Immunomodulatory Role of Plants and Their Constituents on the Management of Metabolic Disorders: An Evidence-Based Review

Introduction

Metabolic disorders encompass a spectrum of conditions that disrupt normal metabolic processes, resulting in various health problems, including type 2 diabetes mellitus (T2DM), obesity, and metabolic syndrome (MetS).^1,2 Furthermore, the pathologies of metabolic diseases are intricate and multifactorial, and elevate the risk for cardiovascular disease (CVD).³ In their recent article, Saeedi et al reported that 9.3% of the global population (463 million people) was estimated to suffer DM, and this number is expected to increase to 10.2% (578 million) by 2030 and further to 10.9% by 2045.⁴ Concurrently, the global prevalence of obesity continues to escalate over the past 50 years, with its consequences encompassing the exacerbation of chronic conditions such as T2DM, coronary heart disease (CHD), hypertension, osteoarthritis, and cancers.^3,5,6

Metabolic diseases and CVD tend to be of long duration and slow progression (chronic) comprising several metabolic disorders due to the involvement of various physiological processes in their development and progression. They are usually the result of genetic, environmental, or lifestyle factors that interfere with the normal functioning of the body’s metabolic pathways. Over time, metabolic disorders manifest as a spectrum of intermediate phenotypes, culminating in metabolic syndrome elevating the risk for T2DM and atherosclerotic conditions.⁷ People with metabolic disorders can be more susceptible to infectious diseases due to several factors such as a weakened immune system, treatment-related immunosuppression, co-existing health conditions, and overlapping risk factors. Many metabolic conditions, including DM, cancer, and chronic kidney disease (CKD), compromise the immune system, thereby the body is difficult to fight off infections.⁸

Concerning the recent pandemic, data indicate a correlation between the severity of COVID-19 and the presence of DM and hyperglycemia. People with DM have been reported to face an augmented risk of SARS-CoV-2 infection, with inadequate glycemic control intensifying treatment and hospitalization necessities and fatality rates. Hyperglycemia, coupled with other risk factors, may tweak immune and inflammatory responses, rendering individuals susceptible to severe COVID-19 manifestations. Complications associated with DM, such as hypertension, obesity, heart failure, and CKDs, further increased COVID-19 mortality risks.^9,10 Notably, the COVID-19 pandemic underscores cardiac patients as particularly vulnerable, with the viral infection instigating cardiovascular complications like myocarditis, arrhythmias, cardiogenic shocks, heart failures, and thromboembolic episodes.¹¹

Current treatments for metabolic syndrome (MetS) disorders focus on managing individual risk factors to reduce the overall risk of developing related complications, such as CVD and T2DM. The main components of treatment include lifestyle modifications and pharmacological intervention. However, these treatments have revealed their limitations.¹¹ Adopting a healthier lifestyle is the cornerstone of MetS treatment. This includes a balanced diet, regular physical activity, weight loss, smoking cessation, and moderate alcohol consumption.¹² Embracing healthier lifestyles, characterized by balanced diets, consistent physical activity, weight management, smoking cessation, and moderate consumption of alcohol, is pivotal for MetS management.¹¹ Notably, dietary choices significantly influence metabolic disorder etiology, rendering them instrumental in CVD, MetS, and T2DM prevention strategies.^13–16

Recently, the therapeutic potential of natural foods in MetS management has garnered significant interest.^16–18 Clinical and epidemiological research underscores a diet dominated by plant-based foods as beneficial for metabolic homeostasis and highlights the potential of fruit and vegetable consumption in curbing CVD onset, attributed to phytoconstituents like polyphenols and flavonoids. These are renowned for their antioxidant and anti-inflammatory activities.^19–21 Those bioactive compounds are predicted to act synergistically via various biological pathways to reduce chronic disease manifestation.²² A sustained dietary regimen lacking these essential components emerges as a primary factor leading to the dysregulation of metabolic homeostasis.¹⁹

In this context, it is important to understand how bioactive compounds act synergistically on metabolic homeostasis and immune system which can play a fundamental role in the prevention and clinical management of metabolic disorders. Several clinical trials have evaluated the efficacy of plant-based or herbal preparations for metabolic disorders and their risk factors.^{2,16,19,20,23,24} Furthermore, the mechanism of actions of bioactive compounds on metabolic biomarkers has also been reported.^25,26 However, their potential on how those bioactive compounds exhibit multiple and synergistic effects on metabolic and immune systems is not thoroughly discussed yet. In this review, we discuss the efficacy of plant-based or herbal preparations for metabolic disorders and the mechanisms of actions of their bioactive compounds on metabolic biomarkers. This review delves into the potency of botanical and herbal formulations for metabolic irregularities and the operational mechanisms of their inherent bioactive constituents on metabolic indicators. We subsequently offer an incisive discourse on the prospective contributions of these natural entities to immune system modulation, positing them as a potential supplementary therapy to mitigate the risks and improve the quality of life of individuals with metabolic disorders.

