Gastrointestinal Manifestations in COVID-19 and the Potential Role of Aniseed (Pimpinella anisum L.) in Management


Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), initially directed attention towards respiratory symptoms like fever and cough. However, as the pandemic evolved, a variety of extrapulmonary manifestations became evident. Notably, over 70 clinical manifestations have been identified, with at least 10 being gastrointestinal (GI) in nature (Luo et al., 2022).

The occurrence of GI symptoms can often precede the respiratory involvement in COVID-19. Symptoms such as anorexia (12.9%), diarrhea (8.1%), nausea (6.7%), constipation (5.5%), melena (5.3%), abdominal pain (3.7%), and heartburn (3.6%) are the most commonly reported (Luo et al., 2022). Although the prevalence of these symptoms in COVID-19 patients is less than 20%, their presence, particularly abdominal pain, is increasingly associated with greater disease severity (Menon et al., 2021; Zeng et al., 2022).

Complications like gastrointestinal bleeding and small intestine necrosis have also been noted (Pan et al., 2020; Menon et al., 2021). Nevertheless, the link between these GI manifestations and the increased mortality risk remains uncertain, with mixed findings reported in systematic reviews (Menon et al., 2021; Wang et al., 2022).

Current clinical guidelines for COVID-19 management offer general recommendations for treating GI symptoms. These include the use of antipyretics for pain and rehydration therapies for vomiting or diarrhea (WHO, 2021). In this context, Persian medicine (PM) presents an intriguing alternative with its rich repertoire of phytomedicines for various GI disorders (Avicenna, 2005; Aghili Shirazi, 2008). A notable example is the fruit of Pimpinella anisum L. (anise), commonly known as aniseed. Prepared as a dried and ground powder (Sáfūf), aniseed is described in PM as having analgesic, anti-bloating, anti-colic, carminative, and astringent properties, attributed to its warm and dry temperament (Ibn-al-Nafis, 2008; Aghili Shirazi, 2009).

The Pimpinella genus, which boasts over 150 species globally, is known for its diverse metabolites that vary based on geographical location. In aniseed essential oil, trans-anethole is often the primary metabolite, comprising between 76.9% to 93.7% of its composition (Akbar, 2020). This diversity in chemical composition contributes to its wide range of therapeutic effects.

Empirical support for the traditional claims of PM comes from various clinical trials. For instance, a randomized, double-blind trial demonstrated that anise oil capsules were more effective in treating symptoms of irritable bowel syndrome than both placebo and Colpermin® (peppermint oil) (Mosaffa-Jahromi et al., 2016). Another trial showed that aniseed powder significantly reduced postprandial distress syndrome symptom severity compared to a placebo (corn starch) powder (Ghoshegir et al., 2015). These findings not only validate the efficacy of aniseed in managing GI disorders but also underscore its safety, as no serious adverse effects were reported in these studies.

In the context of COVID-19, despite reduced mortality rates, the persistent rise in infection rates across different regions highlights the ongoing threat of the virus (Ma et al., 2021). The prevalent and potentially risky GI manifestations in COVID-19 patients necessitate an effective management strategy. Considering the limited evidence-based recommendations for handling these GI symptoms, along with the established efficacy and safety of aniseed for other GI conditions, this study was conceived.

The clinical trial aimed to assess the efficacy and safety of aniseed (P. anisum L.) powder in treating gastrointestinal symptoms among adults with acute SARS-CoV-2 infection. The rationale behind this trial is twofold: first, to address the lack of specific treatments for COVID-19 related GI symptoms; and second, to explore the potential of traditional remedies like aniseed in modern clinical settings. The outcome of this study could not only provide valuable insights into managing COVID-19 but also pave the way for integrating traditional medical wisdom with contemporary healthcare practices.


This study breaks new ground in two key areas. Firstly, it provides a critical examination of the effects of a botanical drug, specifically aniseed (P. anisum L.), on the gastrointestinal symptoms experienced by COVID-19 patients. This was achieved using a robust double-blinded, placebo-controlled add-on therapy trial study design. Secondly, it delves into the efficacy of aniseed, a popular botanical drug in Persian Medicine (PM), in the context of viral infections – a domain where it has previously received minimal attention.

Our research revealed that daily intake of an aniseed-based formulation significantly alleviated three out of five primary gastrointestinal symptoms in COVID-19 patients: abdominal pain, anorexia, and diarrhea. Notably, the formulation was well-tolerated, with no reports of dangerous or life-threatening adverse events, underscoring its safety.

Despite the study’s significance in introducing a novel botanical drug metabolite for the relief of common gastrointestinal symptoms in COVID-19 patients, it is not without its limitations. These include the lack of data on patients’ dietary habits, potential differences in the taste of aniseed and placebo that could affect blinding, the absence of molecular docking results, and a shortfall in long-term patient follow-up. Furthermore, no statistical adjustments were made for multiple comparisons. However, the low p-values recorded for all three significant differences in primary endpoints suggest that a Type 1 error is unlikely.

