. In addition, it is equally crucial to investigate how intestinal cells and metabolic factors influence the colonization and abundance of A. muciniphila . This will contribute to a more in-depth and detailed theoretical foundation for the therapeutic application of A. muciniphila in the treatment of IBD. The role of A. muciniphila in intestinal inflammation is occasionally controversial. A. muciniphila generally exerts protective effects in healthy individuals or those with metabolic disorders (e.g., obesity and type 2 diabetes), but it may become pathogenic under specific conditions, such as a disrupted barrier, coexistence with pathogenic bacteria, and susceptible hosts. Furthermore, interspecies differences (e.g., between humans and mice) and strain-specific variations of A. muciniphila itself collectively determine whether it alleviates or exacerbates IBD. It seems that the effectiveness of A. muciniphila in alleviating intestinal inflammation varies among individuals. Currently, both live and pasteurized A. muciniphila , along with their components and secreted products, have demonstrated potential in alleviating IBD, yet these findings are still at the animal level. The A. muciniphila has potential as a next-generation probiotic for disease therapy, but significant safety issues must be resolved before developing clinically available products for IBD treatment.