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A microbial signature for Crohn's disease

A microbial signature for Crohn's disease

2017 Feb 7
  • Department of Gastroenterology, Barcelona, Spain
  • CIBERehd, Instituto de Salud Carlos III, Madrid, Spain
  • Department of Gastroenterology, University Hospital, Leuven, Belgium
  • Department of Gastroenterology, AP-HP, Hôpital Saint-Antoine, Paris, France
What this study shows is that Crohn's Disease and UC are very distinct diseases with no microbial overlap.

It also shows that Spanish, Belgian, UK and German Crohn's disease patients have high levels of pathogenic Fusobacterium and E Coli, which can be used as a diagnostic marker to help diagnose crohn's disease.

Patients with UC do not have either.
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What is interesting is that those bacterial profiles overlap strongly with small intestinal bacterial overload, especially in patients with stricturing disease. We also see that EN works by bringing down bacterial load in crohn's disease patients, EN works especially well in patients with stricturing disease.

The goal should be to bring down bacterial load to decrease bacterial antigen and to limit the fecal stream by increasing the biovailability of the diet like EN does.

The fact bacterial diversity goes down does not seem to matter, EN brings down bacterial diversity and seems to actually worsen the dysbiosis, but it greatly reduces bacterial antigen by a quick drop in bacterial load which leads to a rather significant drop in inflammation within a few days in patients.

All EN studies shows EN induces 'worsening' dysbiosis, a decrease in diversity, yet a rapid drop in inflammation due to a drop in bacterial load. The dysbiosis is also immediately reversed when people resume a 'normal' diet. This clearly shows dysbiosis itself is not the culprit behind the inflammation but the sheer amount of bacterial antigen interacting with the epithelial barrier and presence of pathogenic species in the lamina propria is behind the inflammation.

Studies have clearly shown that the fecal stream high in bacterial load induces the acute inflammation, and removing that fecal stream or limiting the fecal stream with EN leads to a quick drop in inflammation.

Crohn's disease is clearly not a reaction to the dysbiosis, but a reaction against high bacterial load of pathogenic species. E Coli, Fusobacterium, P mirabilis, these bacteria show highly pathogenic behavior in crohn's disease patients and are far more common in Crohn's disease than in HC or UC.
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The goal should also be to bring down bacterial load in the mouth, I have long argued that the oral cavity serves as a bacterial reservoir that potentially keeps reinfecting patients, because crohn's disease patients have aphthous ulcers. Recent studies have shown Campylobacter concisus might be chronically refinecting people by transporting those bacteria from the mouth, that serves as a reservoir, to the intestine.
It seems they are trying to use the microbiome to discriminate between other microbiomes and ibd, so these are the differences, but there are still similar extinct groups of bacteria in ibd types. This info might be good for assigning some diagnosis though, separate from the usual way they might discriminate between the ibd types, this is my best guess though. It could provide greater accuracy in diagnosis, and perhaps drug choices for therapy. the observation that the diversity in crohns is lower then uc could explain why FMT has been more effective in treating uc then crohns, as mouse studies have shown, the more damaged a microbiome is, the more it takes to correct it.
Im glad you are becoming more interested in the entire microbiome kiny, I know you have been focused on the role of AIEC.

I do recall the study on EN for crohns your are talking about, and this study may have been done at the beginning of establishing a science on the microbiome, so their description in a reduction of diversity as a good thing, may not have reflected an understanding of whether the microbiome was less diverse in good or bad microbes, but either way, disease activity seemed to be reduced anyways. This one observation of EN in CD may not contradict other observations that an increase of diversity in healthy microbes is strongly associated with better health. The patients could have experienced reductions in both pathogens and good bacteria, and still had reduced disease activity. They also may have simply had reduced disease activity due to getting of whatever their previous diet was, and didn't have much to do with the EN itself, so it isnt that EN is anything special its just that the patients previous diet was horrible.

Then there is the data we have that shows the people with the most improvements after FMT are the ones that acquired more of their donors microbiome then other patients, and an increase in diversity. So there are many observations of increased diversity that lead to better health in most cases.
You know my opinion on FMT for crohn's disease. The potential damage a FMT can do to crohn's disease patients is extensive due to the presence of peyer's patches and paneth cells, where stool high in bacterial load ends up entering tissue, like we have seen from the californian study that had to be halted. All FMT crohn's disease trials should have been halted after that study. Rutgeerts and follow up studies have shown that the fecal stream high in bacterial load leads to inflammation

Crohn's disease patients also have issues with tight junctions, the intestinal wall allows translocaton of bacteria deep into tissue, which is not the case in UC, the inflammation in crohn's disease is much more severe and transmural, extending deep into tissue, compared to UC.