Materials and Methods

The information retrieval was carried out through the PubMed database due to its esteemed results yielding the most relevant human clinical trials. The articles were searched using the keywords “metabolic disorders” OR “metabolic disease” AND “medicinal plants” OR “bioactive compounds” AND “clinical trials” (N = 124).

Study Design

A comprehensive literature review was conducted, where sources were screened based on their titles and abstracts. Studies that met the eligibility criteria and were available in full text were chosen for inclusion. Duplicates, unrelated articles, study methodologies, and clinical studies involving pediatric populations were excluded during the filtering process. The final selection of articles was determined after examining reference lists, and evaluations were made based on the aforementioned criteria. The incorporated studies exhibited variability regarding sample sizes and clinical results. The derived data are presented narratively, leading to the resultant conclusions. The process of selecting suitable studies is depicted in Figure 1.

Figure 1 The study design of the evidence-based review.

Literature Search and Study Selection

In the preliminary electronic search, 124 prospective studies were examined. Following the elimination of duplicates, the residual articles were evaluated for pertinence based on the predefined inclusion parameters for this review. Thirty-six trials with plant-based preparations as a treatment for metabolic diseases and their risk factors were identified and further examined as full texts. The characteristics of the included trials are tabulated in Table 1.

Table 1 Characteristics of the Included Trials

Results

The Role of Plant-Based Diets and Phytochemicals in Alleviating Metabolic Disorders

Among the thirty-six eligible studies, ten studies enrolled patients with either T2DM or prediabetes,^{13,27–34,49} seven studies enrolled overweight or obese subjects,^{14–16,36,42,45,47} three studies enrolled patients with metabolic syndrome or their risk factors,^19,20,50 three studies evaluated patients dyslipidemia,^12,21,35 two studies enrolled patients with hepatic steatosis or non-alcoholic fatty liver disease (NAFLD),^39,41 other studies enrolled patients with CVD or CVD risk factors,^37,40 diabetic nephropathy,³⁸ and healthy volunteers.^{1,22,25,26,43,44,46,48}

The primary intervention for metabolic disorders entails dietary and lifestyle modifications. It is well established that enhancing dietary practices—including reduced caloric consumption in instances of overweight and obesity and decreased intake of sodium, saturated fats, cholesterol, and simple sugars—can facilitate the clinical management of MetS-associated comorbidities. Several studies have delineated the positive outcomes of plant-based dietary regimens on parameters such as glucose concentrations, lipid profiles, body mass, blood pressure, and inflammatory indices (as shown in Table 1). In detail, 15 of the 36 studies focused on individuals with hyperglycemia and/or obesity, and 2 of the 36 centered on healthy participants, all of which noted metabolic improvements, including reductions in glycated hemoglobin (HbA1c) and a decrease of blood or plasma glucose concentrations. Additionally, 19 of the 36 studies highlighted a decline in serum concentrations of low-density (LDL) and high-density lipoproteins (HDL), and total cholesterol (TC) post-intervention. One investigation examined the ramifications of plant-based supplementation on DNA methylation patterns. Research by Crescenti et al underscored that cocoa intake considerably curtailed DNA methylation levels, elucidating the causal relationship between DNA methylation perturbations and the onset of cardiovascular diseases and their associated risk factors.⁴⁰

Given the extensive data provided, several key points can be elucidated regarding the various plant and herbal preparations and their mechanism on metabolic disorders. Numerous scientific investigations have underscored the potential of plants in decelerating the advancement of metabolic disorders. Extensive studies suggest a linear association between increased intake of plant-derived foods and reduction of susceptibility to chronic conditions.

