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Overrepresentation of Enterobacteriaceae and Escherichia coli is the major gut microbiome signature in Crohn’s disease and ulcerative coli
- Thread starter kiny
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kiny
Well-known member
The high starch diets in the Western world are troubling when we know Klebsiella is implicated in crohn's disease. Starch ends up as the undigsted energy source that fuels Klebsiella in the ileum and colon. EN works because it consists of glucose and MD, and unlike starch, it is fully absorbed in the upper GI tract.
One thing that is puzzling to me is shouldn't we eradicate the underlying problems and in this case E coli and Klebsiella? Without the antibiotics, how can EN alone make sure that these bacteria don't cause problems anymore?
kiny
Well-known member
Klebsiella is usually antibiotic resistant. If you start using broad spectrum antibiotics, it will gain a fitness advantage. In the post-antibiotic period it will gain the upper hand and become a dominant species. It could explain why taking antibiotics is a precursor to developing crohn's disease.
But several studies are trialing phages for crohn's disease, both against invasive E coli and Klebsiella. You should be able to easily eliminate these bacteria with phages. Biofilms don't bother phages, they lyse right through them.
Klebsiella has always interested me, besides E coli, because people with crohn's disease usually have had aphthous ulcers at one point.
But several studies are trialing phages for crohn's disease, both against invasive E coli and Klebsiella. You should be able to easily eliminate these bacteria with phages. Biofilms don't bother phages, they lyse right through them.
Klebsiella has always interested me, besides E coli, because people with crohn's disease usually have had aphthous ulcers at one point.
kiny
Well-known member
Ideally you would isolate these pathogens and test patients for antibiotic resistance. But that requires a concerted effort from GI to treat people with respect. The last few years many GI have not been trying to eliminate bacteria, but made many people sick by doing the opposite, giving patients fecal transplants in experiments, which I warned of many times on this forum.
But the evidence is clear. Enterobacteriaceae are involved in crohn's disease, and they need to be treated.
But the evidence is clear. Enterobacteriaceae are involved in crohn's disease, and they need to be treated.
Are they also very resilient then? I am assuming that you can't starve them out and by doing EN, they are sort of out of energy but will become active once solids are introduced.
I did see one phage trial taking place at Mt. Sinai but it's just gonna take forever and ever (I figured).
kiny
Well-known member
Haven't seen the video, but it is unlikely crohn's disease is related to a viral infection. The Rutgeerts and Harper studies from the 80s and 90s showed that filtering effluent from patients through ultrafiltration that eliminated bacteria and fungi, but not viruses, no longer evoked any immune response.
kiny
Well-known member
One of the reasons I am not a fan of fasting for crohn's, even though many experiments have tried this unsuccessfully, is the fact that the bacteria involved in crohn's disease happen to be excellent at sustaining themselves in harsh conditions like nutrient deprivation. Especially Klebsiella. By the time Klebsiella is affected by nutrient deprivation, you'll be in a lot more trouble than Klebsiella from fasting. The goal should be depriving Klebsiella of nutrients by depriving it of starches, but without depriving the small intestine of nutrients it needs. The small intestine requires daily nutrients, it is a much more complex organ than the colon. Paneth cells, peyer's patches, these are all exclusive to the small intestine and are very nutrient dependent.
I don't remember you commenting on it before... can bone broth have the same efficacy as EN? Its nutritious, no burden on the GI as well.
Fasting is considered from the angle of "giving the immune cells a rest". I remember seeing a trial on that and the reason is simply reset or unwind the already overly hyped immune systems.
As for fecal transplants... why doesn't it make sense to replace the bad gut with a healthy donor's tissues?
kiny
Well-known member
The fecal stream in crohn's disease causes inflammation. This has been shown by Rutgeerts and Harper in the 80s and 90s.
https://gut.bmj.com/content/gutjnl/26/3/279.full.pdf
https://www.thelancet.com/journals/lancet/article/PII0140-6736(91)90663-A/fulltext
What you're doing if you use a fecal transplant, is injecting a fecal stream.
If the GI doing these experiments had read any of these major studies, they wouldn't have done these disastrous studies where crohn's disease people became sick. A few years ago I said that the GI suggesting to try fecal transplants on crohn's disease patients should be sued.
