Akkermansia muci... muciniphila and diet induced obesity

It just rolls off the tongue: Akkermansia muciniphila*. 

As we speak A.muciniphila is making headlines across the world based on the study by Amandine Everard and colleagues** (open-access) on what happened to mice who had or were lacking in this stalwart of the gut microbiome.

No need for me to go into great detail about the Everard trial because (a) the paper is open-access and (b) it's already received plenty of coverage as per an entry in Nature (see here) and the National Geographic (see here).

The long-and-short of it (I should perhaps rename this blog with those words) was that A.muciniphila is, as it's name suggests, a bacteria with a connection to mucin; in particular it's love of the stuff. The finding: mice who were obese and diabetic (type 2 diabetes) seemed to have lower levels of A.muciniphila, and "that A. muciniphila treatment reversed high-fat diet-induced metabolic disorders, including fat-mass gain, metabolic endotoxemia, adipose tissue inflammation, and insulin resistance". The speculation is whether these mouse findings might, just might turn out to be something truly remarkable for humans presenting with similar symptoms.

But as with everything in life, things are rarely so simple. My first thought when I saw the name A.muciniphila were the intriguing findings reported by Lynne Wang and colleagues*** of lower numbers of A.muciniphila in fecal samples from children diagnosed with an autism spectrum disorder and their siblings. Just in case your interested, I talked about this paper on a post for a sibling blog. So unless we are talking about children with autism subsequently being a greater risk for obesity and type 2 diabetes, I would wager that there is more to A.muciniphila than just weight loss and insulin.

Leaky gut anyone?

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*  Derrien M. et al. Akkermansia muciniphila gen. nov., sp. nov., a human intestinal mucin-degrading bacterium. IJSEM. 2004; 54: 1469-1476.

** Everard A. et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. PNAS. May 2013.

*** Wang L. et al. Low Relative Abundances of the Mucolytic Bacterium Akkermansia muciniphila and Bifidobacterium spp. in Feces of Children with Autism. Appl Environ Microbiol. 2011; 77:  6718–6721.

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Gluten, guts and glory

Yep, I know. First post for several months - indeed first post for 2013 - and more apologies to readers about not keeping up with this blog. A short post on this occasion focused on an interesting opinion piece by Moises Velasquez-Manoff titled: Who has the guts for gluten?

I'll admit to being pretty entertained by the work of Velasquez-Manoff given his previous articles crossing over into topics like autism spectrum disorders (see here and also covered here). This latest piece is equally thought-provoking and alongside the opinions of people like Alessio Fasano, he of the [General] zonulin (see here), asks some potentially important questions about our relationship with gluten.

One quote in particular caught my attention from Dr Fasano: “Keep the lactobacilli high enough in the guts of these kids, and you prevent autoimmunity.” following some observations based on the onset of type 1 diabetes and coeliac (celiac) disease.

I'm intrigued and am waiting for that confirmatory peer-reviewed evidence.

Coeliac disease as a model of autoimmunity

A very short post primarily to link to a recent paper by Kumar and colleagues* (full-text, at least for the moment).

The paper is a sort of 'all you ever wanted to know about coeliac / celiac disease but were afraid to ask' type piece and jolly informative in terms of what we think we know so far about the condition regarding genes, heritability, biochemistry and the like.

Just for good measure, here also are a few other links to some interesting discussions appearing in Nature recently on our gut microbiota and the Barker hypothesis. All I will say is 'all hail our gut bacteria' and onwards with the epigenetic revolution.

Happy reading!

P.S. I know I have been neglecting this blog for a few weeks and apologise. I will hopefully devote more time to it as the year goes on. In the meantime, a link to a peculiar song which has been running through my mind for a few week now.. Gotye and 'Somebody that I used to know' (UK readers might have heard this as an advert for 2Day 2012 from BBC Radio 2).

* Kumar V. et al. From genome-wide association studies to disease mechanisms: celiac disease as a model for autoimmune diseases. Seminars in Immunopathology. May 2012
DOI: 10.1007/s00281-012-0312-1

Does diabetes start in the intestines?

The findings of an interesting paper by Wei and colleagues* (full-text) pose a question: are the origins of diabetes in the intestines?

For those that don't know too much about diabetes, here is a link that should help. The concise version (if there is such a thing) is that diabetes normally manifests as either type-1 diabetes or type-2 diabetes with insulin being the key compound in controlling blood sugar, and corresponding issues either with its production or when resistance is built up to it.

