Akkermansia Muciniphila: Bane or Boon for IBD?

Summary: Akkermansia muciniphila is a commensal bacteria found in healthy human colons that is widely regarded as a promising next-generation probiotic. Researchers have mainly focused on therapeutic potential for obesity and diabetes, but there’s also substantial interest in the field of IBD, particularly for its beneficial effects on gut barrier function. However, a minority of researchers have suggested that Akkermansia muciniphila could worsen colitis. Despite that, most of the evidence thus far suggests that A. muciniphila could potentially be leveraged as a beneficial therapy for IBD and gut health in general once more research has been done.

This post is part of the IBD Index.

Lactobacillus and Bifidobacteria species may still be the darlings of the probiotic world, but there’s a new kid on the block: Akkermansia muciniphila.

This bacteria was isolated for the first time in 2004 (1) so it’s still relatively new to the game, but you can see from this fun trend analysis (2) that research has exploded, especially in the last couple years.

Source: Hojat et al., Global scientific output trend for *Akkermansia muciniphila* research: a bibliometric and scientometric analysis, 2020

So what is Akkermansia muciniphila, and why the interest all of a sudden?

Akkermansia Muciniphila: Fast Facts

Akkermansia muciniphila is part of a normal, healthy microbiome in humans, typically comprising 3-5% of the total bacteria in the gut (which is one of the largest contributions by a single organism, at least that we know of). (3, 4)

It’s a mucosa-associated bacteria, meaning it lives close to the epithelial cells of the intestine, and its preferred food is intestinal mucus (notice the Latin roots “mucin” and “phil” in its name? It literally means mucin-loving!). (1)

Quite a few observational studies have found an association between reduced levels of Akkermansia muciniphila and several disease states, including: (3, 5, 6)

obesity
diabetes
metabolic syndrome
liver disease
autism (7)
aging (8)
asthma (9)
appendicitis (10)

and finally, most relevant to our interests,

ulcerative colitis (11, 12, 13, 14, 15, 16)
Crohn’s disease (17, 18)

Note: As is usually the case, the literature doesn’t reach perfect consensus, and not every analysis has found a negative correlation between A. muciniphila abundance and IBD. For instance, one study found comparable levels of A. muciniphila in patients with IBD vs. healthy controls (with the exception of pediatric Crohn’s disease) (18), and another actually found higher levels of A. muciniphila in pouchitis compared with healthy controls (19). But the vast majority of evidence points to a negative correlation.

There’s also already some fairly promising interventional research investigating A. muciniphila as a therapy for obesity, diabetes, metabolic syndrome, and as a concurrent therapy to increase the efficacy of certain cancer treatments. (3, 5, 20, 21) Of particular note are two pilot trials in humans: one on overweight/obese insulin resistant volunteers and another on patients with type II diabetes. (22, 23) Both of these trials found that supplementation with A. muciniphila was safe and well-tolerated over a 3-month period, and improved glucose control as well as several other markers related to metabolic syndrome.

So that’s a quick and dirty summary of where we’re at with A. muciniphila research in general. With that out of the way, I want to focus on the potential relevance of Akkermansia muciniphila to IBD, beginning with a closer look at its role in the ecosystem of the gut.

Akkermansia Muciniphila Degrades Colonic Mucus – But That’s a Good Thing

As mentioned, the primary metabolic activity of A. muciniphila is mucus degradation. Knowing how important mucus is to the health and protection of our colon, this may initially sound like a bad thing (and as you’ll see, some researchers claim that it is). But in a healthy gut, most agree that Akkermansia muciniphila and its mucus-degrading activities fill a vital ecological niche. (4, 24, 25)

Only a few members of the intestinal microbiota have the ability to metabolize mucin, but these mucin-degraders liberate several by-products that in turn support the growth of other commensal flora, including numerous species of butyrate producers.