Berries, black tea, cocoa, and olive are among plants that exert beneficial effects on metabolic markers. For example, Basu et al found a significant improvement in insulin resistance, lowering LDL-C, and decreased serum PAI-1 in obese adults after 14 weeks of high-dose strawberry consumption.¹⁵ Acute strawberry consumption is also reported to significantly elevate the serum concentrations of vitamin C and folate and prolong the LDL oxidation lag time, suggesting the antioxidant potential of strawberries for CVD prevention.⁴⁸ Consumption of cherry juice is reported to significantly lower oxidized LDL levels in patients with metabolic syndrome.¹⁹ Likewise, Franck et al found a significant reduction in post-prandial glucose, TG level, systolic blood pressure, and inflammatory markers (IL-6 and TNF-alpha) after eight weeks of supplementation of raspberry.²⁰ Plants like Boswellia serrata and Camellia sinensis are reported to improve insulin sensitivity, potentially providing therapeutic options for diabetes management.^33,43,51 Several extracts, including those from Citrus bergamia and Coffea arabica, are instrumental in modulating lipid profiles by inhibiting key enzymes involved in cholesterol and triglyceride synthesis.^26,50

Among 36 studies, two studies observed the effect of olive oil supplementation on metabolic biomarkers and ALT enzymes. The study conducted by Shidfar et al observed that a 12-week intake of extra virgin olive oil led to a marked reduction in ALT enzyme levels in individuals with NAFLD (P = 0.004). Conversely, the severity of liver steatosis remained relatively stable throughout the study duration.⁴¹ Similar favorable results are also reported in the study conducted by Sanchez et al although no significant differences were found among the study group, olive oil supplementation on endothelial function confers beneficial effects biomarker both in vivo and ex vivo studies.¹

Interestingly, while the majority of the studies report improvements in the clinical parameters observed during the intervention using plant-based preparations, two studies that observed the effect of coffee supplementation on metabolic and cardio markers reported similar no significant effect. Studies indicate that the intake of coffee or products derived from cocoa did not elicit notable alterations in cardiometabolic biomarkers. Moreover, within coffee formulations, neither chlorogenic acid nor caffeine showcased enhanced efficacy over placebo in mitigating hepatic lipid accumulation, liver stiffness, or other related hepatic parameters in individuals diagnosed with diabetes and NAFLD.^28,44

Additionally, studies included in this review also observed the effects of herbal preparations as herbal medicine on metabolic disorders. An herbal medicine comprising Radix Ginseng, Poria, Rhizoma Atractylodis macrocephalae, Semen Lablab album, Rhizoma Dioscoreae, Embryo Nelumbinis, Radix Platycodonis, Semen Coicis, Fructus Amomi, Fructus Jujubae, and Radix Glycyrrhizae has been documented to enhance hypoglycemic response and β-cell functionality in overweight or obese individuals presenting with suboptimally managed T2DM. This compound is posited as a compatible adjunctive therapy for oral hypoglycemic agents, offering advantages in weight regulation and lipid metabolism.³¹ In a separate study by Khalili et al, herbal formulation encompassing seeds of Silybum marianum (L) Gaertn (milk thistle), leaves of Urtica dioica L (nettle), and Boswellia serrata (olibanum gum) demonstrated marked reductions in serum fasting glucose, HbA1c, and triglyceride concentrations in patients diagnosed with type II diabetes mellitus.³⁴

Terminalia chebula is one of the herbal medicines that has been studied clinically both in its single preparation and in combination with other medicinal plants. Dietary supplementation of Terminalia chebula in healthy overweight patients has significantly improved joint mobility, comfort, and functional capacity.⁴⁷ Furthermore, its combination with Commiphora mukul and Commiphora myrrha in an herbal formulation is reported to reduce fasting blood glucose, total cholesterol, and low-density lipoprotein cholesterol levels. Shokoohi et al proposed that T. chebula inhibits α-glucosidase, and C. myrrha reduces the rate of gluconeogenesis in hepatocytes.³³

Supplementation with bitter gourd (Momordica charantia) has demonstrated efficacy in reducing elevated levels of fasting plasma glucose among individuals with prediabetes. Various extracts and constituents of M. charantia are postulated to contribute to its glucose-lowering properties through diverse physiological, pharmacological, and biochemical mechanisms. Specifically, the antihyperglycemic action of bitter gourd can be attributed to three primary pathways: reduction of glucose absorption in the intestine, enhancement of insulin secretion, and facilitation of glucose uptake in peripheral tissues.³² In a prior review, Joseph et al outlined multiple potential mechanisms underlying the hypoglycemic effects of M. charantia and its derivatives, including its direct glucose-lowering impact, stimulation of glucose utilization in peripheral and skeletal muscles, inhibition of intestinal glucose absorption, suppression of crucial enzymes involved in gluconeogenesis, activation of key enzymes in the hexose monophosphate pathway, and the preservation of islet β-cell functionality.⁵²

