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Systematic review: gastrointestinal infection and incident inflammatory bowel disease

Aliment Pharmacol Ther. 2020 Jun;51(12):1222-1232. doi: 10.1111/apt.15770. 2020 May 5.

Systematic review: gastrointestinal infection and incident inflammatory bowel disease

Jordan E Axelrad 1 , Ken H Cadwell 1 2 , Jean-Frederic Colombel 3 , Shailja C Shah 4
PMID: 32372471 PMCID: PMC7354095 (available on 2021-06-01) DOI: 10.1111/apt.15770
Free PMC article


: The initiating events of chronic gastrointestinal (GI) inflammation in Crohn's disease (CD) and ulcerative colitis (UC) are not well-defined, but GI infections are implicated.

Aims: To define the role of GI infections in risk of incident inflammatory bowel disease (IBD) and synthesise the current body of relevant translational data to provide biological context for associations between GI infections and IBD risk.

Methods: We systematically reviewed electronic databases through February 2020. Clinical studies that provided risk estimates of the association between GI infections and incident IBD were included. Inclusion criteria were broader for translational studies aiming to define mechanisms of GI infections and predisposition to or protection from IBD.

Results: Of the studies identified, 63 met full inclusion criteria. Among studies of clinical gastroenteritis, bacteria-specifically, Salmonella species, Campylobacter species and Clostridioides difficile-demonstrated consistent positive associations with risk of incident IBD. Of viruses, norovirus was associated with increased risk of incident CD. Regarding inverse associations with incident IBD, Helicobacter pylori and helminth infections were associated with a generally consistent reduced risk of IBD. Based on a qualitative analysis of the translational data, putative mechanisms involve multiple microbial and immunologic pathways.

Conclusions: Based on this systematic review, certain enteric pathogens are associated with an increased risk of incident IBD, while others are potentially protective. Prospective studies are required to clarify the clinical implications of these enteric pathogens on the risk and course of IBD, and possible therapeutic or preventative benefit.

Axelrad JE, Cadwell KH, Colombel JF, Shah SC. Systematic review: gastrointestinal infection and incident inflammatory bowel disease. Aliment Pharmacol Ther. 2020;51(12):1222-1232. doi:10.1111/apt.15770

Full text: https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/apt.15770?download=true



...Relatedly, in developing countries where there is generally also a higher burden of enteric infections, the observed incidence of IBD is also lower, although there are most certainly other underlying contributory factors.
H. pylori is the most common chronic bacterial infection worldwide, with over 4.4 billion people estimated to be infected.76 There is marked global variation in H. pylori prevalence, however, with colonisation significantly more common in developing or recently developed countries, including Asian‐Pacific and Central/South American countries, with a much lower overall prevalence in Western industrialised countries.76 From a population standpoint, the decline in H. pylori corresponds to an increase in immune‐mediated diseases, particularly IBD. Early‐in‐life H. pylori exposure is associated with important immunomodulatory effects and alterations in the gut microbiome.22, 77 IBD is now increasingly diagnosed in populations where the decline in H. pylori has been most striking, especially the Asia‐Pacific region. Epidemiologic studies demonstrate an inverse association between H. pylori exposure and IBD, particularly CD. It is hypothesised that H. pylori strain‐specific constituents, such as CagA, are important mediators of this protective response, although this has not been well studied. A recent small meta‐analysis did provide some supportive evidence for this hypothesis, however, and demonstrated significantly lower odds of IBD associated with CagA seropositivity vs CagA seronegativity that was driven primarily by the reduced odds in CD as opposed to UC. Notably, there was no significant protective benefit of H. pylori exposure with respect to odds of IBD, CD or UC in the absence of CagA seropositivity, suggesting that CagA seropositivity itself or as a surrogate of other unmeasured effects accounted in large part for the protective benefit observed.22 The consistency in H. pylori and risk of IBD across geographic regions,13 albeit with a stronger association in Asian‐Pacific countries, should be highlighted, as other environmental exposures connected with incident IBD, such as childhood antibiotics, appendicitis, and Campylobacter , have not demonstrated this same broad geographic consistency. It should be emphasised, though, that not all Helicobacter species are inversely associated with IBD, particularly EHS.
Declaration of personal interests : Jordan E. Axelrad has served as a consultant for BioFire Diagnostics. Dr. Axelrad has received research grants from BioFire Diagnostics. Ken Cadwell has served as a consultant or received an honorarium from Puretech Health, Genentech, and AbbVie, and has a provisional patent, U.S. Patent Appln. No. 15/625,934. Jean‐Frederic Colombel has served as a consultant or advisory board member for AbbVie, Amgen, Boehringer‐Ingelheim, Celgene Corporation, Celltrion, Enterome, Ferring, Genentech, Janssen and Janssen, Medimmune, Merck & Co., Pfizer, Protagonist, Second Genome, Seres, Shire, Takeda and Theradiag; a speaker for AbbVie, Ferring; speaker's bureau for Amgen. Dr. Colombel has received research grants from Takeda, Johnson and Johnson, and is a stockholder of Intestinal Biotech Development and Genefit. Shailja Shah discloses no relevant personal or financial conflicts of interest.
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Salmonella and Campylobacter infections are very common in the western world. It is inevitable that a considerable portion of crohn's disease patients will be infected with campylobacter and salmonella species.
Acute exposure to macrophage penetratig bacteria like campylobacter and salmonella in a patient with a compromised epithelial barrier and tight junctions, would allow those bacteria easy access into deeper tissue, and could explain flares. There's currently no explanation why crohn's disease patients flare.

