Introduction
Antidepressants are an integral part of the treatment of IBS as a disorder of gut-brain interaction (DGBI). Accordingly also a direct interaction with the gut microbiota might be relevant as an additional mode of action. With its high content of flavonoids, a substance group for which beneficial neuromodulatory effects, mediated by the microbiota, are known. St. John's wort extract, an antidepressant with clinically proven therapeutic equivalence to TCAs and SSRIs, could be a promising candidate for such an additional action, also as there is a history of use also in GI complaints.
Aims & Methods
Aim was to follow the test substance, a St. John's wort extract (STW 3-VI), with clinically proven anti-depressant activity [1] and standardized flavonoid content [2], through the GI tract. According to the Infogest protocol [3,4], first the influence of the upper GI digestion on the extract was modelled by subsequent incubaton with respective enzymes and buffer mixes. The predigested extract was subsequently incubated with fecal samples from ten healthy donors (24h, anoxic, 37°C). The metabolism of the flavonoids by the gut microbiota was captured by UHPLC-HRMS, and also proteolytic markers (BCFA and ammonium) were measured by GC-FID and IPB colorimetric analysis. 16S rRNA gene sequencing was used to assess shifts in microbial community composition, followed by functional analysis via ATLAS, using KEGG, Cazy and Pfam for annotations.
Results
All major extract constituents were stable towards upper intestinal tract digestion. They were, however, readily catabolized by the gut microbiota. Metabolites of the flavonoids included taxifolin, hydroxyphenylpropionic acids and protocatechuic acid. Proteolytic markers were significantly decreased. Differential abundance analysis of the microbial communities showed that several taxa were significantly modulated by the extract, with e.g. Bacteroides (p=0.005) Marinifilaceae (p=0.0007) and Prevotellaceae (p=0.035) decreasing. Functional analysis revealed 540 differently expressed genes (p<0.01), some involved in flavonoid metabolism.
Conclusion
Beyond the known antidepressant activity of St. John's wort extract, its components are also prodrugs for substances with potential therapeutic benefits in IBS as well as in psychic depression [5]. This is in accordance to the results of the functional analysis of the gut microbiota, given that changes of abundance of bacterial taxa by the treatment antagonize abundance shifts described in depressive as well as IBS patients [6]. The decrease of proteolytic markers is also in line with a beneficial action in IBS [7]. In conclusion, St. John's wort might, beyond its known efficacy in mild to moderate depression, also be a promising therapeutic option in IBS patients, especial with co-occurring depressive symptoms.
References
1. Gastpar M, Singer A, Zeller K. Efficacy and tolerability of hypericum extract STW3 in long-term treatment with a once-daily dosage in comparison with sertraline. Pharmacopsychiatry. 2005;38:78-86.
2. www.ema.europa.eu/en/medicines/herbal/hyperici-herba
3. Brodkorb A, Egger L, Alminger M, et al. INFOGEST static in vitro simulation of gastrointestinal food digestion. Nat Protoc 2019; 14: 991-1014.
4. Pérez-Burillo S, Molino S, Navajas-Porras B. et al. An in vitro batch fermentation protocol for studying the contribution of food to gut microbiota composition and functionality. Nat Protoc 2021; 16: 3186–3209.
5. Vissiennon C, Nieber K, Kelber O, Butterweck V. Route of administration determines the anxiolytic activity of the flavonols kaempferol, quercetin and myricetin -- are they prodrugs? J Nutr Biochem. 2012; 23: 733-740
6. Duan R, Zhu S, Wang B, Duan L. Alterations of gut microbiota in patients with irritable bowel syndrome based on 16S rRNA-targeted sequencing: A Systematic Review. Clin Transl Gastroenterol. 2019; 10:e00012.
7. Hou JJ, Wang X, Li Y, Su S, Wang YM, Wang BM. The relationship between gut microbiota and proteolytic activity in irritable bowel syndrome. Microb Pathog. 2021; 157:104995.
Disclosure
MEG, EMPF and RB have received fees from Steigerwald Arzneimittelwerk GmbH, Darmstadt, Germany, HEK and OK are employees of the same company.