Akkermansia muciniphila (A. muciniphila), a type of Gram-negative anaerobe, was first
isolated and identified from the feces of a healthy Caucasian woman at Wageningen
University in 2004.[1] It can stably colonize the human gut 1 year after birth and
accounts for 1%–4% of the total gut microbiota. A. muciniphila specializes in the
degradation of mucin (the glycoprotein in mucus) and uses the mucin as the sole source
of carbon and nitrogen. A. muciniphila is abundant in the host intestinal mucosal
layer, with the greatest abundance in the cecum, where most mucin is produced.[2]
Although degradation of mucin is a pathogen-like behavior; A. muciniphila does not
show any pathogenicity, it resides only in the outer mucosal layer and does not reach
the inner mucosal layer. Recently, several studies have revealed that A. muciniphila
has important regulatory effects on gut homeostasis.
Dysbiosis of the gut microbiota has been associated with the development and progression
of inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's
disease (CD). Colorectal cancer (CRC), including colitis-associated colorectal cancer
(CAC), is inseparably associated with IBD, which is an important influencing factor
for the occurrence of CRC. The abundance of A. muciniphila is inversely associated
with metabolic disorders, which could increase the risk of CRC. Interestingly, supplementation
with A. muciniphila, specific proteins from the outer membrane (Amuc_1100), secreted
proteins (glucagon-like peptide-1-inducing protein), or extracellular vesicles could
alleviate metabolic disease in humans and mice.[3,4] These results indicate that A.
muciniphila is a member of beneficial microbiota in terms of modulating disorders.
However, the role of A. muciniphila in IBD and CRC remains inconclusive. Environmental
factors, such as diet, probiotics, and medications, play a substantial role in shaping
the gut microbiome composition. Therefore, we explored the association between A.
muciniphila and IBD and CRC and addressed the important role of A. muciniphila in
the anti-inflammatory and anti-cancer effects of dietary agents, probiotics, and medications.
Richness of A. muciniphila in intestinal inflammation and tumor: Lower colonization
and abundance of A. muciniphila were also observed in patients with UC and CD.[5]
In agreement with data regarding humans, the abundance of A. muciniphila was also
decreased in experimental colitis induced by dextran sulfate sodium (DSS) or 2,4,6
trinitrobenzenesulfonic acid (TNBS).[6] Moreover, disruption of the gut microbiota
was observed in azoxymethane (AOM)/DSS-induced CAC, reflected by a higher abundance
of harmful bacteria (such as Desulfovibrio and Helicobacter) and a lower abundance
of beneficial bacteria (such as Lactobacillus, Bifidobacterium, A. muciniphila, and
Faecalibaculum). Moreover, the abundance of A. muciniphila in colon biopsies was modestly
and inversely correlated with baseline trimethylamine N-oxide content that has been
identified as a risk factor for CRC.[7] Our previous study revealed that A. muciniphila
could distinguish CRC and AOM/DSS-induced CAC from healthy controls due to a reduced
abundance.[8] However, several studies on the effects of A. muciniphila in IBD and
CRC have drawn opposite conclusions. Limited human studies have revealed an increased
abundance of A. muciniphila in patients with CRC [Supplementary Table 1]. In addition,
the abundance of A. muciniphila has been found to be significantly increased in colitis-prone
mice with certain gene mutations (muc2) or knockouts, such as interleukin (IL)-10.[6]
This discrepancy could be partly explained by health state, disease activity, and
gene functions. Consequently, large-scale human studies, animal studies, and clinical
trials are needed to verify the causality between A. muciniphila and IBD and CRC.
A. muciniphila, dietary target for the treatment of IBD and CRC: Diet may have a role
in the modulation of the microbiota, the metabolome, and gut immunity. Ketogenic diets
have been found to alleviate colitis by reducing the number of colonic group 3 innate
lymphoid cells through altering the gut microbiome, with a reproducible increase in
A. muciniphila abundance. Fermented foods could protect against colitis induced by
pathogenic bacteria or DSS by increasing the abundance of A. muciniphila. Extracts
from various fruits, vegetables, and meat exhibit inhibitory effects on colitis and
augment the abundance of A. muciniphila [Supplementary Table 2]. Moreover, enrichment
of A. muciniphila in association with beneficial effects was observed in colitis mice
treated with phytochemicals, such as caffeic acid derivatives, myricetin, resveratrol,
teasaponin, and polysaccharides. Barley leaf insoluble dietary fiber and egg white
peptides ameliorated colitis, while they inhibited the expansion of A. muciniphila
[Supplementary Table 2]. Host-derived substances, such as primary bile acids, secondary
bile acids, vitamin D, and α-ketoglutarate, could boost the abundance of A. muciniphila.
They have been proven to protect against DSS-induced colitis or inhibit the occurrence
and development of CRC by regulating A. muciniphila-mediated colon barrier integrity
and immunomodulatory effects [Supplementary Table 3].
