Acid reflux and intestinal gas are the two most common problems complained by a large proportion of patients. It is due to malabsorption of nutrients and gases, improper fermentation by colonic bacteria and oxidative stress caused by reactive oxygen species (ROS) which disturbs the reducing equivalents altering the bowel movements and absorption. This review presents the pharmacological properties of thymol including its antioxidant, anti-inflammatory and free radical scavenging activities to alleviate gastrointestinal disorders.
Thymol crystals commonly called ‘Ajwain ka Phool’ is a famous Ayurvedic remedy in India where crystallized thymol is found to heal numerous illnesses. It is a time-tested natural remedy which acts as a potent cleanser and a promising digestive aid. Thymol is found to show rapid absorption in the upper component of the gut, stomach and intestine. It relaxes the smooth muscles and increases the activity of digestive enzymes, scavenging the ROS to protect cells from oxidative stress. It also helps in improving the population of beneficial gut microbes though not yet significantly characterized, providing a gastroprotective effect. This review discusses the synthesis and occurrence of thymol, gastrointestinal disorders and the therapeutic properties of thymol curing the gastric disorders.
Thymol crystal is a white crystalline substance of pleasant aromatic odour extracted from thyme species plants such as Thymus vulgaris, Trachyspermum ammi, Carum opticum, Ocimum gratissimum, Origanum compactum, Satureja intermedia and many more. Thymus vulgaris is a famous species where thyme is present abundantly. Essential oil prepared from seeds comprises monoterpenes like thymol, carvacrol, terpinenes and certain cymene and pinenes. Thymol, also known as 2-isopropyl-5-methylphenol is the frequently occurring constituent of EOs, and is found to show multiple therapeutic actions against various cardiovascular, gastrointestinal, neurological, metabolic and malignant diseases at both molecular and biochemical levels. The remarkable effects of thymol are its anti-inflammatory, antioxidant and antimicrobial properties.
Biosynthesis of Thymol
Geranyl pyrophosphate (GPP) is the precursor for most of the monoterpenes. Ionization of GPP to geranyl cation is isomerized to a linalyl intermediate capable of cyclisation to form central intermediate α-terpinyl cation which is further subjected to cyclisation resulting in γ- terpinene. γ- Terpinene is the component which is involved in the aromatization process which results in the formation of p-cymene, the precursor of possible oxygenated derivatives. Hydroxylation of p-cymene synthesizes thymol and carvacrol. Thymol and carvacrol are structural isomers, having the hydroxyl group at different locations on the phenolic groups. Both essential oils have antimicrobial, antioxidant and antifungal activities. Several studies have described that thymol was more effective than carvacrol.
Fig. 1. Biosynthetic pathway of thymol and carvacrol from geranyl pyrophosphate (GPP) as a precursor.
Gastrointestinal disorders are common and bothersome problems faced by the majority of the population. It causes bloating, irritation, acidity, improper bowel movements, increased intraluminal gas production and constipation. Bloating is a common sensation of increased pressure within the abdomen faced in any gastric disorder, theories suggest it have been because of increased luminal contents like gas, stools or by impaired abdominal emptying i.e., defective propulsion inducing a reflux of gastric and duodenal contents back into the oesophagus.
Intestinal gas: The homeostasis of gas depends on balance between its formation and elimination. Gas input results from swallowing of air, neutralisation of acids and alkali into simpler gases in the upper gut. In the lower gut it occurs due to bacterial fermentation. Gas output is by belching, anal evacuation, absorption of gas into blood and bacterial consumption. Small intestinal gas obstruction occurs with inflammation and altered gas transit. Increased bacterial fermentation by the colonic bacteria overgrowth reduces the absorption capacity of substrates thereby resulting in accumulation of flatus. Thymol can alter or modulate gut transit by reducing inflammation, inhibiting proton pumps and bacteria overgrowth could help in relieving gas problems.