Various benefits have been reported to suggest that the intake of plant-based diets or supplementation of herbal preparations could prevent the development of chronic diseases. A primary rationale is that plants encompass an extensive array of components advantageous to health, including vitamins, minerals, and phytochemicals.^53–56 Phytochemical constituents, including chlorogenic acid, caffeine, cafestol, trigonelline, quercetin-3-O-rhamnoside (quercitrin), diosgenin, α-linolenic acid (ALA), anthocyanins, epicatechin, β-carotene, and quercetin, have been recognized for their multifaceted capacities in mitigating inflammation, anti-oxidative stress, and attenuating metabolic syndrome manifestations, attributed to their regulatory effects on biological and physiological processes.^57,58

Polyphenols are the most reported phytoconstituents that attenuate metabolic disorders by various mechanisms. Berries such as raspberry and strawberry, coffee, prune, and tea are among the plants which rich in polyphenols. Nilsson et al suggest that polyphenols (anthocyanins and flavonols) from berries are attributed to the beneficial effects on CVD and T2DM.⁴⁵ Moreover, research indicates that polyphenols may acutely modulate hemodynamic and vascular responses.¹⁹ Cocoa-derived polyphenols have been observed to decrease global DNA methylation, a change mediated by the regulation of pivotal genes central to this epigenetic mechanism.⁴⁰ Storniolo et al demonstrated that polyphenols confer protection against endothelial dysfunction induced by elevated glucose and free fatty acid levels, potentially via the modulation of nitric oxide and endothelin-1.⁵⁹

Polyphenol derivative compounds such as picceatanol, oleorepin, chlorogenic acid (CGA), curcumin, resveratrol, epigallocatechin-3-gallate (EGCG), and quercetin have been clinically reported for their beneficial effects in alleviating metabolic disorders. Piceatannol, a stilbene, major polyphenol derivative compound from Passiflora edulis, is reported to promote glucose uptake, AMPK phosphorylation, and glucose transporter 4 (GLUT4) translocation, inhibition of intestinal α-glucosidase.⁵⁰ Chlorogenic acid (CGA), a predominant polyphenol in coffee, is instrumental in regulating glucose intolerance and hyperlipidemia. In rat liver microsomes, CGAs specifically competitively inhibit glucose-6-phosphate translocase. Additionally, at the cellular level, they activate adenosine monophosphate-activated protein kinase, which subsequently modulates blood glucose homeostasis and suppresses lipid biosynthesis.⁶⁰

Epigallocatechin-3-gallate, epicatechin-3-gallate, and other related polyphenol derivatives have been demonstrated to augment insulin secretion through the enhancement of GLP1 levels.⁶¹ In a clinical study conducted by Morais et al, it was elucidated that EGCG’s role in mitigating insulin resistance and liver TG concentrations is linked to diminished lipid uptake and a decrease in inflammatory cytokine levels.⁴⁶

Flavonoids, notably anthocyanins, belong to an extensive group of phenolic compounds that possess antioxidant, anticancer, antimicrobial, cytotoxic, and antimutagenic properties. Anthocyanins influence the nitric oxide biosynthetic trajectory and exhibit inhibitory properties against angiotensin-converting enzyme (ACE).⁶² Moreover, anthocyanin-mediated AMPK activation promotes an upsurge in GLUT4 transporters and glucose assimilation while concurrently suppressing gluconeogenesis. Within hepatic lipid metabolic pathways, AMPK modulates the transcriptional levels of PPAR-α, acyl-coenzyme A (acyl-CoA) oxidase, and carnitine palmitoyltransferase-1A.¹⁵,^48,63 Clinical investigations have ascertained that strawberries, rich in anthocyanins, can impede glucose translocation from the intestines to the plasma, particularly through the inhibition of the sodium-glucose co-transporter 1 (SGLT1) and the glucose transporter GLUT2.⁴⁸

Other polyphenol derivatives such as flavanones and flavonols are also reported for their beneficial effects. Flavanones such as naringin, neohesperidin, neoeriocitrin, and brutieridin, major phytoconstituents from citrus species regulate lipid metabolic processes through the inhibition of hepatic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and acyl-CoA cholesterol acyltransferase (ACAT) enzymatic activities. Concurrently, they augment AMPK activity, thereby enhancing glucose assimilation in both muscular and hepatic tissues.¹⁷ Quercetin, bioactive compounds in mulberry, Terminalia chebula, Trigonella foenum-graecum, and Prunus cerasus have been identified to mediate several cellular mechanisms. These include the activation of PPAR-α and PPAR-γ, inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cells, and upregulation of anti-inflammatory cytokine expression.³⁸

