1973. Intravenous alimentation.

[kiny]

1973-1977 discussion on use of Intravenous alimention (bowel rest) in crohn's disease for nutritional support. Subsequent realisation it induces remission in patients with Crohn's disease, but not UC. Crohn's Disease was referred to as Regional Enteritis back then.

DR. FRANCIS C. NANCE (New Orleans, Louisiana):

I think this is a very important study. It represents the tenth anniversary of the
introduction of intravenous hyperalimentation at the University of Pennsylvania, and by definition they have the longest followup of patients managed by this technique.

We have had similar observations in treating patients with inflammatory bowel disease, particularly in patients with regional enteritis and granulomatous colitis. We have been gratified to see resolution of fistulas and what we think is reduction in the severity of
disease.

I'd like to ask Dr. Fitts some specific questions. Have you seen any physical disappearance of the typical granulomatous lesions while the patient is on hyperalimentation? In other words, can this in any way be considered definitive therapy for regional enteritis or granulomatous colitis?

Our own clinical observations are that the patients with regional enteritis and granulomatous lesions respond better than patients with ulcerative colitis. Have you seen patients with florid ulcerative colitis who have not responded at all to hyperalimentation, except in a general increase in their nutritional support?


DR. FRANCIS E. ROSATO (Norfolk, Virginia):

I'd like to thank Dr. Fitts and the other pioneers at the University of Pennsylvania not only for the development of IVH, but for updating their informative and timely experience again.

There are a lot of points in this paper that are worthy of discussion.

First of all, there has been a reported anergy in a fair percentage of patients with chronic inflammatory bowel disease, specifically in their nonreactivity to DNCB, and also in their failure to respond to the mitogen PHA. Along a similar track, there is a body of literature that supports the notion that there is a return to immune competence with intravenous hyperalimentation.

I'm wondering if some of the improvement that one sees in patients with chronic inflammatory bowel disease treated by hyperalimentation might not be due partially, at least, to a restoration to immune competence. Do you have any studies, Dr. Fitts, that would relate to measured immune parameters during the course of treatment?

A last point worth emphasizing is the impressive figure of approximately 40% IVH induced remission, and approximately a 40% rate of non-operative fistula closure with intravenous hyperalimentation.

And to echo Dr. Nance's question, I would ask you again: How long do you persist at the outside in continuing the IVH, in the hope of producing a non-operative remission?

 

[kiny]

I would like to know what happened with GI and research between the 70s and today.

TPN is from 1960 when Stanley Dudrick introduced it in clinical practice. In the 70s doctors realized TPN and EN induced remission in crohn's disease patients.

The data that dietary intervention through TPN and EN induces robust clinical remission and often fistula closure in adult crohn's disease patients is 50 years old. And some GI are waking up to this fact just now. You have had the data for 50 years and you did nothing with it. What happened.

 

[westernbuddy]

How much influence has America had on this, As in America sickness is a business I would guess they can't make as much on drinks as they can for surgery or nights spent in hospital.

 

[kiny]

Not sure, but discussions regaring crohn's disease clearly went completely off track after the 1970s. During the 90s and 2000s, crohn's disease was referred to by GI as an "overreactive immune system" without any proof. GI were adamant that dietary manipulation was useless.

Pathogens didn't matter, regardless of the fact the intestine is exposed to the highest number of bacteria and fungi, crohn's disease was simply "autoimmunity" where our immune system decided to attack our own intestine one day for some reason, no proof of a self-antigen was even required to spout this nonsense.

Only now are we seeing some sense return. EN is again recommended, not only for children, but also adults.

Now we are finally seeing some sense coming back, and papers that show innate immunodeficiencies in crohn's disease manifesting itself as early phagocyte incompetence (macrophage and xenophagy incompetence, ATG16L1), lack of pathogen recognition (NOD2), lack of neutrophil recruitment being referenced again, and the realisation the fecal stream high in bacterial load is involved in inflammation.

Crohn's disease and UC are talked about as independent diseases again. Not just "IBD" which is a horrible term. The fact treatment needs to be disease and location specific, the fact Crohn's disease and UC involve very different genetic anomalies. The realisation that the ileum is very different from the colon and will respond very differently to treatment.

Note that GI from the 70s all knew this already. Note they realized crohn's disease involved immunodeficiency, and the realisation that reversal of immunodeficiency towards immunocompetence is required to see resolve of disease state:

"....nonreactivity to DNCB, and also in their failure to respond to the mitogen PHA.... there is a body of literature that supports the notion that there is a return to immune competence with intravenous hyperalimentation. ..."

