There are strong demands to develop new immunomodulatory drugs to combat chronic diseases. In the broadest sense, we need to inhibit specific arms of the immune system in inflammatory diseases, neurodegeneration and hematological cancers, or enhance them in solid cancers. Most current efforts aim at biologic drugs (antibodies, cytokines, decoy receptors etc.) that are highly specific for extracellular targets, mostly cytokines and their receptors. Biologics are considered faster and less risky to develop than small-molecule drugs, and biologic antagonists of cytokines and paracrine signals are blockbuster medicines in inflammation and cancer. However, small molecules still offer important benefits. Notably, they are much easier to manufacture and more affordable once they come off patent, which suits global needs. One small-molecule class, kinase inhibitors, has been extensively explored for immunomodulation, and inhibitors of JAK, BTK, and SYK kinases have been approved to downregulate specific immune pathways in various diseases (Zarrin et al., 2021). There is also great interest in adding small molecules in combination to help patient subgroups that are insufficiently responsive to single biologics (Adams et al., 2015; van der Zanden et al., 2020; Ahmed et al., 2021).

Here, we discuss the potential of Traditional Chinese Medicines (TCM) and other herbal medicine traditions as starting points for new immunomodulatory drugs from a specific perspective: that plant-derived molecules may have low oral bioavailability and restricted distribution that lead to organ-specific pharmacology. In standard oral pharmacology models, drugs are efficiently adsorbed into the bloodstream and then act throughout the body via transport in blood. This standard model is often assumed for active molecules present in traditional medicines. We will argue that for some TCM molecules, their chemical nature and the xenobiotic defense systems in the human body point to an alternative model, where the drug acts locally to induce circulating mediators with systemic immunomodulatory activity.

In this review we will not address two important areas in TCM pharmacology, combinatorial drug action and modulation of the gut microbiome. Combining ingredients with complementary actions is central to the TCM philosophy (Zhang et al., 2014), which prompted the application of systems pharmacology approaches to rationally decipher existing combinations and develop new ones (Li et al., 2012; Ru et al., 2014). The physical emulsions naturally present in herbal extracts may also increase oral bioavailability of active components compared to pure molecules (Zhao et al., 2020). However, drug approval in the West usually requires a pure molecule with a precisely defined formulation to demonstrate single agent activity before combinations can be tested, and we are convinced that many TCM molecules with useful single agent activity remain to be discovered. Modulation of the gut microbiome by TCMs is an important research frontier (Lin et al., 2019b; Lin et al., 2021; Zhang et al., 2020a; Li et al., 2021b). Here, we will only touch on this topic in the context of immune regulators that act locally in the gut.

Xenobiotic defenses and their role in TCM pharmacology

Traditional TCM prescriptions mainly consist of dried plant and fungal ingredients boiled in water and administered as oral decoctions. Thus, consideration of oral bioavailability is paramount in discussing their mechanisms and pharmacology. Western drugs designed for oral dosing are usually optimized using synthetic chemistry and formulation methodology to maximize adsorption through the gut wall and minimize metabolism by the liver. This leads to drugs with high oral bioavailability, long plasma half-life and high systemic exposure. A drug with these properties is said to display ‘good pharmacology’. Some famous plant-derived drugs display good pharmacology, such as morphine, digoxin, quinine and artemisinin. However, most TCM molecules display ‘poor pharmacology’, that is poor oral bioavailability, short plasma half-life and rapid metabolism by the gut and liver (Lin et al., 2019b; Chen et al., 2016). How molecules with these properties can achieve beneficial systemic action is a long-standing puzzle in TCM pharmacology. The gut microbiome may play a role in mediating systemic actions of some oral TCM components that are poorly absorbed (Chen et al., 2016). We will focus on an alternative model, that local action in the gut or liver generates systemic mediators.

The “poor pharmacology” of most TCM molecules is not a coincidence. Rather, it results from evolutionary fundamentals. Plants and fungi evolved complex, bioactive metabolites, which we will term “xenobiotics”, mainly to deter herbivores through bitter taste or/and poisonous actions. In parallel, animals evolved xenobiotic defenses to protect them from potential toxins in their diets (Florsheim et al., 2021). Animals that could safely digest toxic plants gained a competitive advantage in access to food resources. Xenobiotic defense systems evolved to protect animals against precisely the kinds of molecules present in TCM oral decoctions, which is why, in our view, most TCM molecules exhibit poor pharmacology. Here, we will argue that the detection-response arm of xenobiotic defenses may also help explain their therapeutic actions.