As most of you probably know, butyrate is the preferred fuel of colonocytes (the epithelial cells of the colon), so anything that increases butyrate production is extremely beneficial to gut health. And this increased production of butyrate allows colonocytes to produce more mucin, completing the synergistic cycle. Other beneficial products of this cycle include vitamin B₁₂, 1,2-propanediol, and propionate (which is another short-chain fatty acid like butyrate). (26)

In addition to its natural role in this colonic ecosystem, there’s also some evidence that supplementing A. muciniphila can increase mucin production and thickness of the colonic mucus layer, at least in mice. (11, 25) For instance, in a mouse model of accelerated aging, long-term supplementation with A. muciniphila prevented age-related decline in the thickness of the colonic mucus layer, in fact increasing the thickness approximately 3-fold. (27)

Akkermansia Muciniphila Strengthens the Gut Barrier

An oft-repeated claim in the literature on A. muciniphila that is of great relevance to IBD is that it improves gut barrier function – in other words, it helps make sure that the tight junctions between the epithelial cells of the intestine stay tight, so that no bacteria or large food molecules slip into the bloodstream unauthorized. Indeed, one of the review papers I cite below refers to A. muciniphila as “a sentinel for gut permeability,” and another calls it “the gatekeeper of our mucosa.” (28, 4) That’s high praise!

This claim is primarily supported by in vitro data (such as this widely-cited study (29) using human colonic cell lines) and mouse data demonstrating reductions in circulating lipopolysaccharides (LPS) and/or increases in the expression of tight junction proteins in response to supplementation with A. muciniphila (or, in a couple cases, isolated components of the bacteria). (30, 31, 32, 33, 34) These studies often show that A. muciniphila increases mucus production as well, in line with the previous section.

Another experiment didn’t directly test A. muciniphila, but found that the traditional Japanese herbal medicine Bofutsushosan significantly increased A. muciniphila abundance and resulted in improved gut barrier function (by several measures). (35)

But of special note is the first clinical evidence we have in humans, which corroborates these findings. The first human pilot study, which tested A. muciniphila supplementation in overweight and obese volunteers, observed a statistically significant decrease in circulating LPS in the group receiving a pasteurized A. muciniphila supplement for three months, both compared to baseline and compared to the placebo group. (22)

Akkermansia Muciniphila May Promote Intestinal Wound Healing

One additional activity of A. muciniphila that – if confirmed in humans – is highly relevant to IBD is its potential role in intestinal wound healing. It is well established that certain changes occur in the intestinal microenvironment when epithelial tissue is damaged, and one group of researchers identified A. muciniphila as a key player. (36, 37)

Not only did they find that abundance of A. muciniphila drastically increased in the wounded area, they also found that administering A. muciniphila to mice (rectally) enhanced wound healing compared with controls by promoting enterocyte proliferation.

But, of note – although I’ve seen several papers make conclusive-sounding statements that A. muciniphila promotes wound healing, I have yet to see any additional supporting evidence aside from that one mouse study.

There is a fair bit of evidence showing that A. muciniphila abundance increases in mice after administration of DSS (38, 39, 40), which does support a correlation with wound healing (since DSS injures the intestinal mucosa), but it certainly does nothing to prove that it plays an active helpful role in the process. So as far as I can tell, this one study is all we’ve got for this mechanism, and any conclusive claims are probably a tad premature.

(Although weirdly, I came across a study that A. muciniphila improves healing of bone fractures in mice. (41) The mechanism is different, of course, but interesting nonetheless!)

Akkermansia Muciniphila May Modulate Immune Response to Commensal Bacteria

Another point of relevance to IBD is the potential role of A. muciniphila in promoting a balanced and healthy immune response to bacteria in the gut (because as we know, one of the disease mechanisms in IBD is thought to be a dysregulated immune response to commensal bacteria). (42)

One experiment using human cell lines found that the TNF-α/IL-10 cytokine induction ratio, which is often used to measure the inflammatory potential of emerging probiotics, was lower in A. muciniphila in comparison to two other known commensal bacteria, indicating a greater anti-inflammatory capacity. (43) However, they were careful to note that A. muciniphila “cannot be strictly defined as anti- or pro- inflammatory, but may instead have a more complex role in preserving the balance of the gut ecosystem.”

Interestingly, some evidence in mice shows that A. muciniphila is one of only a small number of commensal intestinal species that induces an antigen-specific T-cell mediated immune response during homeostasis. (44) (Until recently it was thought that this type of immune response to commensal bacteria only occurred in the context of a disrupted gut barrier or other state of dysfunction, not in a state of homeostasis).

Another set of experiments found that extracellular vesicles derived from A. muciniphila also had immunomodulatory effects. In vitro pretreatment with these EVs ameliorated the production of IL-6 (an inflammatory cytokine) from colon epithelial cells in response to a component of E. coli. (45) Additionally, they found that oral supplementation with these EVs protected against DSS-induced colitis in mice.