Fecal transplant experiments with crohn's disease patients have thankfully mostly stopped now.
Phage production is blocked in the adherent-invasive Escherichia coli LF82 upon macrophage infection
Author summary
Adherent-invasive Escherichia coli (AIEC) strains are frequently recovered from stools of patients with dysbiotic microbiota. They have remarkable properties of adherence to the intestinal epithelium, and survive better than other E. coli in macrophages. The best studied of these AIEC is probably strain LF82, which was isolated from a Crohn’s disease patient. This strain contains five complete prophages, which have not been studied until now. We undertook their analysis, both in vitro and inside macrophages, and show that all of them form virions. The Gally prophage is by far the most active, generating spontaneously over 108 viral particles per mL of culture supernatants in vitro, more than 100-fold higher than the other phages. Gally is also over-induced after a genotoxic stress generated by ciprofloxacin and trimethoprim. However, upon macrophage infection, a genotoxic environment, this over-induction is not observed. Analysis of the transcriptome and key steps of its lytic cycle in macrophages suggests that the excision of the Gally prophage continues to be repressed in macrophages. We conclude that strain LF82 has evolved an efficient way to block the lytic cycle of its most active prophage upon macrophage infection, which may participate to its good survival in macrophages.
Author summary
Prophages are bacterial viruses stably integrated into their host, to which they can provide new functions, thus increasing their fitness in the environment. Thereby, they can participate to the virulence of bacterial pathogens. However, prophages are double-edged swords that can be awakened in response to genotoxic stresses, resulting in the death of their bacterial host. This raises the question of the effect of this type of stress in the natural environments where their bacterial hosts exert their virulence. In this study, we characterized the five active prophages present in Escherichia coli LF82, a strain belonging to the intestinal microbiota and suspected to be involved in Crohn’s disease via its ability to invade macrophages, a highly genotoxic environment. We show that LF82 inhibits the awakening of its prophages in macrophages, allowing it to survive there. Moreover, deletion of its most active prophage does not affect the viability of LF82 in this environment. These results suggest that LF82 has tamed its prophages in macrophages and also suggest that if they convey fitness advantages, they probably do so in environments differing from macrophages, and which remain to be discovered.
journals.plos.org
Author summary
Adherent-invasive Escherichia coli (AIEC) strains are frequently recovered from stools of patients with dysbiotic microbiota. They have remarkable properties of adherence to the intestinal epithelium, and survive better than other E. coli in macrophages. The best studied of these AIEC is probably strain LF82, which was isolated from a Crohn’s disease patient. This strain contains five complete prophages, which have not been studied until now. We undertook their analysis, both in vitro and inside macrophages, and show that all of them form virions. The Gally prophage is by far the most active, generating spontaneously over 108 viral particles per mL of culture supernatants in vitro, more than 100-fold higher than the other phages. Gally is also over-induced after a genotoxic stress generated by ciprofloxacin and trimethoprim. However, upon macrophage infection, a genotoxic environment, this over-induction is not observed. Analysis of the transcriptome and key steps of its lytic cycle in macrophages suggests that the excision of the Gally prophage continues to be repressed in macrophages. We conclude that strain LF82 has evolved an efficient way to block the lytic cycle of its most active prophage upon macrophage infection, which may participate to its good survival in macrophages.
Author summary
Prophages are bacterial viruses stably integrated into their host, to which they can provide new functions, thus increasing their fitness in the environment. Thereby, they can participate to the virulence of bacterial pathogens. However, prophages are double-edged swords that can be awakened in response to genotoxic stresses, resulting in the death of their bacterial host. This raises the question of the effect of this type of stress in the natural environments where their bacterial hosts exert their virulence. In this study, we characterized the five active prophages present in Escherichia coli LF82, a strain belonging to the intestinal microbiota and suspected to be involved in Crohn’s disease via its ability to invade macrophages, a highly genotoxic environment. We show that LF82 inhibits the awakening of its prophages in macrophages, allowing it to survive there. Moreover, deletion of its most active prophage does not affect the viability of LF82 in this environment. These results suggest that LF82 has tamed its prophages in macrophages and also suggest that if they convey fitness advantages, they probably do so in environments differing from macrophages, and which remain to be discovered.
