Microbes and ‘Mmunology in the Mountains: Thursday sessions

Thursday was the final day of the conference. The morning session for the conference on the microbiome was called “Microbiota and Metabolism”. And the evening session was “Therapeutic Manipulation of Microbiota”.

Unfortunately, my notes for the morning session seem to have been lost somewhere around here:

I think they're somewhere ahead and to the left...

Not much snow in the Montezuma bowl, but sunny skies and lots of fun anyway.

– The evening session was kicked off by Ferguson Shanahan with a talk entitled “Making Peace: altering host-microbiota relationship in chronic gut inflammation”. He began his talk by pointing out the prevalence of military metaphors that seem to get used when talking about host interactions with its microbiota. Just at this conference, speakers referred to the DMZ that is present between the host epithelium and the microbiota in a healthy host. Others have talked about waging war against pathogens, and “nuking” them with antibiotcs… If we are to make peace, who is it with, when do we do it, and how do we do it? Shanahan addressed these questions witin the IBD framework.

Pathogenesis of IBD relies on host immune response, genetic suscepitbility, and the microbiota (“environment”). We are actually dealing with a bunch of different conditions lumped into ulcerative colitis (UC) and Crohn’s disease (CD). The efficacy of antibiotics treatment is dependent on patient background. Upwards of fifty percent of IBD patients are either overweight or obese. He also noted that it seems that all commensals have the potential to be pathogens, but not all pathogens can be commensals. Much of this may depend on context, i.e. being in the wrong place or wrong host at the wrong time. It is also possible that IBD is a specific infection waiting to be discovered (he didn’t necessarily advocate this view, he just wanted us to make sure that door wasn’t closed).

He then went on to describe some consistent factors of IBD. 50% of IBD patients have Mycobacterium avium subsp paratuberculosis (MAP), and Crohn’s patients have an elevated T cell response to MAP compared to other IBD patients. 10% of asymptomatic IBD patients are carrying Clostridium difficile, a time bomb that prevents their doctors from prescribing them antibiotics. Bifidobacterium infantis protects against Salmonella infection in colitis models by deactivating NFkB and inducing regulatory T cells (Tregs) in mice and children. In humans with IBS, there is significant improvement in symptoms with inoculation of B. infantis that is dependent on the number of cells introduced. When they tested B. infantis‘s efficacy in treating UC, there was a 50% relapse rate in the patients. Shanahan suggested much of the differences in efficacy in mice and humans may be due to the fact that most humans are diagnosed with IBD between 25 and 30 years of age, but in order to effectively treat it, intervention may have to occur much earlier. In the mouse models we use for the disease, treatment usually is administered at a much earlier effective age.

Shanahan ended by talking about the mechanisms by which certain probiotics communicate with the host. For Bifidobacterium, the critical thing for colonization is pili. Without them, the bacterium cannot compete with other microbes, and is uneffective. Exopolsaccharides (EPS) are also important for acid and bile resistance and shielding from antibodies. Without them, many probiotics are treated by the immune system as pathogens. EPS producing Bifidobacterium breve protects mice from infection with Citrobacter rodentium. He also stressed the importance of moving from probiotics to pharmabiotics, or to make it catchy, “from bugs to drugs”.

Philip Sherman, a practicing pediatrician, was next, and talked about “Altering the pediatric intestinal microbiota”. He started out by noting that reduced bacterial diversity is an emerging theme across the diseases we’d discussed so far at the conference. The diversity of gut bacteria of infants increases for one to two years before it reaches a similar diversity to the mother. Some studies have shown that probiotics reduce necrotizing enterocolitis and infant mortality in premature infants as well as reducing diarrhea in children, according to five meta-analyses. These results are statistically significant, but Sherman asked whether they were clinically relevant.

He brought of the E. coli O157:H7, a pathogenic strain of E. coli that is associated with IBS which subverts innate immunity by inhibiting Stat-1 phosphorylation. Then, talked about testing the efficacy of probiotics in dealing with a C. rodentium infection in mice (I know, not where I thought this was going either). The probiotics were effective in reducing the severity of the C. rodentium infection in vivo but, as Shanahan pointed out, the timing of the treatment was very important (and so was dosage). Probiotics administered before the pathogen infection worked best, but co-inoculation, and probiotic administration shortly after infection worked well too. This makes a lot of sense if what the probiotics are doing is competitively excluding the pathogen.

The Sherman group also looked at the effects of some prebiotics, namely oligosaccharides from mother’s milk. Their administration resulted in expansion of Bifidobacterium and Lactobacillus, a reduction in the pH of the stool, and had no effect on weight accretion of the subjects.

– The final full talk of the conference was given by James Versalovic, and was titled “Defining microbial disease signatures in pediatric gut microbiomes – and microbial modification strategies as therapies” (whew, that’s a lot to type). His talk focused mostly on observational studies from 74 children enrolled to study the pediatric Human Microbiome Project.

The neonatal gut microbiota rapidly shifts in time and with dietary transitions. Children with IBS and healthy children both have lots of Bacteroidetes, Firmicutes, and Verrucomicrobia. The children with IBS, however, have an expansion of Proteobacteria (as is tradition) which seems to mostly be comprised of γ-Proteobacteria. The abundance of γ-Proteobacteria is correlated with IBS symptom scores. These group of bacteria is also prominent in dysbiotic short bowel. Within the γ-Proteobacteria, the Escherichia/Shigella and Kelbsiella genera are enriched. Additionally, the γ-Proteobacteria group contains many well known enteric pathogens.

The human-derived probiotic, Lactobacillus reuteri demonstrates anti-microbial effects against enteric pathogens. Some bacteria, including L. reuteri and L. vaginalis can convert histadine to histamine, which correlates with TNF inhibitory activity. This is a bit counter to how host-derived histamine affects the immune system (which is to cause inflammation). It is possible that either bacterial derived histamine is different from host-derived histamine, or that, being produced in the lumen, it associates with different receptors/cells than host histamine, and may actually be anti-inflammatory.

So that’s it for my summaries of the talks at the 2012 Keystone Symposium on the Microbiome (and joint sessions on Innate Immunity). I hope they were interesting and helpful. If you have any questions, comments or quemments, email me at stagaman@uoregon.edu .

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