The potential for a FMT to harm a crohn's disease patient is real, FMT in crohn's disease is now increasingly controversial and several voices in the research community have rightfully suggested halting FMT experiments in crohn's patients after the disastrous california trial where CRP, Calpotectrin and HBI showed extensive inflammation in several patients 2 days after FMT treatment (which matches Rutgeerts findings that the fecal stream will evoke an inflammatory response days after coming into contact with previously unaffected tissue).

Aministering supposedly "good" bacteria to crohn's disease patients with probiotics or other means is not feasable since the few that might be beneficial are oxygen sensitive, like Faecalibacterium prausnitzii. One can't administer this bacteria in any shape or form because it simply dies off in the presence of oxygen.

F prausnitzii counts also drop significantly when people use EN who go in remission, which again puts into question if certain bacteria are actually that beneficial as claimed.

Several types of Lactobacillus are able to halt the spread of E coli in a petri dish, but when administered to crohn's disease patients in the form of probiotics, it does not help, again, this puts into question this idea of "beneficial" bacteria for crohn's disease.

UC and C difficile are very different diseases exclusive to the colon where FMT seems to be effective. But a side-note, it is likely the bacteriophages that make the FMT effective, when you filter out the bacteria by using a 2um filter, the FMT is just as effective. The bacteriophages likely bring down the bacterial load in the colon.
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We also simply do not understand at all which bacteria live in the intestine and are present in stool. We have not identified the large majority of bacteria.

Fusobacterium was one of those bacteria that was intially cateogrized as harmless and even beneficial, only now do we understand this bacteria is a pathogen that enters tissue and caused an inflammatory response.

When certain doctors administer FMT to patients, they have no clue whatsoever what they are doing. These experiments are going to lead to disastrous outcomes, the californian study will not be the last where crohn's disease patients are actively harmed since the few voices in the research community that express worries and are asking for these experiments to stop in crohn's disease patients, are not listened to and science that shows the fecal stream evokes an immune response in crohn's disease patients is ignored.

It will not be until the FDA steps in and when patients start to sue these doctors harming them, or when another FMT leads to a dead patient, that the experiments will stop.

I thought that patients dying on FMT due to out of control E Coli and Salmonella infections would be enough for the research community to call out some of these doctors and hold them accountable. Apparently not, when all the scientific evidence shows the potential for harm, yet these doctors administered a FMT loaded with E Coli that ends up killing a patient, that doctor should be charged with murder and the wider research community has a responsibility to address these issues instead of trying to sweep them under a rug.
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Thanks for a response, some opinions and some facts Kiny.

Processing an FMT in a blender reduces and kills off many of the anaerobic microbes and increases some of the more pathogenic aerotolerant microbes, so in some cases a bad response is possible in crohns patients, rarely has it been life threatening. But the time has come for research to get beyond repeating the same studies, its time for improving the known issues in FMT methods.

The data on the bacterial role and functions of the microbiome is pretty solid now though, any contribution of phages could be minimal but this is why right now whole spectrum fecal transplant is the way to a real restoration of a damaged microbiome, but bacterial selections in pill form are perhaps the future, despite 4 companies that are focused on them right now for FDA approval, it's nice to know everyone is working on something right now.
any contribution of phages could be minimal
There are now multiple C Difficile studies that have filtered the fecal transplant and removed the bacteria completely, called FFT (filtered fecal transplant), a sterile transplant without bacteria.

The filtered FMT without bacteria but intact bacteriophages (bacteriophages being viruses are far smaller and get through the ultrafiltrate) is just as effective as the one with bacteria.

This completely undermines the idea that the mechanic of action of FMT is due to the presence of bacteria, but instead confirms that the effect is due to the presence of bacteriophages that wiped out the bacteria and bring down bacterial load.

Efficacy of Sterile Fecal Filtrate Transfer for Treating Patients With Clostridium difficile Infection

Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany.

Background & aims:

Fecal microbiota transplantation (FMT) is a highly effective therapy for recurrent Clostridium difficile infection (CDI). However, transferring undefined living bacteria entails uncontrollable risks for infectious and metabolic or malignant diseases, particularly in immunocompromised patients. We investigated whether sterile fecal filtrates (containing bacterial debris, proteins, antimicrobial compounds, metabolic products, and oligonucleotides/DNA), rather than intact microorganisms, are effective in patients with CDI.