Phage production is blocked in the adherent-invasive Escherichia coli LF82 upon macrophage infection
Author summary Prophages are bacterial viruses stably integrated into their host, to which they can provide new functions, thus increasing their fitness in the environment. Thereby, they can participate to the virulence of bacterial pathogens. However, prophages are double-edged swords that can...
journals.plos.org
kiny
Well-known member
I watched the video up there.
I have my own experience and read many stories about people on this forum developing crohn's disease. It happens suddenly after an episode of gastroenteritis. People often throw up, develop fevers, night sweats etc.
This can be caused by an acute foodborne infection. Salmonella, E coli (closely related to salmonella), campylobacter, Yersinia.
But gastroenteritis can also be caused by a Norovirus.
A Norovirus would explain the clustering of crohn's disease, it would make crohn's disease a transmissible disease. We still don't know if crohn's disease is transmissible or not. The general consensus among doctors is that it is not transmissible, the truth is that we don't know at all.
I have my own experience and read many stories about people on this forum developing crohn's disease. It happens suddenly after an episode of gastroenteritis. People often throw up, develop fevers, night sweats etc.
This can be caused by an acute foodborne infection. Salmonella, E coli (closely related to salmonella), campylobacter, Yersinia.
But gastroenteritis can also be caused by a Norovirus.
A Norovirus would explain the clustering of crohn's disease, it would make crohn's disease a transmissible disease. We still don't know if crohn's disease is transmissible or not. The general consensus among doctors is that it is not transmissible, the truth is that we don't know at all.
Obviously Moderna wants to have a play in this so they brought Dr. Jeffrey out of academics and made her the head of this new division. Her findings esp the second part of the video are impressive. She was certain, backed up by all the patient data at her hospital and proposed to solve it using vaccines. She believes she is in a good position to carry this to the finish line since Moderna is experienced with trials and making vaccines. This, virome, is all very new compared to what we have been talking about for years.
kiny
Well-known member
Hm. Well a question that hasn't been answered yet is why crohn's disease patients relapse.
The inflammation in crohn's disease is deep and transmural, yet people can achieve full mucosal healing. But yet people relapse. The small intestine is densely packed with peyer's patches, paneth cells, TLR. If there's some kind of pathogen out there sticking to the intestinal wall, it knows. People in remission have somehow eliminated a great number of these bacteria, by modulating the microbiome, by starving them out, or because dendritic cells and macrophages removed them.
Something is causing people to relapse. A bacteria, fungi or a virus.
The inflammation in crohn's disease is deep and transmural, yet people can achieve full mucosal healing. But yet people relapse. The small intestine is densely packed with peyer's patches, paneth cells, TLR. If there's some kind of pathogen out there sticking to the intestinal wall, it knows. People in remission have somehow eliminated a great number of these bacteria, by modulating the microbiome, by starving them out, or because dendritic cells and macrophages removed them.
Something is causing people to relapse. A bacteria, fungi or a virus.
OK, now I am in a knot. So if a person on medication achieves mucosal healing, are we saying that 1) the pathogen is successfully eliminated *and* 2) the immune system on overdrive is calmed to a normal level? I don't think so, right? It seems to me that the medication only does 2) and when the medicine is stopped, then the inflammation comes back and the patient relapses because 1) is never dealt with.
Unless... we are saying that the mucosal healing by medication is never true mucosal healing.
kiny
Well-known member
If they're not on immune suppressors, if they're on EN for example, and achieve remission, we see a large reduction in pathogenic bacteria.
That doesn't mean these bacteria are no longer present, they have just been removed from the intestinal wall. Most of the bacteria reside in the lumen, and don't come into contact with the intestinal wall.
It is pathogenic bacteria that try to enter tissue, pathogenic E coli through fimbriae for example.
The small intestine is highly sensitive to pathogens. It is an epicenter of macrophages waiting to spring into action. If any TLR or peyer's patch detect any pathogen near the intestinal wall, the immune system will react, and within 2 or 3 days there will be a full adaptive immune response.