 

[longzhiwu]

Not sure, but discussions regaring crohn's disease clearly went completely off track after the 1970s. During the 90s and 2000s, crohn's disease was referred to by GI as an "overreactive immune system" without any proof. GI were adamant that dietary manipulation was useless.

Pathogens didn't matter, regardless of the fact the intestine is exposed to the highest number of bacteria and fungi, crohn's disease was simply "autoimmunity" where our immune system decided to attack our own intestine one day for some reason, no proof of a self-antigen was even required to spout this nonsense.

Only now are we seeing some sense return. EN is again recommended, not only for children, but also adults.

Now we are finally seeing some sense coming back, and papers that show innate immunodeficiencies in crohn's disease manifesting itself as early phagocyte incompetence (macrophage and xenophagy incompetence, ATG16L1), lack of pathogen recognition (NOD2), lack of neutrophil recruitment being referenced again, and the realisation the fecal stream high in bacterial load is involved in inflammation.

Crohn's disease and UC are talked about as independent diseases again. Not just "IBD" which is a horrible term. The fact treatment needs to be disease and location specific, the fact Crohn's disease and UC involve very different genetic anomalies. The realisation that the ileum is very different from the colon and will respond very differently to treatment.

Note that GI from the 70s all knew this already. Note they realized crohn's disease involved immunodeficiency, and the realisation that reversal of immunodeficiency towards immunocompetence is required to see resolve of disease state:

"....nonreactivity to DNCB, and also in their failure to respond to the mitogen PHA.... there is a body of literature that supports the notion that there is a return to immune competence with intravenous hyperalimentation. ..."

There was a trial that tested the efficacy of antibiotics(Ciprofloxacin+ Rifaximin) targeting AIEC in CD patients. But the results are not optimistic.In the conclusion, they think that there was no association between AIEC clearance and endoscopic endpoints. What do you think of the conclusion?

https://academic.oup.com/ecco-jcc/article/18/Supplement_1/i1650/7586692?login=false

 

[kiny]

Rifaximin is only advised for noninvasive E coli like travellers diarrhoea. Rifaximin is non-systemic, unable to penetrate activated tissue macrophages in crohn's disease, so I don't understand the intention of that study. In crohn's disease you have chronically activated lamina propria macrophages, the immune reaction is not targeted at non-invasive lumen species, but at pathogens in tissue and the fecal stream.

However, broad spectrum macrophage penetrating quinolones, like cipro, are very effective in inducing acute remission in crohn's disease. Plenty of studies have shown this, they're able to penetrate tissue very successfully and penetrate activated macrophages very well. And because they are so broad spectrum, they limit the antigenic potential of the fecal stream. But you can't give macrophage penetrating antibiotics for very long, you can't leave someone on cipro for months, due to potential side effects, and you simply will run into resistance in a matter of weeks.

The study mentioned they ran into cipro resistance. Long-term use of cipro will cause significant resistance, it's not a long-term solution to induce remission. It's certainly not going to be very effective in combination with rifaximin at 12 weeks like that study tried to do, you will just create resistance and give pathogenic species a fitness advantage by wiping out everything else.

Antibiotics use and foodborne infections are highly linked to crohn's disease onset, it's ill advised to just concoct antibiotic cocktails that wipe out the gut flora, it leaves patients vulnerable to foodborne infections by giving resistant pathogens a nutrient and fitness advantage. Whatever benefit they thought Rifaximin would offer, could be quickly undone if you wipe out the gut flora and give pathogenic bacteria and fungi a nutrient advantage.

Antibiotics are however useful for crohn's disease cases where you simply can not induce remission with anti-inflammatories but you want to induce acute remission, there cipro has shown to be very helpful. Cipro causes acute but short-lived remission in stubborn cases, and requires a longer-term solution.

 

[kiny]

Those studies where multiple macrophage penetrating antibiotics are successfully used to induce remission for months in crohn's disease patients, the so-called antibiotic cocktails, likely are effective. But you're exposing patients to an aggressive course of antibiotics, you require 3 or 4 antibiotics to overcome resistance, and you leave patients not only vulnerable to side effects, but you're in uncharted territory when patients develop a resistant secondary infection while you've put them on months of antibiotics.