The first layer of xenobiotic defenses in animals are sensory cues, such as bitter taste or bright colors, which signal avoidance of potentially poisonous foods. The second is a series of barriers that prevent systemic exposure, of which the gut wall is the most important. The third is a complex series of detection, transport and metabolism systems which rapidly detoxify xenobiotics that enter the bloodstream and trigger protective gene expression in exposed organs. The latter are concentrated in the liver in humans and, to a lesser extent, in the kidney. The liver efficiently removes many xenobiotics from the portal circulation before they enter the systemic circulation. This is achieved by its filter-like anatomy, drug transporters expressed on the sinusoidal (blood facing) membrane of hepatocytes and enzymes that rapidly metabolize xenobiotics into derivatives that are less toxic and easier to be excreted. This filtering effect of the liver, which can be upregulated by prior exposure to xenobiotics, is called ‘first pass metabolism’ and is responsible for the poor pharmacology of many plant-derived xenobiotics that cross the gut barrier.

Importantly, the xenobiotic defense systems of the gut, liver and kidney are dynamic. Maintaining high levels of defense is metabolically costly, therefore these systems evolved to be inducible. Exposure to xenobiotics induces defense proteins, notably metabolic enzymes and transporters, at the transcriptional level in the gut, liver and other organs (Xie et al., 2004; Müller, 2000). Xenobiotics are detected in part by their toxic actions on cellular organelles and in part by dedicated receptor proteins which are thought to have evolved for xenobiotic sensing (Negishi et al., 2020; Hoffmann and Partridge, 2015). Examples of xenobiotic sensors that are prominent in hepatocytes include the nuclear receptors PXR (Pregnane X receptor), FXR (Farnesoid X receptor) and AHR (Aryl Hydrocarbon Receptor). These receptors bind xenobiotics through the ligand-binding domains, leading to allosteric activation of their gene expression domains (Mackowiak and Wang, 2016). The chaperone-like sensor KEAP1 (Kelch Like ECH Associated Protein 1) detects oxidizing and alkylating xenobiotics using thiol chemistry. Oxidation and alkylation of cysteines on KEAP1 cause it to be degraded, which releases and activates its client protein, the transcription factor NRF2 (Baird and Yamamoto, 2020). NRF2 then serves as a master activator of anti-oxidant and xenobiotic defenses. Activation of xenobiotic sensors in hepatocytes leads to induction of drug metabolizing enzymes, such as cytochrome P450s, as well as efflux pumps, anti-oxidant proteins and other defense factors. Induction of xenobiotic defenses, especially P450s, is an important cause of drug-drug interactions (Ma, 2008). This is one reason patients must inform their doctors of all the drugs they are taking, including herbal supplements and traditional medicines. Induction of xenobiotic defenses by drugs has been most studied in the liver, but it also occurs in the gut and other tissues (Dressman and Thelen, 2009; Stresser et al., 2021).

The most important cell type for detecting and responding to xenobiotics is the hepatocyte. Research on xenobiotic sensors and the protective genes that they regulate has focused on two functions that are local to hepatocytes, that is, regulation of drug metabolism (Guengerich, 2017) and protection from the cytopathic effects of toxins, particularly by the KEAP1-NRF2 system (Taguchi and Kensler, 2020). Their roles in regulating inflammatory pathways and promoting whole-organism homeostasis have been much less studied. Of particular importance to this review is that activation of xenobiotic sensors in the gut or liver can induce secreted proteins, whose effects extend to the whole body. Signaling proteins secreted by the gut or liver are termed, respectively, enterokines and hepatokines. A systematic analysis of drug- and toxin-induced changes in rat liver gene expression revealed that many xenobiotics induce or repress hepatokines with known systemic actions, including IGF1, IGFALS, IGFBP, and GDF15 (Shimada and Mitchison, 2019). This regulation implies that xenobiotic sensors in the liver can mobilize the whole human body to regulate feeding, metabolism and other physiological processes. The same is likely true of the gut, although this has been less studied. Activation of xenobiotic defenses has been implicated in healthy aging of entire organisms (Hoffmann and Partridge, 2015). Here, we will link it to the action of herbal medicines. Xenobiotic sensors also monitor gut microbiome metabolites (Stockinger et al., 2021), so they are a point of integration between direct- and microbiome-mediated effects of small molecules on the human body.

