Opinion The Untapped Pharmacopeic Potential of Helminths Janina Kahl, 1 Norbert Brattig, 2 and Eva Liebau 1, * The dramatic rise in immunological disorders that occurs with socioeconomic development is associated with alterations in microbial colonization and reduced exposure to helminths. Excretory–secretory (E/S) helminth products contain a mixture of proteins and low-molecular-weight molecules represent- ing the primary interface between parasite and host. Research has shown great pharmacopeic potential for helminth-derived products in animal disease models and even in clinical trials. Although in its infancy, the translation of worm-derived products into therapeutics is highly promising. Here, we focus on important key aspects in the development of immunomodulatory drugs, also highlighting novel approaches that hold great promise for future development of innovative research strategies. Helminth Infections – ‘World Wide Worms’ It has been estimated that at least 1.8 billion people are infected with helminths (see Glossary) [1]. Since helminth infections disproportionately affect low-income populations in developing regions of Africa, Asia, and America, they belong to a group of diseases referred to as the ‘major neglected tropical diseases’. According to the Global Burden of Disease Study 2016, helminth infections cause more than 10 million disability-adjusted life years (DALYs) [2]. Although highly parasitized individuals display serious symptoms and, for example, filarial worms can cause severe diseases such as lymphatic filariosis and river blindness (onchocercosis), other helminth infections are relatively well tolerated by their host and are often asymptomatic. Characteristically, many helminth species can reside within their hosts for a long period of time without provoking an inflammatory response or severe tissue damage. Immune-Related Disorders Epidemiological studies have shown a rise in prevalence of immune-related disorders, including autoimmune and allergic diseases. Inflammatory bowel disease (IBD) [encompassing Crohń s disease (CD) and ulcerative colitis (UC)], type 1 diabetes (T1D), multiple sclerosis (MS), and rheumatoid arthritis (RA) are just a few examples of more than 80 autoimmune diseases that affect approximately 5–8% of the population worldwide, with the highest prevalence in the developed world [3]. Since these chronic diseases are neither preventable nor curable, the current increase in prevalence is a subject of topical interest. Although it is generally recognized that a high-risk genetic background in combination with epigenetic modifications and environ- mental factors, such as metabolic surplus, contribute to the pathogenesis [3,4], much remains to be understood. However, the underlying immunological mechanisms are far better under- stood and the characteristic feature of these hypersensitivity disorders is an inappropriate or exaggerated immune cell response to a self (autoimmunity and autoinflammation), microbiota- derived or foreign (allergy) antigen, which involves the innate as well as the adaptive branch of the immune system (Box 1). Highlights The current increase in the prevalence of immunological disorders is inversely correlated with the occurrence of hel- minth infections in highly developed countries. The underlying protective helminth- mediated mechanism against immune-related diseases appears to be a shift in the proinflammatory Th1/Th17 immune response to a more balanced Th2/Treg immune profile. Mouse models and clinical trials con- ducted with live parasitic worms or Trichuris suis ova have gained much attention as a possible treatment for immune-related diseases. Worm-derived E/S products may serve as an important source of defined immunomodulatory molecules that can provide a safer and more con- trollable alternative for the treatment of immunological disorders rather than using unpredictable long-term hel- minth infections. Apart from their immunomodulatory capacity, research has revealed other intriguing and exploitable activities of helminth-derived molecules. 1 Institute of Animal Physiology, University of Münster, Schlossplatz 8, 48143 Münster, Germany 2 Bernhard-Nocht-Institute for Tropical Medicine, Bernhard-Nocht-Strasse 74, 20359 Hamburg, Germany *Correspondence: liebaue@uni-muenster.de (E. Liebau). TREPAR 1769 No. of Pages 15 Trends in Parasitology, Month Year, Vol. xx, No. yy https://doi.org/10.1016/j.pt.2018.05.011 1 © 2018 Elsevier Ltd. All rights reserved.