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Irritable Bowel Syndrome, Intestinal Permeability, and Low-Grade Chronic Inflammation — Scientific Review

by luciano

(Related article no. 2: Irritable Bowel Syndrome (IBS) and Intestinal Permeability)
1. Introduction
Irritable Bowel Syndrome (IBS) is a chronic functional disorder of the gastrointestinal tract characterized by abdominal pain and altered bowel habits, in the absence of evident structural abnormalities. It is classified as a Disorder of Gut–Brain Interaction (DGBI) and presents heterogeneous clinical phenotypes.

2. Intestinal Permeability and IBS: Scientific Evidence
2.1 Clinical Review on Intestinal Permeability
“Intestinal barrier dysfunction in irritable bowel syndrome: a systematic review”
Hanning et al. (2021) — Review of 66 studies on the role of the intestinal barrier in IBS.
Summary: Increased intestinal permeability is observed in a significant proportion of IBS patients, particularly in diarrhea-predominant (IBS-D) and post-infectious IBS (PI-IBS), while it is less frequent in constipation-predominant IBS (IBS-C) and nearly absent in mixed IBS (IBS-M). Increased permeability is also associated with greater symptom severity. (PubMed)

2.2 Correlations Between Permeability and Clinical Factors
Anthropometric studies and challenge tests indicate that increased permeability is frequently associated with:
Alterations in tight junction proteins (e.g., occludin, ZO-1)
Visceral hypersensitivity
Local and systemic inflammatory markers
(as shown in reviews on IBS and other gastrointestinal models) (Springer Nature)

3. Intestinal Permeability and Low-Grade Chronic Inflammation
3.1 General Concept and Proposed Mechanisms
“Gut microbiota, intestinal permeability, and systemic inflammation: a narrative review”
Di Vincenzo et al. (2023)
Summary: The intestinal barrier is a dynamic system integrated with the microbiota, nutrients, and immune system. Increased permeability (“leaky gut”) may facilitate the interaction between luminal antigens and immune cells, triggering pro-inflammatory activation. (MedNews Care)

3.2 Interaction Between Inflammation and Barrier Function
“Intestinal permeability – a new target for disease prevention and therapy”
BMC Gastroenterology
Summary: Barrier dysfunction is associated with low-grade inflammation, visceral sensitivity, and IBS symptoms. Local inflammation may contribute to degradation of tight junction proteins, promoting a self-perpetuating cycle of permeability and inflammation. (SpringerLink)

3.3 Bibliometrics and Research Trends
“Mapping research trends on intestinal permeability in IBS …”
Recent bibliometric analysis
Summary: There is growing research interest in microbiota, diet, intestinal permeability, and inflammation in IBS. Interactions among the intestinal barrier, microbiome, and nutritional/environmental factors represent major emerging topics. (PubMed)

4. Low-Grade Inflammation in IBS and Its Relationship with Permeability
4.1 Inflammatory Markers in IBS
Preview of meta-analysis (Digestive Diseases and Sciences, 2025)
Summary: Pro-inflammatory cytokines such as IL-6 and TNF-α are frequently elevated in IBS patients, together with intestinal dysbiosis, suggesting chronic immune activation. (Springer Nature)

4.2 Relationship Between Inflammation and Permeability
“Increased Intestinal Permeability and Decreased Barrier Function: Does It Really Influence the Risk of Inflammation?”
Summary: Although increased permeability is associated with inflammatory markers in several diseases, a mandatory causal relationship is not demonstrated. Permeability may accompany inflammation but does not inevitably generate it. (PubMed)

5. Synthesis: IBS Is Multifactorial — Permeability Is Not Mandatory
Main points of consensus:
1. Many IBS patients exhibit increased permeability, particularly IBS-D and PI-IBS, but many do not.
2. Low-grade chronic inflammation is common in IBS but not always accompanied by increased permeability.
3. Inflammation may contribute to barrier dysfunction, yet IBS-like symptoms can occur with normal permeability.
Emerging consensus model:
Intestinal permeability acts as a pathogenic amplifier in specific IBS subgroups, interacting with microbiota, diet, stress, and immune function, but it is not a universal prerequisite.