We performed a clinical case series to investigate the effects of fecal filtrate transfer (FFT) in 5 patients with symptomatic chronic-relapsing CDI at the Department of Internal Medicine I at the University Hospital Schleswig-Holstein (Kiel, Germany). Patients were followed up for at least 6 months and for up to 33 months. Stool was collected from 5 donors selected by the patients, and fully characterized according to FMT standards. Stool was sterile-filtered to remove small particles and bacteria; the filtrate was transferred to patients in a single administration via nasojejunal tube. Fecal samples were collected from patients before and at 1 week and 6 weeks after FFT. Microbiome, virome, and proteome profiles of donors and patients were compared.

In all 5 patients, FFT restored normal stool habits and eliminated symptoms of CDI for a minimum period of 6 months. Proteome analyses of selected FFT filtrates showed no obvious protein candidates associated with therapeutic efficacy. 16S ribosomal RNA gene sequencing detected diverse bacterial DNA signatures in the filtrates. Analysis of virus-like particles from a filtrate found to reduce symptoms of CDI showed a complex signature of bacteriophages. Bacterial phylogeny and virome profile analyses of fecal samples from recipients indicated longitudinal changes in microbial and viral community structures after FFT.

A preliminary investigation of 5 patients with CDI shows that transfer of sterile filtrates from donor stool (FFT), rather than fecal microbiota, can be sufficient to restore normal stool habits and eliminate symptoms. This finding indicates that bacterial components, metabolites, or bacteriophages mediate many of the effects of FMT, and that FFT might be an alternative approach, particularly for immunocompromised patients.
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Sterile FFT being just as effective as FMT loaded with bacteria means there is no reason anyone with C Diff or UC should be undergoing an FMT that is not sterile.

Filtering out bacteria from stool is done with cheap ultrafiltrate membranes that simply relies on the fact bacteria and fungi are that much bigger in size than viruses like bacteriophages. All the E Coli risks can be avoided for these people by simply removing the bacteria.

This undermines the whole microbiota research so it will take a while for some researches to admit that their fecal trasnplants were not successful due to the bacteria but due to the presence of phages. I'm sure they will keep risking the lives of many people before admitting their mistakes.

This idea that just giving people millions of bacteria (potentially dangerous ones) that would somehow outcompete existing bacteria and magically cure them of an infection is a ridiculous idea. The C difficile infection is clearly being reduced by bacteriophages that lyse them, not by just dumping millions of bacteria into people's intestines, which is very dangerous.

Bacteriophage Combinations Significantly Reduce Clostridium difficile Growth In Vitro and Proliferation In Vivo

The microbiome dysbiosis caused by antibiotic treatment has been associated with both susceptibility to and relapse of Clostridium difficile infection (CDI). Bacteriophage (phage) therapy offers target specificity and dose amplification in situ, but few studies have focused on its use in CDI treatment. This mainly reflects the lack of strictly virulent phages that target this pathogen. While it is widely accepted that temperate phages are unsuitable for therapeutic purposes due to their transduction potential, analysis of seven C. difficile phages confirmed that this impact could be curtailed by the application of multiple phage types. Here, host range analysis of six myoviruses and one siphovirus was conducted on 80 strains representing 21 major epidemic and clinically severe ribotypes. The phages had complementary coverage, lysing 18 and 62 of the ribotypes and strains tested, respectively. Single-phage treatments of ribotype 076, 014/020, and 027 strains showed an initial reduction in the bacterial load followed by the emergence of phage-resistant colonies. However, these colonies remained susceptible to infection with an unrelated phage. In contrast, specific phage combinations caused the complete lysis of C. difficile in vitro and prevented the appearance of resistant/lysogenic clones. Using a hamster model, the oral delivery of optimized phage combinations resulted in reduced C. difficile colonization at 36 h postinfection. Interestingly, free phages were recovered from the bowel at this time. In a challenge model of the disease, phage treatment delayed the onset of symptoms by 33 h compared to the time of onset of symptoms in untreated animals. These data demonstrate the therapeutic potential of phage combinations to treat CDI.
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If we could remove pathogenic bacteria by just dumping millions of so called "good bacteria" in the intestine, that would be great, everyone with crohn's disease would drink some probiotics and they would be cured. Probiotics don't do anything for crohn's disease, they simply don't work and can potentially worsen the inflammation as we have seen with some Lactobacillus probiotics that were supposedly "harmless".