The crux of the paper by Wei et al is that an insulin-responsive super enzyme called fatty acid synthase (FAS) involved in lipogenesis is also involved in gut barrier regulation through its action on Mucin 2 (Muc2), a gel-forming component of mucus. The authors' suggestion is that becoming resistant to insulin is associated with issues with FAS and correspondingly problems with mucus in the gut, inflammation and diabetes. No pressure then.

The paper summarised (deep breath):

• Several groups of mice were included for study: (a) mice with chemically-induced (tamoxifen induction of Cre recombinase) decreases of FAS protein and mRNA, (b) mice bred with inactivated FAS in the intestine and (c) control germ-free mice. For group (b) mice, diabetes was induced by administration of streptozotocin, a toxin to the beta cells which produce insulin in the pancreas.
• Assays looking at gut bacteria, intestinal permeability, cytokine release and protein S-palmitoylation were used to investigate various parameters.
• The findings: a chemically-induced deficiency of FAS in mice started a cascade of events linked to inflammation. One of the primary cytokine markers of this inflammation was elevated levels of TNF-α although animals were also noted to show weight loss and other gastrointestinal symptoms. A quarter of these mice actually died within 14 days.
• The authors deduced that although some changes were noted to the intestinal bacterial makeup of FAS reduced mice, these changes were not enough to cause the inflammation observed but rather were as a result of the inflammation. They demonstrated this via a previously discussed method on this blog, bacterial transplantation; in this case to the germ-free mice (group c) who did not show the accompanying inflammation as a result of their donor bacteria. That is not however to say that gut microbiota did not have some effect, as per the reduction in inflammation noted in the FAS deficient mice following administration of the antibiotics ciprofloxacin and metronidazole.
• The link between FAS deficiency and Muc2 was evidenced by the lower levels of Muc2 shown in FAS deficient mice and reduced inner mucus layer thickness in the colon of affected mice. 
• Looking at the inactivated FAS (group b) diabetic mice, a similar pattern of issues with Muc2 and reductions in the mucus layer was seen alongside penetration of bacteria indicating intestinal hyperpermeability (leaky gut). Interestingly, insulin supplementation seemed to positively affect some of the permeability issues.

This is quite a complicated paper and so please do not take my summary as gospel. It is intriguing that inflammation is at the heart of their theory and in particular, inflammation as a result of not having enough FAS present in the gut with the knock-on effects on gut permeability. Indeed not for the first time has it been suggested that diabetes and leaky gut are connected as per articles like this one. Makes you wonder also about any other possible dietary inter-related connections?

* Wei X. et al. Fatty acid synthase modulates intestinal barrier function through palmitoylation of mucin. Cell Host & Microbe. February 2012.
DOI:  10.1016/j.chom.2011.12.00

Coeliac disease in Type 1 diabetes

When I think of coeliac (celiac) disease and the various names attached to research on this exquisite sensitivity to gluten, I think of a few names with a good publishing track record in this area. First name out of the hat is Mario Hadjivassiliou. Second is David Sanders. Without turning this post into some idol worship, when I see new papers appearing from one or other of these guys, my interest is piqued.

So when this paper from Leeds and colleagues* appeared bearing both names on the author group, I was interested. When I saw that the paper was also looking at another autoimmune condition, type-1 diabetes alongside coeliac disease (CD), I was even more interested.

The main facts from the Leeds case-control study are:

• The prevalence of CD in their cohort of people with type-1 diabetes was 3.3%. Although there is still some debate about prevalence of CD in the general population, it is generally accepted to be currently around 1%. Interestingly, 3.3% is exactly the prevalence of CD in cases of autism described in this paper from a few years back. What a coincidence. 
• At diagnosis of CD, type-1 diabetes seemed to be associated with a higher prevalence of retinopathy, nephropathy and peripheral neuropathy. Some of these conditions have been noted in 'gluten sensitivity' alone.
• Glycemic control was also worse in the diabetes-CD group, accompanied by lower HDL (good guy) and total cholesterol.
• A gluten-free diet is generally well tolerated by individuals with CD and comorbid type-1 diabetes. 

I am excited by this research. Excited because as well as linking two autoimmune conditions, the genetics of which are starting to receive some attention, it extends into some other areas already discussed on this blog that may affect quality of life and importantly, longevity.

* Leeds JS. et al. High prevalence of microvascular complications in adults with type 1 diabetes and newly diagnosed celiac disease. Diabetes Care. September 2011.