Gluten Sensitivity and its Possible Relationship to Inflammation

Introduction

Gluten sensitivity, also known as non-celiac gluten sensitivity (NCGS), has emerged as a subject of interest and debate in the context of gluten-related disorders. NCGS is distinct from celiac disease, an autoimmune disorder triggered by gluten ingestion that damages the small intestine. The primary focus of this article is to investigate whether gluten sensitivity is a genuine phenomenon and, if so, whether it causes inflammation. The potential mechanisms and evidence for gluten sensitivity will also be discussed, with appropriate sources cited and references provided.

Gluten Sensitivity: A Real Condition?

Gluten sensitivity is defined as a clinical condition characterized by intestinal and extraintestinal symptoms related to the ingestion of gluten-containing foods in individuals who do not have celiac disease or wheat allergy (1). While some researchers and healthcare professionals acknowledge NCGS as a distinct entity, others argue that it may be attributed to factors other than gluten, such as fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) found in wheat and other foods (2). However, a growing body of evidence, including double-blind, placebo-controlled studies, supports the existence of NCGS as a genuine clinical condition (3, 4).

Inflammation and Gluten Sensitivity

Several studies have suggested that gluten sensitivity may be associated with inflammation. Individuals with NCGS have been reported to have elevated levels of pro-inflammatory cytokines, such as interleukin (IL)-6, IL-8, and tumor necrosis factor-alpha (TNF-α), compared to healthy controls (5, 6). Additionally, some research has demonstrated increased intestinal permeability in NCGS patients, which may contribute to the activation of the immune system and the subsequent inflammatory response (7, 8).

Mechanisms and Evidence

Although the exact mechanisms underlying gluten sensitivity and its potential relationship with inflammation are not yet fully understood, several hypotheses have been proposed:

Innate immune response:

Unlike celiac disease, which involves both innate and adaptive immune responses, NCGS appears to be primarily driven by the innate immune system (9). Some studies have shown that gluten and its components can stimulate the release of pro-inflammatory cytokines from immune cells in NCGS patients, suggesting a role for the innate immune response in mediating inflammation (10).

Intestinal permeability:

Increased intestinal permeability, or "leaky gut," has been implicated in the pathogenesis of NCGS (7). This increased permeability may allow gluten peptides and other potentially harmful substances to enter the bloodstream, triggering an immune response and inflammation (11).

FODMAPs:

Some researchers argue that the symptoms of NCGS may be due to FODMAPs, rather than gluten itself (2). FODMAPs can cause gastrointestinal symptoms by increasing osmotic pressure and fermenting in the gut, leading to gas production and inflammation (12). However, further research is needed to clarify the relative contributions of gluten and FODMAPs to the symptoms of NCGS and any associated inflammation.

Amylase-trypsin inhibitors (ATIs):

ATIs are proteins found in wheat and other gluten-containing grains that can activate the innate immune system and contribute to inflammation (13). Some evidence suggests that ATIs may play a role in the development of NCGS and the associated inflammatory response (14).

Conclusion

The question of gluten sensitivity and its possible relationship to inflammation remains a topic of ongoing research and debate. While the existence of NCGS as a distinct clinical entity is supported by several studies, the precise mechanisms underlying the condition and its potential association with inflammation are not yet fully understood. Further research is needed to elucidate the relative contributions of gluten, FODMAPs, and other components of gluten-containing grains to the symptoms of NCGS and any associated inflammation.

In the meantime, individuals who suspect they have gluten sensitivity should consult with a healthcare professional to rule out other conditions, such as celiac disease or wheat allergy, and to receive guidance on appropriate dietary modifications. For those with a confirmed diagnosis of NCGS, adopting a gluten-free diet may help alleviate symptoms and potentially reduce inflammation. However, it is crucial to ensure that any dietary changes are nutritionally balanced and do not result in deficiencies of essential nutrients.