So yes, I assume someone with full mucosal healing has to have largely eliminated any pathogens near the intestinal wall and within the lamina propria.
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kiny
Well-known member
Right. And there's no straightforward explanation for this. Healthy controls harbour AIEC for example, they're less virulent and in smaller numbers, but some healthy controls harbour them.
There's no reason why someone with crohn's disease in clinical remission, should suddenly relapse if the intestinal wall has healed. Something is triggering a relapse in patients.
I mean we can use the case of people who slowly add solids back into the diet once they achieve full remission using EEN. The inflammation comes back and it's very hard for me to think that solids bring on the problem especially if the gut is healed fully. However solid foods are an event for sure that kicks off a chain reaction, everytime.
kiny
Well-known member
Right. Let me put it this way, these bacteria like AIEC and Klebsiella cause inflammation in crohn's disease. If these can be successfully removed through bacteriophages or disarmed through FimH blockers, there should be a large reduction in inflammation. Crohn's disease might become a much milder and more manageable disease like IBS.
Even if people relapse, maybe because these bacteria can not be fully eliminated. Maybe because there is a virus at play. The disease should become milder as we discover more about what triggers the inflammation.
We don't know the exact trigger that causes relapses. What we do know is that certain bacteria are bad actors that cause a lot of the damage and inflammation in the intestine. Maybe these bacteria are the trigger, maybe they are just exploiting a viral infection, they need to be removed.
Does anyone know how the phage trials are progressing? I think a lot of us are very ready for a positive leap forward with understanding and treating this wretched disease
I am only aware of one such trial at Mt Sinai:
Intralytix, Inc. Bacteriophage Home
Intralytix is a biotechnology company based in Baltimore, Maryland, USA that specializes in the development and commercialization of bacteriophage-based products for food safety and human health.
www.intralytix.com
Active recruiting:
Dr. Hirten's email: robert.hirten@mountsinai.org
He is super accessible. My son is too young to participate but perhaps you can reach out.
Interesting article on progress in using phages to kill bacteria instead of antibiotics (not specifically about IBD):
www.nature.com
Microbiome-friendly phages join the campaign for better antimicrobials - Nature Biotechnology
Biotech companies are racing to test bacteriophages — some as found in nature, others armed with CRISPR–Cas — to destroy drug-resistant bacteria selectively while keeping the microbiome intact.
www.nature.com
We don't. That's the big problem with pretty much all microbiome studies that show an association between some organism and a given disease - can't distinguish cause from effect. No one has ever proven cause by fulfilling Koch's Postulates for IBD, and it would probably be unethical to try.
kiny
Well-known member
There's enough pieces of evidence that show host-pathogen interactions are driving the inflammation in crohn's disease.
1) The inflammation happens where the bacteria are. In the very distal part of the small intestine (ileum) and colon. Bacterial populations drop exponentially the more you move up the GI tract. Crohn's disease doesn't manifest itself more proximally, the number of people who supposedly have crohn's disease in the duodenum is less than 1%, extremely rare, and they tend to have mild and manageable symptoms. Do these people even have crohn's disease, it's unlikely.
2) Genetic anomalies that tilt a person's chance to develop crohn's disease, are related to the recognition (NOD2) of pathogens, or to cell authophagy (xenophagy) processes to eliminated these bacteria (ATG16L1)
3) Crohn's disease looks like a form of chronic relapsing gastroenteritis. Crohn's disease mimics most closely intestinal TB, the type of granuloma found in intestinal TB can look exactly like those found in crohn's. Because intestinal TB is rare in the Western world, misdiganosis is uncommon, but now that crohn's disease is increasingly found in Asia and South America, crohn's disease is often mistakingly diagnosed as intestinal TB. In fact Dalziel initially thought the first cases of crohn's disease he identified were TB, a pathologist looked at tissue, to his surprise he didn't find TB, and Dalziel concluded it was a form of chronic ileitis, crohn's.
4) Germ free mice don't develop ileitis, they don't develop crohn's disease, you need this host-bacteria interaction to mimic the immune response in crohn's disease. In a germ free world crohn's disease wouldn't exist, it can't exist, it is the host-pathogen interaction that is driving the inflammation, it is the required precursor for the inflammation we see. You have to have pathogens interacting with immune cells residing in the lamina propria and in peyer's patches to have this inflammatory cascade.
