Background/Objectives: Unhealthy nutrition and lifestyles contribute to the development of chronic diseases such as cardiovascular disease, type 2 diabetes, and colorectal cancer. The Western diet can impair gastrointestinal motility and function. The underlying mechanisms that lead to changes in the mucus barrier and mucin profiles in response to these dietary patterns are still being studied. In mice, dietary fiber intake can improve the intestinal mucosal barrier function, enhance the differentiation process of goblet cells, and increase acidic mucin production. Our study aimed to investigate the effects of a high-fat diet (HFD) on colonic mucin expression and to assess whether chickpea accessions, known for their nutritional benefits, can mitigate these adverse effects. Methods: We investigated the effects of an HFD and an HFD associated with two accessions of chickpeas (HFD + MG_13; HFD + PI358934) on the mucin expression in murine colons of mice by conventional histochemistry and lectin-histochemistry, combined with chemical treatment and enzymatic digestion and immunohistochemistry. We evaluated possible alterations of Muc2, the main mucin secreted by the mucous cells of the colon. Results: HFD significantly reduced the expression of the mucin Muc2 and altered its composition in the colon. Compared to the CTRL group, distal and proximal measurements for HFD + PI, respectively, showed reductions of 78% and 36%; for the distal colon, a reduction of 34% was also observed for both the HFD and HFD + MG_13 diets. Changes in mucin glycosylation, including sialylation and sulfation, as well as residues such as N-acetylglucosamine, GalNAc, Mannose, and Galactose, were observed, suggesting a beneficial influence of chickpeas on mucosal integrity. In HFD + MG_13 these effects were reduced and resulted similar to the control. Conclusions: HFD reduces Muc2 expression in the colon and alters mucin composition: chickpea accessions, particularly MG_13, partially restore Muc2 levels and mucin oligosaccharide profiles, suggesting protective effects on the intestinal mucosal barrier.

Fructose, a key component of modern diets, is closely linked to the growing prevalence of pediatric obesity and metabolic alterations. Although numerous studies highlight its systemic consequences, including altered carbohydrate and lipid metabolism and increased cardiovascular risk, the direct impact of fructose, particularly its role in modulating mucin composition, a key determinant of the mucosal barrier, remains poorly explored. This study investigated whether fructose supplementation modifies high-fat diet (HFD)-induced changes in duodenal mucin production and whether these effects vary depending on age in animals. To this end, young and adult mice were fed a normal diet (ND), HFD, or an HFD supplemented with 30% fructose (w/v) in drinking water (HFD+Fru) for 16 weeks. Brunner’s glands and villus goblet cells were then analyzed using conventional histochemistry and a panel of lectins to evaluate possible alterations in intestinal mucus glycosylation. Results showed that both HFD and HFD+Fru significantly increased body weight. In young mice, HFD+Fru induced a compensatory mucosal phenotype characterized by increased villus PAS (Periodic Acid–Schiff) reactivity (2% vs. ND), elevated sialylated mucin secretion rate (SSR) in Brunner’s glands (25% vs. ND) and villi (17% vs. ND), and higher SNA (up to 46% vs. ND) and PNA (up to 39% vs. ND) in villus goblet cells. In contrast, adult mice receiving HFD+Fru exhibited a maladaptive response, characterized by a reduction in villus PAS-positive mucins (6% vs. ND), decreased villus SSR (5% vs. ND), diminished sialylation (up to 43% SNA vs. ND) and GlcNAc (up to 50% reduction in WGA vs. ND) in villus goblet cells, and marked loss of fucosylation in Brunner’s glands (81% vs. ND) and villus goblet cells (66% vs. ND). These results reveal that fructose-enriched HFD remodels duodenal mucin O-glycosylation in an age-dependent manner, suggesting that while young mice exhibit transient adaptive responses, prolonged exposure can deplete these mechanisms, leading to a compromised adult epithelial barrier. This age-specific vulnerability may significantly contribute to the pathogenesis of diet-related intestinal disorders and obesity-related complications in later life, highlighting the need for early dietary interventions.

Oligosaccharides are structurally diverse glycans that influence intestinal homeostasis through mechanisms extending beyond conventional prebiotic activity. This review examines how dietary, human milk, host-derived, and biotechnologically produced oligosaccharides modulate the gut microbiota and mucosal host–microbe interactions, with particular attention to pediatric health. Non-digestible oligosaccharides support saccharolytic microbial communities, cross-feeding networks, and short-chain fatty acid production, thereby affecting luminal pH, epithelial metabolism, mucus production, barrier integrity, and immune signaling. Their biological effects are strongly determined by monosaccharide composition, linkage configuration, branching, charge, degree of polymerization, terminal residues, and spatial presentation. Neutral human milk oligosaccharides and galacto-oligosaccharides may reduce pathogen colonization by mimicking host glycans, occupying adhesin-binding sites, modifying epithelial glycosylation, and limiting biofilm initiation. Selected chitooligosaccharides can exert direct antibacterial effects through charge-dependent interactions with bacterial envelopes, although these effects depend on molecular size, charge, and chemical derivatization. In addition, the α1,4-GlcNAc-terminated O-glycan motif of gastric MUC6 provides a distinct example of host-associated glycan-mediated inhibition of bacterial metabolism. During infancy, human milk oligosaccharides promote a Bifidobacterium-enriched microbiota and may contribute to intestinal and immune maturation. Galacto- and fructo-oligosaccharide-supplemented formulas reproduce some microbiota- and metabolite-related effects, although evidence for preventing infectious, allergic, or inflammatory disease remains inconsistent. Experimental findings also suggest a role in recovery from antibiotic-associated dysbiosis, but clinical evidence is limited by heterogeneous populations, exposures, formulations, and endpoints. Future studies should use structurally defined compounds, mechanism-specific assays, and clinically relevant outcomes to establish causal structure–function relationships and identify pediatric populations most likely to benefit.