From Mechanisms to Colitis Models in Mice

All four of these mechanisms – promotion of mucus production, strengthening of gut barrier, intestinal wound healing, and immune modulation – would suggest a beneficial role of Akkermansia muciniphila in IBD, and indeed, most researchers writing on the topic so far have come to that conclusion.

But what have we learned from experiments that actually pit Akkermansia muciniphila against animal models of colitis* in the metaphorical fighting ring? The results, as you’ll see, are mixed. And not only that, in many cases, researchers appear to be entirely unaware that other scientists in this same small field are saying the exact opposite of them. Fascinating, right? (Or disheartening?)

*I discuss this in far more detail in this post on animal models of colitis, but note that although animal models are extremely useful in the field of IBD research and are used extensively (and in many cases are the best we’ve got!), it would be incorrect to call them animal models of IBD, because the disease states achieved in these models are still insufficiently similar to human IBD to have direct practical therapeutic relevance.

Schrödinger’s Bacteria: Akkermansia Muciniphila Both Promotes and Ameliorates Colitis

This is where the plot thickens (much like the mucosal layer in response to Akkermansia muciniphila, one could say).

The first experiment I’m aware of that specifically investigated the effect of A. muciniphila in a mouse model of colitis was published in 2013, and is a particularly interesting one because they tested both live A. muciniphila as well as extracellular vesicles (EVs) derived from the bacteria. (45) Unexpectedly, while administration of the EVs significantly ameliorated the effects of DSS-induced colitis, administration of A. muciniphila itself made the colitis worse.

Another experiment, published almost simultaneously, found that administration of A. muciniphila exacerbated pathogen-induced intestinal inflammation in gnotobiotic SIHUMI mice (germ-free mice that were colonized with a “simplified human intestinal microbiota” (aka SIHUMI) of eight strains). (46)

On the other hand, a couple papers published very recently found that, contrary to those results, administration of A. muciniphila actually improved DSS-induced colitis in mice (47, 48) A third study that wasn’t even investigating colitis directly (it’s actually the bone-healing study I mentioned earlier) nonetheless found that A. muciniphila ameliorated the effects of DSS by strengthening the gut barrier. (41)

One group of researchers tested A. muciniphila in a different mouse model of colitis, the IL-10 knockout mouse, and found that colitis was significantly exacerbated both in gnotobiotic mice and germ-free mice monocolonized with A. muciniphila. (49) But a few years later, another group of researchers replicated those experiments using a different strain of A. muciniphila and found no evidence of a pro-inflammatory effect. (50) (This paper is an excellent one to read if you want to better understand the nuances of the existing A. muciniphila research in mouse models of colitis. The authors do a really excellent job summarizing and explaining things.)

Two additional papers suggest a potentially colitogenic effect of A. muciniphila, but by proxy – they did not administer A. muciniphila directly, but the tested interventions that worsened colitis (a low-fiber diet and a high-glucose diet, respectively) were found to markedly increase A. muciniphila abundance, and both papers suggested this increase as a potential mechanism behind the colitis exacerbation. (51, 52)

In contrast, three other papers suggest an anti-inflammatory effect by proxy: “Chlorogenic Acid Ameliorates Experimental Colitis by Promoting Growth of Akkermansia in Mice,” (53) “Caffeic acid ameliorates colitis in association with increased Akkermansia population in the gut microbiota of mice,” (54) and “Lactobacillus pentosus Increases the Abundance of Akkermansia and Affects the Serum Metabolome to Alleviate DSS-Induced Colitis in a Murine Model.” (55) (Gotta love descriptive titles, hey?)

All of the researchers who observed colitogenic effects from A. muciniphila posited the same potential mechanism: that as a mucin-degrader, A. muciniphila may cause thinning of the protective colonic mucus layer in certain contexts, making the epithelial cells more vulnerable and easily accessed by inflammation-inducing pathogens. It would therefore act as a pathobiont, i.e. a commensal species that can become a contributor to disease in certain contexts.

But notably, those writing the most recent of these negative papers (52) appear to be almost completely unaware of the rest of the body of evidence on A. muciniphila and colitis, or – more broadly – A. muciniphila and gut health. It’s a bit hard for me to take their conclusions (that A. muciniphila is colitogenic) seriously when they don’t even acknowledge the widely disparate results from other experiments and the overall tenor of the existing research. (I talked (ranted?) more about this on a YouTube stream with my friend Kyle.)