Crohn's disease does not exist in a sterile environment. Crohn's disease does not exist higher up the GI tract, it manifests itself in the ileum, colon and mouth, not in the duodenum where bacterial load is low. If tissue phagocytes are not exposed to pathogens and can't present antigen to lymphocytes, no inflammation is possible. But there are limits to what you can do to make that environment sterile.

Antibiotics have side effects and run into resistance. IV feeds to remove the fecal stream have the risk of infection. EN however has no known side effects (slight potassium shortage which is easily corrected), and is effective at lowering bacterial load.

 

[J100]

Can the viral macrophages help in treating AIEC?

 

[Scipio]

Can the viral macrophages help in treating AIEC?

I assume you mean bacteriophages, and they could in theory help. But bacteriophage (usually just called "phage") therapy research has progressed only slowly over the decades. It has usually proven to be cheaper and easier to chase a new antibiotic than it is to develop a phage into an FDA-approvable product.

 

[Andersen007]

What I dont get in all this - if I get a strep throat, or even something as bad as C Diff, you get antibiotics - yes sometimes for complicated stuff you get many rounds of cocktails etc - but once its done, its done, you are healed. Of course you may get infected again but more likely than not it wont happen for a long time. So what is so special about a potential Crohn's causing bacteria, that it seems to come back pretty much as soon as the antibiotics stop? Can these antibiotics never completely eliminate them? Or is it something so common that we get 'reinfected' all the time?

 

[Scipio]

So what is so special about a potential Crohn's causing bacteria, that it seems to come back pretty much as soon as the antibiotics stop? Can these antibiotics never completely eliminate them? Or is it something so common that we get 'reinfected' all the time?

If we knew a hard, fast answer to that question we would understand the cause (by implication perhaps the cure) of Crohn's a lot better than we do right now. That question also assumes there is one big bacterial answer to Crohn's, and it's probably not nearly so simple.

To begin with, IMO, the phrase "Crohn's causing bacteria" would more accurately be stated as Crohn's-triggering micro-organisms. The "cause" is likely multi-factorial - with genetics, immune system (mal)function, diet, environmental toxin exposure, as well as an infection with a triggering micro-organism (not necessarily bacterial) playing a role. Some variable permutation of these factors combine in a given patient to start the Crohn's ball rolling. And once it starts rolling, it's going to take more than a course of antibiotics to stop it.

The various current therapies address one or more of these factors in an attempt to stop, or at least slow, the rolling:

• There is nothing to be done about a patient's genetics, at least not yet. You are stuck with the genes you are born with.
• Biologics and immunosuppressants attempt to prevent or at least reduce the gut-damaging activity of the immune system.
• Special diets, avoidance of food additives and other chemicals, and perhaps EEN attempt address diet problems and toxin exposure.
• Antibiotics and EEN attempt to remove or reduce exposure to triggering micro-organisms.

And they all work - up to a point. But none of them alone is the one solution to Crohn's.

Some bacteria and certainly some viruses can hide out inside of phagocytic cells, more or less forever, where antibiotics have a hard time getting after them, and antibiotics have no effect on viruses in the first place. And some gut bacteria do readily come right back after being wiped out by the antibiotics. Plus, in active Crohn's, the immune system has shredded the bowel tissue, leaving the gut much more exposed and susceptible to whatever bacteria come back or maybe never went completely away. So these facts may well explain why antibiotics have been a disappointment when it comes to curing Crohn's disease.

And thus a search for cure continues....

 

[longzhiwu]

I assume you mean bacteriophages, and they could in theory help. But bacteriophage (usually just called "phage") therapy research has progressed only slowly over the decades. It has usually proven to be cheaper and easier to chase a new antibiotic than it is to develop a phage into an FDA-approvable product.

Do you know the Ecoactive？It's a collection of bacteriophages targeting AIEC and undergoing phase 2. Are you looking for it?

https://classic.clinicaltrials.gov/ct2/show/NCT03808103?term=aiec&draw=2&rank=3

 

[kiny]

Crohn's disease involves a defective innate immune response. You can see this from the susceptibility loci. NOD2 and ATG16L1 mutations hinders competent authophagy required for clearance of intracellular pathogens.

ATG16L1, or Autophagy related 16 like 1. Most people know autophagy can be induced through starvation, fewer know it is just as essential during infection. The type of autophagy directed at microbes is called "xenophagy". It's especially important when pathogens escape phagocytosis, one could make the assumption people with crohn's disease are likely not just more susceptible to intracellular pathogens, but specifically mycobateria like TB and leprae, luckily in the Western world TB is "relatively" rare.