References

1. Catassi, C., Alaedini, A., Bojarski, C., Bonaz, B., Bouma, G., Carroccio, A., ... & Fasano, A. (2017). The overlapping area of non-celiac gluten sensitivity (NCGS) and wheat-sensitive irritable bowel syndrome (IBS): an update. Nutrients, 9(11), 1268. https://doi.org/10.3390/nu9111268

2. Gibson, P. R., & Shepherd, S. J. (2012). Food choice as a key management strategy for functional gastrointestinal symptoms. The American Journal of Gastroenterology, 107(5), 657-666. https://doi.org/10.1038/ajg.2012.49

3. Biesiekierski, J. R., Peters, S. L., Newnham, E. D., Rosella, O., Muir, J. G., & Gibson, P. R. (2011). No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates. Gastroenterology, 141(2), 369-378. https://doi.org/10.1053/j.gastro.2011.04.051

4. Di Sabatino, A., Volta, U., Salvatore, C., Biancheri, P., Caio, G., De Giorgio, R., ... & Corazza, G. R. (2015). Small amounts of gluten in subjects with suspected nonceliac gluten sensitivity: a randomized, double-blind, placebo-controlled, cross-over trial. Clinical Gastroenterology and Hepatology, 13(9), 1604-1612. https://doi.org/10.1016/j.cgh.2015.01.029

5. Sapone, A., Lammers, K. M., Casolaro, V., Cammarota, M., Giuliano, M. T., De Rosa, M., ... & Fasano, A. (2011). Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity. BMC Medicine, 9(1), 23. https://doi.org/10.1186/1741-7015-9-23

6. Carroccio, A., Mansueto, P., Iacono, G., Soresi, M., D'Alcamo, A., Cavataio, F., ... & Di Fede, G. (2012). Non-celiac wheat sensitivity diagnosed by double-blind placebo-controlled challenge: exploring a new clinical entity. The American Journal of Gastroenterology, 107(12), 1898-1906. https://doi.org/10.1038/ajg.2012.236

7. Hollon, J., Puppa, E. L., Greenwald

   , B., Goldberg, E., Guerrerio, A., & Fasano, A. (2015). Effect of gliadin on permeability of intestinal biopsy explants from celiac disease patients and patients with non-celiac gluten sensitivity. Nutrients, 7(3), 1565-1576. https://doi.org/10.3390/nu7031565

8. Fasano, A. (2012). Leaky gut and autoimmune diseases. Clinical Reviews in Allergy & Immunology, 42(1), 71-78. https://doi.org/10.1007/s12016-011-8291-x

9. Fasano, A., Sapone, A., Zevallos, V., & Schuppan, D. (2015). Nonceliac gluten sensitivity. Gastroenterology, 148(6), 1195-1204. https://doi.org/10.1053/j.gastro.2014.12.049

10. Uhde, M., Ajamian, M., Caio, G., De Giorgio, R., Indart, A., Green, P. H., ... & Alaedini, A. (2016). Intestinal cell damage and systemic immune activation in individuals reporting sensitivity to wheat in the absence of coeliac disease. Gut, 65(12), 1930-1937. https://doi.org/10.1136/gutjnl-2016-311964

11. Fasano, A. (2011). Zonulin and its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer. Physiological Reviews, 91(1), 151-175. https://doi.org/10.1152/physrev.00003.2008

12. Staudacher, H. M., & Gibson, P. R. (2017). How healthy is a gluten-free diet? British Journal of Nutrition, 118(10), 810-811. https://doi.org/10.1017/S0007114517002900

13. Junker, Y., Zeissig, S., Kim, S. J., Barisani, D., Wieser, H., Leffler, D. A., ... & Schuppan, D. (2012). Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4. Journal of Experimental Medicine, 209(13), 2395-2408. https://doi.org/10.1084/jem.20102660

14. Zevallos, V. F., Raker, V., Tenzer, S., Jimenez-Calvente, C., Ashfaq-Khan, M., Rüssel, N., ... & Schuppan, D. (2017). Nutritional wheat amylase-trypsin inhibitors promote intestinal inflammation via activation of myeloid cells. Gastroenterology, 152(5), 1100-1113. https://doi.org/10.1053/j.gastro.2016.12.006

In conclusion, the question of gluten sensitivity and its possible relationship to inflammation is complex and requires further investigation. Although there is evidence to support the existence of NCGS as a distinct clinical condition, the precise mechanisms underlying the condition and its potential association with inflammation are not yet fully understood. By understanding these mechanisms, healthcare professionals can better guide patients with gluten sensitivity in managing their symptoms and reducing inflammation.