(in fact I still need to see the first repeatable study that shows probiotics are helpful for any disease)

What does result in remission in crohn's disease is antibiotics (until you run into resistance), starving them with by intravenous feeding or EN, or lysing them with phages (see Institut Pasteur research).
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Intestinal diseases involving bacteria and the small intestine have always had very straightforward explanations. Intestinal TB, foodborne infections, yersinia, listeria, campylobacter, E Coli, Salmonella.

Each and every time it involves pathogens that enter tissue and set off an inflammatory macrophage response, if the pathogen is not killed it become chronic.

It's no different in crohn's disease.

It is time that voices of certain doctors that we need to 'shape the microbiome' or 'inject people with stool until patients become sick and the study is halted'... are silenced, they are putting the lives of crohn's disease patients in danger with their baloney theories that are not grounded in reality. When Rutgeerts showed that the fecal stream high in bacterial load causes inflammation in crohn's patients in the 1980s, and when this data was confirmed twice by London researchers, that should have been enough to realise that these experiments could have disastrous consequences.

Thankfully we have some bright minds like Segal and people in Clermont-Ferrand and Institut Pasteur who realise the cause of crohn's disease is pathogenic bacteria entering tissue.
this is interesting research.

The first study did state "This finding indicates that bacterial components, metabolites, or bacteriophages mediate many of the effects of FMT, and that FFT might be an alternative approach, particularly for immunocompromised patients. "

So at first glance there didn't seem to be anything conclusive about phages and they need to narrow it down more if desired. Another thing i noticed is that efficacy was defined by elimination of c diff symptoms, not restoration of microbiome. Another thing to consider is phages live on bacteria, and need them to survive and have no biological activity outside of bacteria, so bacteria still come first in this systemic order of the microbiome/ecosystem.
The intestine and stool is full of bacteriophages. Researches sample bacteriophages from infected waterways, not from sterile waterways.

Once they can effectively and easily isolate those phages that are bringing down the load of C Difficile, they can just grow the phages and give people the phage cocktail instead of relying on a sterile transplant.
Phage therapy also doesn't result in any known resistance, phages have no issues lysing bacteria in a biofilm, and they seem to have very little to no side effects. The only side effects so far reported have been due to the vehicle used prior to the phage administration, people usually get a product to bring down the acidity of the stomach before the phages are administered, the side effects are incredibly mild and are negligible.
The ability for phages to lyse through the biofilm is pretty important, biofilms is one of the ways bacteria protect themselves from antibiotics.

Even though we sometimes mention that AIEC lives in biofilm, the truth is that all bacteria use biofilms, some (like AIEC) are just more effective at it than others.

They use those biofilms to stick to the intestine, to fend off immune cells, to gobble up nutrients, without a biofilm bacteria would be highly ineffective and not nearly as pathogenic.

Phages being so small (they are tiny viruses) have no trouble getting through those biofilms, which is one of the reasons they are so good at what they do, killing bacteria.
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A couple of questions if I may. Is there any idea about how close phage therapy is to potentially becoming available? Is EN something that can be maintained in the longer term to reduce inflammation? (Studies I've seen have been for a few weeks, usually versus steroids, with relapse when normal eating resumes). And lastly, would it make sense to try and reduce bacterial load with herbal antimicrobial given antibiotics are unsustainable/ lead to resistance. Sorry that's three!
The trial looking at treating AIEC infection with phages is the Intralytix trial taking place in a NY hospital, it is still ongoing. The main goal of the trial is to see if AIEC that was initially detected in stool in patients, is still present after the phage therapy. If the AIEC disappears from stool it would indicate the phage therapy is effective in treating the infection and that the trial is successful. That doesn't mean it is therefore effective in reducing inflammation in patients, since I believe they chose patients who weren't on active medication and perhaps had mild cases of crohn's.

I'm sure there are other phage trials ongoing.

I am not aware of any contraindication that would limit the use of EN. There are EN studies that have lasted weeks, months, and studies from the 80s that lasted years. The limiting factor is always patient compliance. What EN does do is create dysbiosis, but the extent of the dysbiosis and any shifts in the microbiome doesn't seem to have any negative impact over time.

I don't know anything about herbs to be honest. I'm sure you can kill all sorts of bacteria in a petri dish with herbs, that doesn't mean it actually works in a living organism where bacteria live in biofilms and reside inside cells. The reason quinolones work for crohn's is because they can penetrate immune cells.
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