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 could alleviate the colitis symptoms via modulation
of the immune response, accompanied by increased A. muciniphila abundance and short-chain
fatty acid (SCFA) [Supplementary Table 2]. Moreover, probiotic mixtures of 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,
especially increased abundances of Bifidobacterium, Akkermansia, and Lactobacillus.[9]
In addition, several studies have revealed that probiotics alone or in combination
with therapeutic proteins or plant extracts reduced tumor volume, inhibited tumor
growth, and increased the abundance of A. muciniphila in CAC mice [Supplementary Table
3]. However, several probiotics exert anti-inflammatory activities, while their administration
significantly decreases the abundance of A. muciniphila.[10] These results indicate
that probiotic effectiveness can be species- and disease-specific. The underlying
mechanism involved in direct interaction with intestinal epithelial cells and immune
cells has been proposed. In addition, they may also interact with other gut microbiota
constituents, such as A. muciniphila, to support gut homeostasis by producing beneficial
metabolites.
A. muciniphila is a potential target for pharmaceutical interventions: A major known
stressor of the intestinal microbiota is exposure to antibiotics, which significantly
modulate the relative abundance of A. muciniphila.[6] 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 frequently coincide
with alleviated colonic inflammation in colitis mice.[11] TAK-242 (resatorvid), an
inhibitor of Toll-like receptor 4 (TLR4), was 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 found to be associated with enrichment
of A. muciniphila, regulate innate immune responses, and exert potent therapeutic
efficacy against colitis. HuR inhibition of human antigen R by MS-444 could increase
the abundance of A. muciniphila and attenuate tumorigenesis in APCMin/+ mice, a model
of familial adenomatosis polyposis and CRC. Expansion of A. muciniphila is associated
with the anti-inflammatory and anti-tumor effects of various traditional Chinese medicines
[Supplementary Table 2]. Berberine and alisol B 23-acetate prevented the development
of CAC, whereas they decreased the relative abundance of A. muciniphila. Although
these results support the positive or negative influences of medication on the gut
microbiota in hosts with IBD and CRC, A. muciniphila can serve as an intermediary
for pharmaceutical interventions of 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) accelerated the recovery from colitis in the
mice fed the casein diet by decreasing the disease activity index and increasing the
mucus thickness and muc2 mRNA level.[12]
A. muciniphila type strain ATCC BAA-835 has been shown to alleviate DSS-induced colitis
via microbe–host interactions and improving the microbial community.[13] Both the
murine A. muciniphila strain (designated 139) and the A. muciniphila type strain ATCC
BAA-835 have been reported to exert anti-inflammatory effects on chronic colitis.[14]
However, the anti-inflammatory effects of strain ATCC BAA-835 were stronger than those
of strain 139, emphasizing the importance of the further study of the function of
A. muciniphila at the strain level. Oral administration of A. muciniphila to low-cellulose
diet-fed mice elevated crypt length, increased goblet cell numbers, and ameliorated
colitis induced by DSS.[15]
A. muciniphila-derived extracellular vesicles, Amuc_1100, and pasteurized bacteria
(strain ATCC BAA-835) could improve colitis via regulation of intestinal barrier integrity
and the immune response.[8,16] Oral administration of A. muciniphila elevated systemic
anti-aging and anti-cancer metabolite levels, such as SCFAs, polyamines, and multiple
bile acids. These effects were more pronounced after pasteurized A. muciniphila treatment
than after live bacterium treatment. Our previous study showed that pasteurized A.
muciniphila and Amuc_1100 could blunt AOM/DSS-induced CAC by expanding CD8+ T cells
and enhancing their cytotoxic effects.[8] Targeted regulation of the intestinal flora,
especially A. muciniphila, might be a novel and promising therapeutic strategy for
preventing and curing IBD and CRC. However, A. muciniphila (strain ATCC BAA-835) failed
to promote short-term intestinal inflammation in gnotobiotic IL10-deficient mice.
Moreover, repeated oral gavage of A. muciniphila could induce spontaneous colitis
in germ-free IL10-deficient mice, suggesting that A. muciniphila can act as a pathobiont
to promote colitis in a genetically susceptible host.[17] Thus, genotypes and disease
states should be considered to evaluate 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 host-A. muciniphila symbiotic equilibrium is disrupted in IBD and
CRC [Figure 1]. Increased levels of A. muciniphila are associated with the prevention
of and protection against IBD and CRC following dietary ingredients, nutrients, probiotics,
and medication intervention. Despite these impressive 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 have emerged. However,
the application of A. muciniphila, A. muciniphila-derived extracellular vesicles,
and the therapeutic protein Amuc_1100 has been revealed to effectively protect against
IBD and CRC, and the cellular and molecular mechanism needs extensive further investigation.
In addition, 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 for the prevention
and treatment of intestinal diseases.
Figure 1
The role of A. muciniphila in IBD and CRC. Decreased abundance of A. muciniphila was
observed in patients and animal models with IBD or CRC. Increased level of A. muciniphila
was associated with the prevention and protection in IBD and CRC following dietary
ingredients, nutrients, probiotics, and medication intervention. Supplementation with
A. muciniphila, A. muciniphila-derived extracellular vesicles, and the therapeutic
protein Amuc_1100 could also protect against IBD and CRC by increasing the production
of SCFA and modulation of an immune response. A. muciniphila: Akkermansia muciniphila;
CRC: Colorectal cancer; IBD: Inflammatory bowel disease; SCFA: Short-chain fatty acid;
TNFα: Tumor necrosis factor α; IFNγ: Interferon γ; IL: Interleukin.
Funding
The work was supported by the grants from the National Natural Science Foundation
of China (Nos. 81973096 and 81502801) and the Jiangsu Province Natural Science Foundation
(No. BK20201354).
Conflicts of interest
None.
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