The innate immune system can detect and respond to xenobiotics and we believe this system plays an important role in immunomodulation by herbal medicines, especially for molecules that lack oral bioavailability and act locally in the gut. This is a newer area of research compared to xenobiotic defenses in hepatocytes and much remains to be learned. Macrophages and dendritic cells in the lamina propria continuously sample the gut luminal contents by extending phagocytic processes directly into the gut lumen (‘periscoping’) and also by receiving material that is transcytosed out of the lumen by Microfold cells (M cells) (Bain and Schridde, 2018; Strober, 2009). This sampling is important for monitoring the microbiome and triggering immune responses in the gut. We propose it also constitutes a path by which insoluble xenobiotics that are unable to cross the gut wall due to their particulate form can access the immune system. Xenobiotic receptors in gut macrophages that have been implicated in sensing both microbiome metabolites and xenobiotics include AHR (Stockinger et al., 2021) and Toll-like receptors (TLRs) (Abreu, 2010). TLRs are usually thought of as receptors for pathogen-derived molecules, but as we will discuss below, they can also bind TCM polysaccharides. Modulation of gut macrophages and dendritic cells by luminal TCM molecules is expected to modulate inflammation locally, which may be important in treatment of gut inflammatory diseases, as discussed below. It can also give rise to systemic effects in at least two ways, by triggering secretion of circulating cytokines and by trafficking of educated leukocytes from the gut to other organs. We speculate both are important for relaying the effects of xenobiotic exposure from the gut to distant sites.

Figure 1 illustrates a series of models to explain how TCM molecules with ‘poor pharmacology’ can act both locally and systemically. The green line on the far left, labeled ‘direct actions’, is the standard oral pharmacology paradigm, where a molecule with ‘good pharmacology’ is absorbed through the gut wall, distributed by the bloodstream and acts directly on target cells throughout the body. Circulating metabolites, usually generated by the liver, may also contribute to systemic action in this model. The other lines illustrate a series of potential indirect action models that may apply to TCM molecules with ‘poor pharmacology’. In these models, the TCM molecule acts locally in the gut or liver to generate mediators that act systemically. These mediators can, in principle, be small molecules, signaling proteins, or immune cells that have been educated by drug exposure or carry insoluble drug particles in their lysosomes. Below, we will explore roles of these indirect mechanisms in the immunomodulatory effects of specific components of traditional herbal medicines. Our emphasis in this review is on pathways in human cells and organs. The blue arrow in Figure 1 indicates direct action of TCM molecules on gut microbes, which is an important research frontier that we do not discuss. For reviews see Lin et al., 2019b; Lin et al., 2021; Zhang et al., 2020a; Li et al., 2021b; Chen et al., 2016.

Figure 1

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Before discussing specific exemplars of local pharmacology, we must sound a note of caution. In recent years, TCM has evolved in the direction of injectable formulations that bypass the gut barrier and achieve plasma concentrations that are much higher than those achieved by traditional oral dosing (Li et al., 2018; Jiabo, 2010). For example, an injectable formulation of Panax ginseng extract can achieve transient plasma concentrations and systemic exposure (AUC) values of the ginsenoside active ingredients that are many hundreds-fold higher than an oral decoction of the same herb, due to the poor oral bioavailability of ginsenosides (Choi et al., 2020; Zhang et al., 2020b). Injection of TCM ingredients allows for much stronger direct, systemic actions, but at significant risk. The safety of TCM prescriptions is mostly based on experience from traditional oral dosing so it is important to critically evaluate the potential for toxicity when systemic exposure is drastically increased (Li et al., 2019).

Below, we discuss four examples of plant- and fungus-derived molecules with immunomodulatory activity, where we believe restricted distribution and organ-specific pharmacology are central to their therapeutic mechanism. The pharmacology concepts exemplified by these molecules may have much broader implications.