1) The inflammation happens where the bacteria are. In the very distal part of the small intestine (ileum) and colon. Bacterial populations drop exponentially the more you move up the GI tract. Crohn's disease doesn't manifest itself more proximally, the number of people who supposedly have crohn's disease in the duodenum is less than 1%, extremely rare, and they tend to have mild and manageable symptoms. Do these people even have crohn's disease, it's unlikely.
2) Genetic anomalies that tilt a person's chance to develop crohn's disease, are related to the recognition (NOD2) of pathogens, or to cell authophagy (xenophagy) processes to eliminated these bacteria (ATG16L1)
3) Crohn's disease looks like a form of chronic relapsing gastroenteritis. Crohn's disease mimics most closely intestinal TB, the type of granuloma found in intestinal TB can look exactly like those found in crohn's. Because intestinal TB is rare in the Western world, misdiganosis is uncommon, but now that crohn's disease is increasingly found in Asia and South America, crohn's disease is often mistakingly diagnosed as intestinal TB. In fact Dalziel initially thought the first cases of crohn's disease he identified were TB, a pathologist looked at tissue, to his surprise he didn't find TB, and Dalziel concluded it was a form of chronic ileitis, crohn's.
4) Germ free mice don't develop ileitis, they don't develop crohn's disease, you need this host-bacteria interaction to mimic the immune response in crohn's disease. In a germ free world crohn's disease wouldn't exist, it can't exist, it is the host-pathogen interaction that is driving the inflammation, it is the required precursor for the inflammation we see. You have to have pathogens interacting with immune cells residing in the lamina propria and in peyer's patches to have this inflammatory cascade.
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kiny
Well-known member
The question if crohn's disease is related to host-pathogen interactions is really no longer up for debate, it's clearly driving the inflammation.
What is up for debate is what drives dysbiosis, does dysbiosis drive inflammation or is dysbiosis a result of inflammation.
The idea that dysbiosis could simply be a result of inflammation is supported by evidence other inflammatory conditions result in dysbios. Another piece of evidence that dysbiosis might not result in inflammation is the fact people using EN to bring down inflammation tend to have very dysbiotic microbiomes, yet they are in remission.
What is up for debate is what drives dysbiosis, does dysbiosis drive inflammation or is dysbiosis a result of inflammation.
The idea that dysbiosis could simply be a result of inflammation is supported by evidence other inflammatory conditions result in dysbios. Another piece of evidence that dysbiosis might not result in inflammation is the fact people using EN to bring down inflammation tend to have very dysbiotic microbiomes, yet they are in remission.
kiny
Well-known member
That's not to say one can't entertain the idea that pathogens aren't involved. But we've looked at these theories and excluded them one by one.
A compelling theory has been the idea that these immune cells are not responding to pathogens, but to inert particles that somehow cross the epithelial barrier. Titanium Dioxide has been suggested a few times, but you would expect inflammation to be present everywhere, people would develop inflammation higher up the GI tract. In mice models these reactions to Tio2 are not limited to one part of the GI tract. These theories don't make that much sense, they don't translate well to crohn's disease. Crohn's disease consistently develops in parts of the GI tract where bacteria reside.
A compelling theory has been the idea that these immune cells are not responding to pathogens, but to inert particles that somehow cross the epithelial barrier. Titanium Dioxide has been suggested a few times, but you would expect inflammation to be present everywhere, people would develop inflammation higher up the GI tract. In mice models these reactions to Tio2 are not limited to one part of the GI tract. These theories don't make that much sense, they don't translate well to crohn's disease. Crohn's disease consistently develops in parts of the GI tract where bacteria reside.
I'm curious about this whole idea because one of my twins was given flagyl by his PCP before we really knew he had Crohn's and when we were desperate because he wasn't eating. He was negative for C Diff.The flagyl correlated with by far a more dramatic improvement in his symptoms than any other crohn's medication either of my kids have been given since then. When we mentioned this to a few different docs, they just sort of scratched their heads and moved on.