So What Does This Mean for Humans with IBD?

Clearly, context matters greatly here, which should come as no great surprise. After all, in a healthy colon, A. muciniphila acts in symbiosis with a diverse community of intricately interwoven organisms – a far cry from gnotobiotic mice with a simulated microbiome comprising 8 species.

We’ve seen that while negative effects have been observed in mouse models of intestinal inflammation, including some of those often used to model IBD, this has not been observed across the board, with most studies concluding the opposite. But more importantly, as discussed in a previous article, those models have limited to no translational relevance in the absence of corroborating data in human trials.

So, what data do we have in humans? To my knowledge, the only interventional data we have is the two pilot trials I mentioned earlier on diabetes and metabolic syndrome. If you’ll recall, both found the supplement to be well-tolerated, and one found that a pasteurized A. muciniphila supplement lowered circulating LPS levels in the participants.

Of specific relevance to IBD, we do also have some data from FMT trials for UC patients, where one analysis found that stool from donors with a high relative abundance of Akkermansia muciniphila was more likely to induce remission in patients with refractory UC. (56)

Akkermansia Muciniphila and IBD? It’s Complicated.

There’s more one could dig into here (for instance, what of the observation that A. muciniphila exhibits increased binding to mucin isolated from UC patients vs. healthy controls? (13, 57) Or its affects on serotonin in the gut? (58)) but to avoid getting even further into the weeds, the bottom line is that the effects of Akkermansia muciniphila on gut health appear to be context-dependent, and we don’t yet have enough data to draw conclusions for human IBD.

However, the preponderance of evidence, including the human data we have, points to a beneficial role and therapeutic potential for IBD. Further, the evidence that researchers have invoked to accuse A. muciniphila of being “colitogenic” is extremely limited. Unless I’m missing any (and please tell me if I am!), that evidence comprises three mouse experiments directly testing A. muciniphila, plus two additional experiments making mechanistic inferences based on correlations. Further, the negative results of one of those mouse experiments failed to be replicated by another group of researchers when they tried to repeat the experiment.

Should I Take Akkermansia Muciniphila?

I think the research so far is promising, and given research trends and the growing popularity of probiotics, I expect to see more developments in this area soon.

For now, the probiotic formulation tested in the human diabetes trial is already on the market under the brand Pendulum (marketed for diabetes, of course), so anyone wanting to experiment can! The formulation includes five total strains, with live A. muciniphila being one of them.

Personally, I would be open to trying Pendulum (and I’ll let you know if I do!), but just keep in mind we do not yet have any data on A. muciniphila supplements in humans with IBD.

There’s also a European company called A-Mansia Biotech that has facilitated much of the recent progress in translational research on Akkermansia muciniphila and has already received $19.8 million in funding. They do not yet have a probiotic on the market, but one of the recent papers associated with the group suggests that given the beneficial effects exerted even when pasteurized, one promising area of research involves investigating which of the bacterial components (particularly Amuc_1100) may be responsible for these benefits, and whether said component could be isolated and developed into a more targeted pharmaceutical. (3)

But if you don’t want to experiment with Pendulum or wait for Amuc_1100 pills, you can still harness the beneficial effects of Akkermansia mucniniphila by doing many of the things you have already been told are good for you. Isn’t it funny how that always seems to be the conclusion we come to?

Some of the things that have been found to increase the abundance of A. muciniphila (but are not necessarily good choices for everyone!) include:

dietary polyphenols (59, 60)
dietary prebiotics (FODMAPs) (59, 60)
supplementation with other probiotics (59)
supplementation with prebiotics (fructo-oligosaccharides, inulin) (59, 60)
fasting (61, 62) (which makes sense when you consider that with no food coming in, Akkermansia muciniphila is at a distinct advantage being able to survive solely on mucin produced by the host)

It’s also interesting to note that metformin increases A. muciniphila abundance, so that could be a mechanism by which metformin is therapeutic for type II diabetes. (63)

Finally, it’s worth emphasizing that Akkermansia muciniphila is a strict anaerobe, so promoting healthy butyrate production and maintaining an anaerobic colonic environment will help support its growth (and is something you should do anyway for gut health! More on this in my friend Lucy Mailing’s excellent article).

So there you have it! The current status on Akkermansia muciniphila and IBD, as well as I could manage. Any thoughts, comments, experiences – let me know below!

References

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