(1) Indigo – gut-restricted stimulation of AHR by insoluble drug particles

The plant Indigo naturalis is best known as a source of blue dye, but it also has traditional medicinal uses in China. Its main bioactive components are the bis-indoles indigo and indirubin, which are formed by non-biological reactions during processing (Sun et al., 2021). Therapeutic benefit of Indigo naturalis in ulcerative colitis (UC, a common inflammatory disease of the colon) was proven by recent clinical trials (Naganuma et al., 2018; Naganuma et al., 2020; Uchiyama et al., 2020). Response rates for the herbal medicine were comparable to the most effective western drugs, including biologics that target TNFα, and patients whose disease was not well-managed by western drugs responded well to the herbal preparation (Naganuma et al., 2020). The active ingredients in Indigo Naturalis, Indigo and indirubin, are almost insoluble in water and have very poor oral bioavailability (Sun et al., 2021). They are thought to act directly in the gut, where their concentration is locally high following ingestion of Indigo naturalis powder. Both are potent agonist ligands of the prototypical xenobiotic sensor AHR (Adachi et al., 2001) and tests in knockout mice showed that AHR expression is required for the therapeutic activity of both Indigo naturalis and pure indigo (Kawai et al., 2017). Therapeutic action is thought to proceed via secretion of the protective cytokines IL-10 and IL-22 from gut-associated immune cells (Lin et al., 2019a; Figure 2). The insolubility of indigo makes a traditional oral absorption route unlikely. We propose that indigo particles are delivered to gut macrophages and dendritic cells by phagocytosis, either directly from the gut lumen or following transcytosis by M cells (Bain and Schridde, 2018; Strober, 2009). Once ingested, active molecule slowly leaches from the phagocytosed particle to activate AHR. Limited clinical evidence suggests that the beneficial effects of Indigo naturalis power can extend systemically (Sun et al., 2021). This is unlikely to occur by systemic distribution of indigo itself, again due to its insolubility. Rather, it may involve one of the indirect action pathways proposed in Figure 1, such as trafficking of indigo-loaded immune cells from the gut into the systemic immune system. Systemic activation of AHR carries toxicity risk, as exemplified by the reference AHR agonist TCDD-dioxin (Bock and Köhle, 2006). The gut-restricted distribution of the indigo molecule, which we propose is due to its insoluble nature and selective delivery to gut by transcytosis and phagocytosis of particles, may be key to the therapeutic index of Indigo naturalis power. One of the proposed functions of AHR in gut macrophages is to monitor the gut microbiome and its metabolites (Stockinger et al., 2021). From this perspective, the therapeutic action of indigo in UC can be viewed as restoring balance to an endogenous immuno-regulatory circuit that monitors the gut microbiome.

Figure 2

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(3) Colchicine - induction of anti-inflammatory hepatokines

The alkaloid colchicine has a long history as a herbal medicine through use of Colchicum autumnale in the West and Gloriosa superba in Africa and Asia. It is still widely prescribed as a pure molecule for treating gout, Familial Mediterranean Fever and other inflammatory diseases and is being actively explored as a preventive in cardiovascular disease (Dasgeb et al., 2018; Tardif et al., 2019; Cocco et al., 2010). Colchicine targets tubulin, the subunit of microtubules, and promotes their depolymerization (Borisy and Taylor, 1967). Following oral dosing in humans, it reduces the adhesiveness of circulating myeloid cells and inhibits their recruitment to inflamed tissues (Fordham et al., 1981; Malawista, 1968). Colchicine has a high oral bioavailability and the standard model for its systemic anti-inflammatory action proposes that it acts on circulating myeloid cells to inhibit chemotaxis and IL-1β secretion (Dasgeb et al., 2018). However, this model is problematic. Colchicine is rapidly cleared from the blood to the liver (Thomas et al., 1989; Hunter and Klaassen, 1975). This rapid clearance, combined with its very slow association rate constant for tubulin binding, resulted in very low systemic exposure at safe doses, and microtubules in circulating leukocytes were not damaged following a safe, anti-inflammatory dose in mice (Weng et al., 2021). The same is likely true in humans, since colchicine at safe doses lacks anti-mitotic side effects, such as neutropenia and alopecia. In mice, colchicine damaged microtubules selectively in hepatocytes, presumably because it is concentrated across the sinusoidal membrane by xenobiotic transporters (Weng et al., 2021). Microtubule damage in hepatocytes activated NRF2, a master regulator of xenobiotic defenses, leading to induction of cytoprotective defense proteins (Figure 3). NRF2 activation also caused secretion of a novel form of GDF15 that acts systemically to inhibit inflammatory signaling in circulating myeloid cells (Weng et al., 2021). This new, indirect action model for colchicine has not been validated in humans and the anti-inflammatory form of GDF15 produced by the liver requires further characterization. Nevertheless, the concept that a plant-derived molecule with poor pharmacology can systemically modulate the immune system by inducing hepatokines has broad implications for the pharmacology of plant-derived molecules which enter the blood and act in the liver. The signature clinical activity of colchicine is relieving the symptoms of gout, a common rheumatic disease caused by the buildup of urate crystals in joints. Multiple TCM prescriptions are effective for gout treatment (Chi et al., 2020) and one demonstrated equal efficacy and superior therapeutic index when compared to colchicine in a double-blind trial (Wang et al., 2014). It would be interesting to test whether the active molecules in gout-active TCM prescriptions share colchicine’s ability to induce protective hepatokines.