We know the epithelial barrier and tight junctions are compromised in crohn's disease patients, and E Coli (AIEC) and other species are taking advanvtage of this, leading to chronic inflammation.

But this doesn't solely explain flares, it also doesn't fully explain disease onset. We can now predict crohn's disease years in advance by looking at species like E Coli, but you still need an acute environmental trigger that results in the breakdown of the epithelial barrier. The trigger needs to be a common environmental trigger considering the number of patients with crohn's disease. The trigger also needs to be one that can explain the household clustering seen in crohn's disease. Campylobacter, Yersinia and Salmonella are candidates that are common enough to explain disease onset and flares. Food poisoning with those bacteria would also explain household clustering.
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If you argue crohn's disease is a reaciton to the microbiome, the explanation hits a roadblock once you notice how patchy the inflammation is in patients. The ileum isn't inflamed, it is specific patches in the ileum.

If it was a reaction against the microbiome, you would expect there to be inflammation everywhere. That is not the case.

The immune system is not reacting to the microbiome, it is reacting to a very specific antigen. Neither superficial nor broad. It is a very deliberate and targeted response that happens in deeper tissue of the lamina propria.

Commensal E Coli species are part of the healthy microbiome, pathogenic E coli species are not, they are pathogens and aren't part of the microbiome. Describing them as pathobionts is rather far fetched too, AIEC are clearly pathogenic in nature, they are invasive and provoke an an acute inflammatory response, macrophages are keenly aware they don't belong in the human intestine.

The one immunological differentiator that makes the ileum unlike the rest of the small intestine and colon, is the presence of peyer's patches. They are only found in the ileum, and lymphoid follicles of peyer's patches are prime targets of entry for foodborne bacteria like salmonella, e coli and yersinia.

The few images we have of early onset crohn's disease through an edoscope, show a patchwork of inflamed lymphoid follicles.
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Regarding the Norovirus results. If the disease and flares are explained by chronic Norovirus infections, it would mean that Crohn's disease is communicable.

Bacterial foodbrone infections explain the household clustering of crohn's disease because one shares the same food source. Norovirus infections on the other hand, would mean that the household clustering is because crohn's disease is contageous.
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It's difficult to explain household clustering seen in crohn's diseasse, without attributing it to an infectious agent.

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AIEC has been seen in household pets like cats and dogs, it is one of the possible explanations for the household clustering. Another explanation would be foodborne infections with campylobacter or salmonella, this is a theory Anthony Segal supports. An initial Campylobacter or salmonella infection would compromise the epithelial barrier, allowing the chronic entry of other pathogens like E coli .

The theory that makes the most sense to me is the Foodborne theory that Anthony Segal supports. A foodborne infection would be the trigger. Salmonella and Campylobacter infections are common in the Western world. Even Yersinia and Listeria infections are common enough in the western world to explain the numbers of crohn's disease patients. Species like AIEC would then maintain the chronic inflammation.

The foodborne infecion is the trigger that would explain the rapid onset of crohn's disease, fevers, night sweats, these all happen in the first few days when people develop crohn's disease. This infection is overcome, which is why the fevers and night sweats tend to subside, but this leaves a permeable bowel behind, a compromised epithelial barrier that would allow entry into the lamina propria of pathogens like AIEC, and would make it easier to enter M cells of peyer's patches, this then leads to chronic inflammation.

We can now predict crohn's disease with high accuracy by looking at invasive E coli species with stool samples. The trigger that's needed is a microorganism that does enough damage to allow those E Coli species deeper access into tissue. Foodborne infections are the most reasonable explanation.

The OP's metastudy did support the theory of active campylobacter, salmonella and yersinia in crohn's disease patients, but that is not even a requirement to support the theory. The foodborne infection is simply a trigger event, AIEC just needs the epithelial barrier to be sufficiently damage to gain easy access to deeper tissue, the presence of those foodborne bacteria is no longer needed at that point. Most studies, including clustering one, do not find an active foodborne infection in patients, and why would they, the initial trigger is simply a trigger, it is overcome. When family clustering studies were done, species that are able to maintain chronic inflammation such as AIEC were yet unknown.

Of course, some people with crohn's disease will get reinfected with Salmonella and Campylobacter, it is statistically inevitable due to the sheer amount of infections in the Western world. When a patient has crohn's disease, this event would simply be explained by arguing the patient has a flare, without checking for any offending pathogens.
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I don't believe in this idea that there are 'protective species'. That somehow if you have certain bacteria, you are protected from developing crohn's disease.

The idea that you can somehow cure crohn's disease by introducing millions of new bacteria into the intestine, is something I think is crazy. Probiotics have never been shown to help in crohn's disease and stool transplants actually cause crohn's disease patients to flare. Who in the right mind would support the idea of introducing bacteria when it is known that crohn's disease patients suffer from breakdown of the epithelial barrier and have immunodeficiencies. AIEC live in biofilms that stick to the epithelial barrier like glue, the only thing that gets through are phages that lyse them.

The few bacteria that might be able to outcompete AIEC are ones like Nissle 1917, another E coli species, but these are very dangerous, toxic producing bacteria that got taken off the market. There's research going on that is trying to 'disarm' Nissle 1917', where it would no longer be toxic, yet would still be able to outcompete AIEC. But regular probiotics are useless against AIEC.
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