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Relationship: 2495

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Disruption of the intestinal barrier leads to Hyperinflammation

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Disruption of the intestinal barrier
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Hyperinflammation

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Male High
Female High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Increased intestinal permeability, sign of an impaired barrier function (KE1931), enhances the translocation of gut bacteria and of bacterial toxins from the intestinal lumen into systemic circulation. This endotoxemia contributes to low-grade systemic inflammation (KE1868).

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

The literature was screened manually for evidence regarding this KER, particularly in the context of COVID-19.

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

The intestinal barrier constitutes an essential interface between the environment and the internal milieu of the body. Together with the mucosal barrier and the cellular immune system, the intestinal epithelial cell monolayer, and the tight junction (TJ) proteins act simultaneously as a physical barrier against harmful external substances, as well as a selective barrier. Increased intestinal permeability, sign of an impaired barrier function (KE1931), enhances the translocation of gut bacteria and of bacterial toxins, such as peptidoglycans (PGN) and LPS, from the intestinal lumen into systemic circulation (KE1868). Increased levels of LPS in the blood (endotoxemia) activates TLRs, leading to the production of numerous pro-inflammatory cytokines and, hence, low-grade systemic inflammation. In critically ill patients with sepsis, bacterial translocation is widely documented, and intestinal barrier disruption is considered as an event perpetuating systemic inflammation.

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Modulating Factor (MF) MF Specification Effect(s) on the KER Reference(s)

Chemicals

(weak evidence)

 PFAS (PFOS) Accumulation of PFOA was observed in the gut tissues of orally-treated mice along with lower expression of many TJ genes [1,2]. PFOS was shown to alter gut microbiota, resulting in a decreased bacterial metabolic activity, which in turn altered gene expression damaging intestinal tissue [3]. In mice, chronic exposure to PFOS decreased the expression of the TJ genes in the intestine and reduced the height of the intestinal villi, indicators of altered intestinal barrier [4]. PFOS exacerbated macrophage and neutrophil recruitment to the intestine in both zebrafish and mice and increased epithelial permeability in mice, which led to a systemic expansion of CD4+ T-cells in a neutrophil-dependent manner [5].

1. doi: 10.3390/toxics8030064

2.doi: 10.1016/j.ecoenv.2020.110590

3. doi: 10.1016/j.tox.2020.152365

4.doi: 10.1016/j.jhazmat.2021.127950

5. doi: 10.1242/dmm.049104

Age

(not in humans)

 Old people Disruption of the intestinal barrier was associated with aging in baboons, along with upregulation of inflammatory cytokines [1]. However, a cross-sectional study in humans assessing gut permeability by validated multi-sugar test and by expression of intestinal barrier-related genes showed no differences between healthy young adults and elderly [2]. Thus, although age-related medication or co-morbidities may impact barrier function, there seems to be currently no indication of impaired intestinal barrier by aging per se in humans.

1. doi: 10.1093/gerona/glt106

2. doi: 10.1038/s41598-019-57106-2
Gut microbiota Gut dysbiosis (alteration of the gut microbiota)

The gut microbiota ensures the integrity of the intestinal barrier through multiple mechanisms, either by releasing antibacterial molecules and anti-inflammatory short chain fatty acids (SCFAs) or by activating essential cell receptors for the immune response [1]. The reduction of beneficial butyrate-producing bacteria contributes to increased intestinal permeability, as butyrate facilitates the regeneration of colonocytes [2,3]. Overgrowth of pathobionts, such as E.coli or S.enterica, disrupts intestinal barrier function, enhancing permeability [4-7].

In COVID-19. Lower levels of butyrate-producers and higher levels of pathogens, including E.coli and S.enterica, have been observed in COVID-19 patients compared to healthy controls [8,9], and changes in gut microbiota composition correlated with plasma levels of tissue damage markers [10]. Another study associated COVID-19 severity-related gut microbial features (higher abundance of four microbial species and ten virulence genes) with higher levels of inflammation biomarkers and lower levels of immune cells and markers of gut barrier dysfunction in COVID-19 patients [11].

1. doi: 10.3389/fmicb.2019.01676

2. doi: 10.3390/cells10071775

3. doi: 10.1186/1757-4749-5-23

4. doi: 10.1111/j.1365-2958.2004.04308.x

5. doi: 10.1128/IAI.72.6.3218-3227.2004

6. doi: 10.1128/IAI.71.2.872-881.2003

7. doi: 10.1073/pnas.88.12.5242

8. doi: 10.1093/cid/ciaa709

9. doi: 10.1002/ctm2.643

10. doi: 10.1136/gutjnl-2020-323020

11. doi: 10.1186/s12916-021-02212-0
Lipids Obesity In obese mice, gut microbiota was shown to regulate metabolic endotoxemia and associated inflammation through intestinal permeability [1]. In addition, obesity can alter the gut microbiota [2-7] and escalate intestinal permeability, enhancing the translocation of bacteria and LPS from the intestine to the blood and adipose tissue, which fuels systemic inflammation.

1. doi: 10.2337/db07-1403

2. doi: 10.1073/pnas.040707610

3. doi: 10.1038/4441022a

4. doi: 10.1073/pnas.050497810

5. doi: 10.1038/nature05414

6. doi: 10.1038/nature06244

7. doi: 10.1126/science.1104816
Vitamin D (moderate evidence) Vitamin D deficiency

Vitamin D deficiency was shown to promote intestinal mucosal barrier dysfunction with higher permeability in infection-induced or TNF-treated cells and in in vivo colitis models [1,2]. An association between increased markers of intestinal permeability and vitamin D deficiency has been observed in critically ill subjects from ICU [3].

[1] doi: 10.1093/infdis/jiu235

[2] doi: 10.1097/MIB.0000000000000526

[3] doi: 10.1136/jim-2019-001132
Genetic factors  

The epithelial cells of the intestinal barrier express TLRs, which upon recognition of LPS induce epithelial cell proliferation, secretion of mucins, and antimicrobial peptides into the lumen, thereby promoting intestinal barrier function. Polymorphisms of TLR2, TLR4 and TLR9 contributing to individual susceptibility to inflammatory bowel disease, characterized by chronic intestinal inflammation and intestinal barrier disruption had originally attracted attention, but currently no strong association has been observed [1,2,3]. Further research is needed to evaluate the impact of TLR polymorphisms on intestinal barrier in the context of COVID-19.

[1] doi: 10.1371/journal.pone.0126803

[2] doi: 10.1371/journal.pone.0175180

[3] doi: 10.1007/s12026-018-9061-0
Air pollution Particulate air pollution

Particulate air pollution may disrupt the intestinal barrier. 

Based on animal studies, exposure to particulate air pollution may disrupt the intestinal barrier by inducing inflammation. This, in turn, makes it a more susceptible site for the entry of pathogens and contributes to hyperinflammation [1].

 [1] doi: 10.1186/1743-8977-8-19
Diet Dietary components or patterns can affect intestinal permeability.
  • A “Western style” diet has been identified as strongly associated with increased intestinal permeability [474].
  • A recent review suggests that high-fat diets increase intestinal permeability by directly and indirectly disrupting TJs, inducing oxidative stress, and increasing pathogenic intestinal bacteria, which further damage barrier integrity [475] and enhance systemic inflammation.
  • Fibrous foods and foods containing prebiotics boost intestinal barrier function [476].
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Time-scale
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Inflammation is known t

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

References

List of the literature that was cited for this KER description. More help