Figure 3

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We believe that TCM is a viable starting point in the hunt for new immunomodulators but that previous research was handicapped by assuming systemic exposure, pre-selecting molecules with particular physical properties during fractionation and lack of realistic immune models. Below, we provide a short list of strategies designed to broaden the hunt and discovery of immune-active TCM molecules that were previously overlooked. The TCM field has made huge progress in chemistry and pharmacology in recent decades and powerful strategies for identification of bioactive molecules have been described elsewhere. Therefore, the suggestions below, based on the concepts in Figure 1, are not intended as a universal approach, but rather to supplement current approaches to fractionation and bioactivity analysis.

(2) Comprehensive and disease-specific immuno-profiling

TCM-derived molecules have often been tested for activity on immune cells in culture, but these tests were typically restricted to one single cell type and measurement. The human immune system is immensely complex and a single measurement is clearly insufficient to predict the immunomodulatory activity of a molecule in vivo. It is now possible to reconstitute many of the cell types and processes that constitute our immune systems in culture, but a comprehensive panel of assays is required (Figure 4). On this point, it is instructive to read papers from pharmaceutical companies which report comprehensive immuno-profiling of small-molecule immunomodulators, such as kinase inhibitors, using a battery of assays with multiple immune cell types, inputs and outputs (Braselmann et al., 2006; Zhu et al., 2007; Blomgren et al., 2020).

Figure 4

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While testing across a panel of normal immune cell types is much more informative than a single assay, testing cells only in their normal state may still not be sufficient. Immune cells exhibit specific forms of dis-regulation in disease contexts. If the therapeutic goal is to correct these aberrant cellular phenotypes, it is necessary to model them in culture. For example, there is a need for drugs that rejuvenate exhausted T cells in solid tumors to improve immunotherapy (Jiang et al., 2015). To identify such drug candidates, it is necessary to develop a cell culture model of exhausted T cells and assay their metabolic and cytotoxic activities. The closer the culture model matches the state of T cells in patient tumors, the more predictive the assay will be. Recent development of various single cell analysis methods has revolutionized our ability to profile and describe the variable states of immune cells in disease situations, which, as discussed above, often differ from any known healthy states of the same cells. These data should, in principle, help us model disease-specific states of the immune system in cell culture and then seek molecules that reverse them.

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Author details

1. Jue Shi

   Centre for Quantitative Systems Biology, Department of Physics and Department of Biology, Hong Kong Baptist University, Hong Kong, China

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Writing – original draft, Writing – review and editing

   For correspondence

   jshi@hkbu.edu.hk

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-4061-3496

2. Jui-Hsia Weng

   1. Department of Systems Biology, Harvard Medical School, Boston, United States
   2. Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan

   Contribution

   Conceptualization, Data curation, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

3. Timothy J Mitchison

   Department of Systems Biology, Harvard Medical School, Boston, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Writing – original draft, Writing – review and editing

   For correspondence

   Timothy_Mitchison@hms.harvard.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-7781-1897

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