Gastroesophageal reflux: Gastroesophageal reflux or acid reflux is a condition where the acidic liquid contents of stomach regurgitates into the oesophagus. It occurs due to imbalance between mucosal lining aggressive factors and defensive factors caused by the inflammation and oxidative stress. Various cytokines like IL- 4, IL-8 and IL-10 in esophageal mucosa are released which causes lipid peroxidation, oxidative stress by activating inflammatory cells as well as increasing the production of reactive oxygen species and free radicals. Antioxidant treatment of thymol can scavenge the ROS, which could prevent esophageal damage causing ulceration. Proton pump inhibitors are the first line drugs for its treatment which are strong inhibitors of acid secretion. They are the most potent antacid class medications which helps in suppressing the inflammatory responses.
Pharmacological properties of Thymol
Anti-inflammatory property: Thymol is found to interfere with elastase, an independent marker enzyme to identify the inflammatory bowel disease. Thymol affected the elastase released from neutrophils as a result of inflammation, by inhibiting the synthetic chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (fMLP), this peptide is required for initiation of elastase release. Calcium mobilization is inhibited which affects the elastase release. The hydrophobic nature of thymol alters the local environment of calcium channels inactivating the calcium channels machinery. Thymol acts as a proton pump inhibitor which helps in exhibiting potent anti-inflammatory responses. It also diminishes the release of inflammatory mediators like cytokines, interleukins, leukocytes and prostaglandins.
Antioxidant property: Studies have revealed that thymol can scavenge reactive oxygen species and free radicals and increase the activities of antioxidant enzymes. The hydroxyl free radicals are added to the phenolic group of thymol producing phenoxyl radicals which undergo dehydration and neutralization. Thymol showed potent antioxidant properties scavenging superoxide, hydroxyl and DPPH radicals. It also shows good reducing power, donates a hydrogen atom to a lipid radical preventing lipid peroxidation and reducing oxidative stress which damages the mucosal linings. It also decelerates the radical initiation reaction rate by elimination of initiators, preventing generation of ROS and deactivating high energy species.
In the acid reflux and intestinal gas problems, inflammation in epithelial mucosal linings of esophagus and intestine occurs in response to cytokines and inflammatory factors and cells, free radicals and reactive oxygen species are increased which thereby causes oxidative stress, lipid peroxidation in membranes alter the gut transit due to which acid contents flow back into esophagus tract and gas flow is obstructed. Thymol having both antioxidant and anti-inflammatory properties act as a proton pump inhibitor inhibiting the acid secretion inactivating calcium channel machinery and reducing inflammation and oxidative stress. It inhibits the activation of neutrophils and cytokines hence knocking down the ROS concentrations. Therefore thymol has potent properties which can help in alleviating gastrointestinal disorders.
I would sincerely like to thank Dr. Sudeshna Menon from the Department of Biochemistry and Biotechnology, St. Xavier’s College Ahmedabad for providing us an opportunity to present a review article on such a fascinating topic. I would also like to thank In-Xitu, a student run company of St. Xavier’s College Ahmedabad for providing me with an exceptional learning platform.
Department of Biochemistry and Biotechnology
St. Xavier's College, Ahmedabad
1. Nagoor Meeran, M. F., Javed, H., Al Taee, H., Azimullah, S., & Ojha, S. K. (2017). Pharmacological Properties and Molecular Mechanisms of Thymol: Prospects for Its Therapeutic Potential and Pharmaceutical Development. Frontiers in pharmacology, 8, 380.
2. Iovino, P., Bucci, C., Tremolaterra, F., Santonicola, A., & Chiarioni, G. (2014). Bloating and functional gastro-intestinal disorders: where are we and where are we going?. World journal of gastroenterology, 20(39), 14407–14419.
3. Ribeiro, A. R., Diniz, P. B., Pinheiro, M. S., Albuquerque-Júnior, R. L., & Thomazzi, S. M. (2016). Gastroprotective effects of thymol on acute and chronic ulcers in rats: The role of prostaglandins, ATP-sensitive K(+) channels, and gastric mucus secretion. Chemico-biological interactions, 244, 121–128.