The association with very young children with crohn's disease and ATG16L1 is a lot weaker. Which is why I sometimes wonder if 5-10 year olds actually have the same "crohn's disease" as people who generally develop it during puberty who do have a strong association with ATG16L1 and NOD2 mutations.

Note there is no association with ATG16L1 nor NOD2 and UC. The association between Crohn's disease and pathogens is very strong, but is actually quite weak in UC.

Many people without crohn's disease have these mutations too. They are likely more susceptible to a salmonella infection for example, but they somehow don't develop crohn's disease. Why not. And many people with crohn's disease don't have these mutations.

A clue is likely in the fact EN induces very high rates of remission. There is something within the fecal stream triggering the disease, and EN is somehow able to either limit this exposure, or somehow helps to restore innate immune competence.

 

[Scipio]

Many people without crohn's disease have these mutations too.

And conversely, many people without these mutations have Crohn's disease too - including me. I have ileal Crohn's disease yet I have the "normal" non-mutant alleles at both these loci. These genetic associations are merely that: associations, not yes or no causes.

 

[kiny]

Can the viral macrophages help in treating AIEC?

Macrophages are the immune cells of the innate immune system. They're very important in crohn's disease, they are the primary defense when microbes manage to get past our first defense, the physical intestinal barrier made up of the mucus layer and epithelial cells. Pathogens will encounter macrophages next, in the lamina propria. The intestine has very high concentractions of these macrophages compared to the rest of the body. These macrophages literally ingest pathogens into vesicles, and they produce substances that kill them.

For some reason, these macrophages are chronically activated in crohn's disease. They seem unable to kill whatever it is they are trying to kill.

This causes a chronic immune response, which ends up unwillingly damaging the intestinal lining, resulting in fecal matter and other substances entering tissue, making the situation even worse.

When people go on anti-inflammatories, this destructive inflammation subsides, anti-TNF for example blocks the inflammatory cytokine that macrophages release, namely TNF-a, and you get mucosal healing. But the moment anti-inflammatories are stopped, or people develop resistance, inflammation returns, which seems to show the offending pathogen either is still there, or is chronically being ingested.

 

[kiny]

It's very possible that the innate immunodeficiency stage presented in crohn's dsiease is actually quite minor. We don't tend to have major issues clearing non-GI infections.

But when the epithelial barrier is compromised after chronic inflammation due to innate immunodeficiencies, large amounts of lumen content will suddenly enter tissue, and likely overwhelm the intestine. Removal of the fecal stream or limiting the fecal stream likely is one reason why IV feeds and EN work. EN limits fecal matter and limits bowel movements, which limits bacterial content entering tissue.

It's interesting that when remission is achieved with IV or EN, calprotectin drops below 200 in patients, but rarely goes all the way down to <50. It might be that the offending pathogens is actually not the main driver of inflammation, but initiates the chronic inflammation, which leads to bowel content entering tissue, which then leads to deep transmural inflammation.

 

[J100]

It's very possible that the innate immunodeficiency stage presented in crohn's dsiease is actually quite minor. We don't tend to have major issues clearing non-GI infections.

But when the epithelial barrier is compromised after chronic inflammation due to innate immunodeficiencies, large amounts of lumen content will suddenly enter tissue, and likely overwhelm the intestine. Removal of the fecal stream or limiting the fecal stream likely is one reason why IV feeds and EN work. EN limits fecal matter and limits bowel movements, which limits bacterial content entering tissue.

It's interesting that when remission is achieved with IV or EN, calprotectin drops below 200 in patients, but rarely goes all the way down to <50. It might be that the offending pathogens is actually not the main driver of inflammation, but initiates the chronic inflammation, which leads to bowel content entering tissue, which then leads to deep transmural inflammation.

Thanks for your response. How can we measure the integrity of epithelial wall of the intestines? Is there a nin-invasive test such as an ultrasound?

 

[kiny]

MRI and ultrasound are cross-sectional, they can show increased wall thickness indicating inflammation. You compare wall thickness on the slide with other parts of the intestine, and you can literally measure it, below 3mm is normal, above 4mm indicates disease activity.

But only colonoscopies and biopsies can show mucosal and epithelial integrity. They can also show immune cell activity like granuloma. And you can take biopsies, do histology, stain it to find foodborne or myco infections, etc.

Of course, these 2 are linked, inflammation subsiding allows for mucosal healing. Besides CRP and calprotectin, mucosal healing is how we judge the effectiveness of treatment inducing remission.