(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.
