Inflammatory Bowel Disease (IBD) are polygenic autoimmune disorders characterized by intestinal chronic inflammation. In 2017, an estimated 6.8 million people in 192 countries and territories were diagnosed with IBD; the United States and Europe accounted for 3 million of these newly diagnosed IBD patients (Alatab et al., 2020). Until the mid-20th century, high income, and highly industrialized countries, including the United States, United Kingdom, and Australia, had a significant increase in IBD incidence (Alatab et al., 2020; Mak, Zhao, Ng, & Burisch, 2020). However, by the end of the 20th century, incidence started to plateau, and prevalence took the lead; this was in part due to better treatments and patients' increased life expectancy. Traditionally, IBD has been considered a disease of the West and most often associated with a low nutrition diet and exposure to environmental toxins. In the beginning of the 21st century, the global IBD prevalence and incidence scenario progressed. Countries including China, South Korea, Japan, and India developed further economically and as a result, there was a steep increase in IBD incidence. Interestingly, as countries develop their industrial market, their populations begin to experience increased incidence much like their counterparts in the West. Regarding India, there is a sharp increase in incidence and as of now, a plateau of incidence has not been reached. Based on these populations studies, the evidence suggests that IBD is no longer described as a Western disease significant efforts will be needed to reduce the global impact of IBD on the healthcare industry.

IBD is a highly heterogenous disease classified into four types: Crohn's disease (CD), ulcerative colitis (UC), microscopic colitis, and intermediate colitis. Within the major forms, CD and UC, multiple subtypes can be observed and are indicated by their location in the digestive tract and/or mutated molecular pathways (Chang, 2020). For consistency, in this review we will be referring to IBD as Crohn's disease and ulcerative colitis. IBD is a polygenic disease which becomes active when susceptible individuals are triggered by environmental factors. Researchers have identified more than 240 genetic risk loci for IBD with around 40 unique to CD and around 30 to UC. These loci include genes involved in epithelial barrier function, microbial defense, immune system, and cellular homeostasis. The first CD mutation found was a polymorphism in the nucleotide binding oligomerization domain containing 2 (NOD2) gene which encodes for an intracellular peptidoglycan sensor (Chang, 2020; Abraham & Cho, 2009). This mutation is prevalent in CD patients of European descent (30%), however, it is not as common in other ethnic groups. Another well-known CD mutation is polymorphisms in the autophagy related 16 like 1 gene that leads to abnormal Paneth cell formation and like NOD2, knockout studies show no causation. These alterations account for 8–13% of known CD and 4–7% of known UC disease variance, and 70% of them are present in other immune-modulated disease; therefore suggesting the importance of the environment in IBD progression (Chang, 2020; Ramos & Papadakis, 2019).

Terpenes are the largest class of plant-derived secondary metabolites and are classified based on the number of isoprene units in their backbone (Tetali, 2019; Ninkuu et al., 2021). Isoprene is the most abundant hydrocarbon in the planet, thus the high number of terpene species is estimated to exceed 300,000 terpene molecules. From a phytochemistry perspective, this explains the high amount of encoded terpene synthases in the plant genome and the role of plants as major producers of terpenes. Terpenes are often differentiated from terpenoids -oxidized, hydrated, or dehydrated terpenes- however, in this review, we will use the broader term terpenes (Ninkuu et al., 2021).

The most basic terpenes, hemiterpenes, have one isoprene unit (5C); meanwhile, monoterpenes have 2 units (10C) and sesquiterpenes have 3 units (15C) (Tetali, 2019). These three subclasses have low molecular weight conferring them volatility and aromaticity. Bigger species grouped as diterpenes (20C), sesterterpenes (25C), triterpenes (30C), tetraterpenes (40C), and polyterpenes (40C to 5 x 104C) can be aromatic but not volatile. Nonetheless, as shown in Fig. 1, their structural diversity is richer due to the vast number of possible combinations. In addition to their abundance, terpenes typically display superior pharmacokinetics and are metabolized by phase two enzymes (Papada et al., 2018; Romo Vaquero et al., 2013; Veenstra, Vemu, Tocmo, Nauman, & Johnson, 2021; Vemu et al., 2021). For example, carnosic acid and carnosol from rosemary had a Tmax of 0.25 h and a Cmax of 54.016 and 5.008 μM, respectively when administered through a rosemary oil extract at 100 mg/kg (Veenstra et al., 2021).

Due to their abundance and above-mentioned characteristics, terpenes have been studied in multiple disease states (Tetali, 2019). As a class, they have the following medicinal properties: antioxidant, anti-inflammatory, anti-tumor, anti-coagulant, anti-bacterial, anti-fungal, anti-viral, anti-parasitic, anti-aggregatory, analgesic, and sedative. The most popular terpene-derived drugs include the anti-cancer diterpene paclitaxel, and the anti-malarial sesquiterpene artemisinin. In this review we describe terpenes and the targeting of selected cell signaling pathways for the treatment of IBD as shown in Table 1 and Fig. 2. In 2020, Araruna et al., published a review focusing on terpene modulation of IBD, however, they only included 12 compounds (Araruna et al., 2020). By focusing on basic inflammation pathways we present a comprehensive article that reviewed 80 phytochemicals as of May 1, 2023.