Acknowledging these limitations, we proceeded to explore potential mechanisms through which P. anisum and its metabolites, particularly trans-anethole, might have mediated symptom improvement. This exploration involved suppressing SARS-CoV-2 or interfering in the pathophysiological processes of COVID-19.

Inhibition of SARS-CoV-2 Proteins by Aniseed – In Silico Studies

In silico studies have shown promising results where P. anisum exhibits potential in inhibiting key SARS-CoV-2 proteins, specifically the Spike (S) protein and the Chymotrypsin-like protease or main protease (3CLPRO or MPRO). These proteins are crucial in the virus’s lifecycle, facilitating its entry and replication within the host cells. The abundance of ACE-2 receptors in the gastrointestinal tract, notably higher than in the lungs (Hikmet et al., 2020), positions the GI tract as a significant portal for SARS-CoV-2 entry, underlining the relevance of these findings.

Antiviral Properties of Aniseed – In Vitro Studies

In vitro studies, although limited, have demonstrated the antiviral capabilities of P. anisum and its constituent trans-anethole. Notably, the water extract of P. anisum showed effectiveness against herpes simplex virus and cytomegalovirus, among others (Lee et al., 2011). In a similar vein, trans-anethole has proven to be a potent inhibitor of HSV-1, suggesting a direct inactivation of viral particles (Astani et al., 2011).

Anti-inflammatory Properties of Aniseed

COVID-19 infection induces a surge in inflammatory factors, especially in the GI tract. Research shows a marked elevation in various cytokines and chemokines in COVID-19 patients, indicating an inflammatory response (Costela-Ruiz et al., 2020). Aniseed, with its anti-inflammatory properties, particularly due to the presence of trans-anethole, may help modulate this inflammatory response. Previous studies have validated the anti-inflammatory capacity of aniseed extracts and essential oil (Iannarelli et al., 2018; Dargahi et al., 2021).

Hepatoprotective and Antioxidant Effects of Aniseed

Liver complications are a noted consequence of COVID-19. Studies suggest that SARS-CoV-2 can induce liver injury through multiple pathways, including systemic inflammation and oxidative stress (Ma et al., 2020; Zhong et al., 2020). Aniseed, particularly trans-anethole, has demonstrated hepatoprotective and antioxidant properties in various studies, suggesting its potential in mitigating COVID-19 induced liver damage (da Rocha et al., 2017; Samadi-Noshahr et al., 2021).

Action of Aniseed on COVID-19 Microbiome and Gut Epithelial Barrier

The impact of SARS-CoV-2 on the gut microbiome is another critical aspect of COVID-19. Research indicates significant alterations in the gut microbiota of infected patients, with a notable increase in opportunistic pathogens (Sun et al., 2022; Zuo et al., 2020). The essential oil of P. anisum and its metabolites may help restore the balance in gut microbiota and protect the gut epithelial barrier, potentially reducing systemic dissemination of the virus.

Potential Effects of Aniseed on the Gut-Lung Axis in COVID-19

The gut-lung axis is an emerging area of interest in COVID-19 research. Inflammatory factors in the GI tract may serve as a bridge between respiratory and gastrointestinal systems, influencing the course of the disease (Astani et al., 2011; de Oliveira et al., 2021). Aniseed’s dual action on both respiratory and GI systems places it as a candidate for managing infections that affect both these systems.

Prospective Use of Aniseed on Long COVID-19

Considering the prolonged viral shedding in the GI tract and its association with long COVID-19 symptoms, aniseed formulations might have a role in preventing long-term complications and viral dissemination (Natarajan et al., 2022).

Persian Medicine, Nutrition, and Traditional Chinese Medicine

In the realm of Persian medicine and traditional Chinese medicine, aniseed’s warm and dry temperament is aligned with its traditional use in treating GI symptoms associated with COVID-19, such as diarrhea and bloating (Pasalar et al., 2016; Shahrajabian et al., 2019). Furthermore, the study of botanical drugs in TCM has highlighted the need to consider variations in drug metabolites and interactions in managing GI symptoms (Shi et al., 2021).

In summary, this study not only adds a new dimension to

the use of botanical drugs in treating COVID-19 but also underscores the potential of integrating traditional medical knowledge with modern clinical practices. The findings advocate for a broader acceptance and understanding of botanical drugs like aniseed in managing complex diseases such as COVID-19, especially regarding gastrointestinal symptoms. Future research should aim to address the limitations of this study and expand our understanding of how traditional remedies can be effectively harnessed in contemporary medical interventions. This integration could offer more holistic and efficacious treatment options, not only for COVID-19 but potentially for other viral infections and health conditions that challenge modern healthcare.

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