6. Examples of Relevant Studies (Rapid Summary)
Hanning et al., 2021 — IBS/barrier systematic review
Di Vincenzo et al., 2023 — Microbiota–permeability–inflammation narrative review
Digestive Diseases and Sciences, 2025 — Inflammation & microbiome meta-analysis
BMC Gastroenterology — Barrier loss, mild inflammation, visceral sensation
Bibliometric analysis — IBS/permeability research trends

7. Conceptual Conclusions
IBS is multifactorial, and its pathophysiology cannot be reduced to a single “barrier defect.”
Increased permeability and low-grade inflammation may co-occur but are not universal.
Their presence depends on clinical phenotype, microbiota composition, immune factors, diet, and psychobiological stress. Clinical assessment should consider biomarkers, microbiota, and immune-barrier interactions, not epithelial integrity alone.

Undigested Food → Low-Grade Intestinal Inflammation → Increased Intestinal Permeability

by luciano

(Related Article No. 3 – Series: Irritable Bowel Syndrome (IBS) and Intestinal Permeability)
Introduction
Recent scientific literature suggests that the presence of incompletely digested food within the intestinal lumen may, in specific contexts, contribute to low-grade chronic inflammatory processes and to increased intestinal permeability.
This relationship emerges particularly from the review by Riccio and Rossano (2019), which proposes that undigested food residues and the intestinal microbiota may cooperate in the pathogenesis of systemic inflammatory conditions, including those with possible neurological manifestations. In this model, loss of intestinal barrier integrity allows the passage of luminal molecules—food fragments, peptides, endotoxins, and microbial components—into the internal compartment, thereby promoting immune activation.
From this perspective, digestion is not merely a nutritional process, but also a fundamental biological defense mechanism.

The Concept of Dietary “Non-Self”
Before complete digestion, food retains a biological identity distinct from that of the host organism.
According to Riccio and Rossano:
Intact or partially digested food is biologically perceived as “non-self”
Only after complete breakdown into simple molecules (amino acids, monosaccharides, fatty acids) does it become “self”
The intestinal barrier therefore plays a crucial role in preventing the systemic passage of structurally complex material.
When this containment system weakens, partially digested food fragments may cross the epithelium and contribute to:
Intestinal inflammation
Chronic immune activation
Alterations of the microbiota
Potential systemic effects

Gastric Digestion as the First Level of Protection
Gastric digestion represents the first major filter against dietary antigenic load.
1. Protein Fragmentation
The acidic environment of the stomach:
Denatures proteins
Activates pepsin
Produces smaller, more manageable peptides
The more extensively proteins are hydrolyzed early, the smaller the amount of complex fragments reaching the small intestine.
This is relevant because: Macromolecular proteins are more immunogenic
Large peptides can interact with the mucosa
Excess protein residues increase intestinal digestive burden
2. Support of the Enzymatic Cascade
Adequate gastric acidity promotes efficient activation of pancreatic proteases (trypsin, chymotrypsin, elastase, carboxypeptidases).
If gastric digestion is inefficient:
Downstream enzymatic activity is reduced
The probability of incompletely degraded protein residues increases
Thus, the stomach functions as both a mechanical and chemical filter that reduces mucosal exposure to potentially immunogenic molecules.

Incomplete Digestion and Intestinal Permeability
When larger quantities of complex peptides reach the intestine:
Interaction with the epithelium increases
In the presence of a weakened barrier, the probability of translocation rises
Local immune activation is promoted
In “leaky gut” models, this is associated with:
Alterations of tight junctions
Increased paracellular permeability
Passage of peptides, endotoxins, and antigens
This may generate a vicious cycle:
Inefficient digestion → increased antigenic load → mucosal stress → increased permeability → increased inflammation

The Special Case of Gluten
Gluten represents a well-studied example of a partially digestible dietary protein.
Reviews by Cenni et al. (2023) and other studies show that:
Gluten is rich in proline and glutamine
Human digestion generates enzyme-resistant peptides
Some of these peptides can alter tight junctions via zonulin
In predisposed individuals (celiac disease, non-celiac gluten sensitivity):
Gluten peptides increase intestinal permeability
Facilitate bacterial translocation
Activate mucosal immune responses
It is important to emphasize that:
The human digestive system possesses proteases capable of degrading many gluten peptides
Nevertheless, some highly immunogenic fragments may persist
Therefore, gluten is not universally pathogenic, but may become clinically relevant in vulnerable contexts.