4. Almanea A, El-Aziz G. S. A, Ahmed M. M. M. The Potential Gastrointestinal Health Benefits of Thymus Vulgaris Essential Oil: A Review. Biomed Pharmacol J 2019;12(4).
5. Memar, Mohammad Y, Raei, Parisa Alizadeh, Naser, Akbari Aghdam, Masoud, Kafil, Hossein Samadi (2017). Carvacrol and thymol: strong antimicrobial agents against resistant isolates. Reviews in Medical Microbiology, 28(2), 63-68
6. Hasler W. L. (2006). Gas and Bloating. Gastroenterology & hepatology, 2(9), 654–662.
7. Dwivedi S.N., Mishra R.P & Alawa S. (2012). Phytochemistry, Pharmacological studies and Traditional benefits of Trachysperrum ammi(Linn.) Spargue. International Journal of Pharmacy & Life Sciences.3(5), 1705-1709
8. Yadav R., Pradhan C.K., Gupta D., Kaoshik R. (2011) Health benefits of Indian aromatic plant ajwain (Trachycpermum ammi). International Journal Of Pharmacy & Technology. 3(3), 1356- 1366
9. Koc, K., Cerig, S., Ucar, S., Colak, S., Bakir, M., Erol, H. S., Yildirim, S., Hosseini Jouzdani, M., Simsek Ozek, N., Aysin, F., Fehim Kocpinar, E., Budak, H., & Geyikoglu, F. (2020). Gastroprotective effects of oleuropein and thymol on indomethacin-induced gastric ulcer in Sprague-Dawley rats. Drug and chemical toxicology, 43(5), 441–453.
10. Miguel M. G. (2010). Antioxidant and anti-inflammatory activities of essential oils: a short review. Molecules J., 15(12), 9252–9287.
11. Nelkine, L., Vrolijk, M. F., Drent, M., & Bast, A. (2020). Role of antioxidants in the treatment of gastroesophageal reflux disease-associated idiopathic pulmonary fibrosis. Current opinion in pulmonary medicine, 26(4), 363–371.
12. Escobar, A., Pérez, M., Romanelli, G., & Blustein, G. (2020). Thymol bioactivity: A review focusing on practical applications. Arabian Journal of Chemistry, 13, 9243-9269.
Yoshida N. (2007). Inflammation and oxidative stress in gastroesophageal reflux disease. Journal of clinical biochemistry and nutrition, 40(1), 13–23.
13. Yoshida N. (2007). Inflammation and oxidative stress in gastroesophageal reflux disease. Journal of clinical biochemistry and nutrition, 40(1), 13–23.
14. Braga, P. C., Dal Sasso, M., Culici, M., Bianchi, T., Bordoni, L., & Marabini, L. (2006). Anti- inflammatory activity of thymol: inhibitory effect on the release of human neutrophil elastase. Pharmacology, 77(3), 130–136.
15. Clarrett, D. M., & Hachem, C. (2018). Gastroesophageal Reflux Disease (GERD). Missouri medicine, 115(3), 214–218.
16. Badillo, R., & Francis, D. (2014). Diagnosis and treatment of gastroesophageal reflux disease. World journal of gastrointestinal pharmacology and therapeutics, 5(3), 105–112.
17. Yoshida, N., & Yoshikawa, T. (2003). Defense mechanism of the esophageal mucosa and esophageal inflammation. Journal of gastroenterology, 38 Suppl 15, 31–34.
18. Sihvo, E. I., Salminen, J. T., Rantanen, T. K., Rämö, O. J., Ahotupa, M., Färkkilä, M., Auvinen, M. I., & Salo, J. A. (2002). Oxidative stress has a role in malignant transformation in Barrett's esophagus. International journal of cancer, 102(6), 551–555.
19. Yildiz, S., Turan, S., Kiralan, M. et al. (2021) Antioxidant properties of thymol, carvacrol, and thymoquinone and its efficiencies on the stabilization of refined and stripped corn oils. Food Measure J. 15, 621–632