It is also interesting to note that major phytoconstituents such as charantin, a typical cucurbitane-type triterpenoid in M. charantia, exhibit notable anti-diabetic attributes. Comparative studies indicate that this compound surpasses the efficacy of the oral hypoglycemic drug, tolbutamide.⁵² Pterocarpan and kaempferol glycosides from soya (Glycine max) are reported to ameliorate insulin sensitivity and improve the plasma glucose levels in high-fat diet (HFD)-induced type 2 diabetic mice.^16,64 Furthermore, compounds such as cinnamyl isobutyrate from Cinnamomum cassia and berberine from Rhizoma coptidis contribute to glucose homeostasis through various mechanisms, including AMP-activated protein kinase (AMPK) activation.

The Underlying Mechanism of Bioactive Compounds Affecting the Metabolic and Immune System

The relationship between the immune system and metabolic disorders is intricate and multifaceted and increasingly recognized as critical to understanding conditions like obesity, diabetes, and cardiovascular diseases. Modulating the immune system in patients with metabolic disorders can offer several potential benefits including reducing chronic low-grade inflammation, enhancing insulin sensitivity as the immune system plays a role in the development of insulin resistance, and influencing the gut microbiota creating a more balanced metabolic environment.⁶⁵

Table 2 elucidates a compelling cross-section of plant-based interventions that exert both metabolic and immunomodulatory effects, substantiated by specific bioactive constituents and corresponding mechanisms of action. These plants’ dual roles suggest a complex interplay between metabolic and immune systems, potentially mediated by a range of molecular targets, including but not limited to cytokines, lipid metabolism pathways, and glucose transport mechanisms.

Table 2 Mechanism of Action of Plants on Metabolic Disorders and Immune System

Among thirty-six studies, thirty-eight plants are employed either in their single preparations, combination or enriched with other phytoconstituents to enhance their pharmacological effect. Several plant-based supplementation or herbal preparations containing key phytoconstituents are reported to exhibit beneficial effects not only for various metabolic diseases but also on the immune system. Bioactive compounds are often associated with diverse potentials possessing a multifaceted capacity to manifest anti-inflammatory, antioxidative, and anti-metabolic syndrome effects; these agents adeptly regulate both biological and physiological processes.^57,58

Interestingly, the majority of plants that work on metabolic disorders were reported to activate the immune system. Alterations in metabolic responses are linked to numerous immunological signaling pathways, for example, metabolic hormones (leptin, resistin, and adiponectin) play various roles in immunological functions.⁹² Plants such as Boswellia serrata, Cinnamomum cassia, Citrus bergamia, Coffea arabica, Ficus racemosa, Momordica charantia, Morus Alba, Trigonella foenum graecum, and many others (depicted in Figure 2) affect multiple biochemical pathways, displaying not just metabolic but also immunological benefits. Boswellia serrata, Camellia sinensis, and Citrus bergamia are reported to not only improve insulin sensitivity but also reduce the levels of pro-inflammatory cytokines such as IL-6 and TNF-α and positively modulate T lymphocyte proliferation and natural killer (NK) cell function.^65,68,90

Figure 2 Plants that alleviate metabolic disorders and activate the immune system. The thin black outline denotes the plants that have been reported clinically solely for their activity in metabolic disorder and their mechanisms in immune system have not been reported in details. While the boxes with a red outline signify that the plants are reported not only for their benefit in metabolic disorders clinically but also affect multiple biochemical pathways in immune system.

The multifaceted impact of phytoconstituents on various physiological processes suggests a complex network of interactions. Consequently, attributing the potential metabolic benefits of phytoconstituents to a singular component or attribute appears challenging. Instead, phytoconstituents may exert their effects through a range of mechanisms, such as improved glucose regulation, reduced inflammatory responses, and immune system modulation. Trigonelline in fenugreek seeds helps improve diabetes through several mechanisms, such as regulating insulin release, decreasing oxidative stress, and enhancing both glucose tolerance and insulin sensitivity. Additionally, it has been documented that there is an augmentation in the phagocytic index and antibody titer. Additionally, there is modulation of the expression of pro-inflammatory and M1/M2 immunoregulatory markers within THP-1 macrophage cells mediated by NF-κB activity. Concurrently, an increase in CD4+ and CD8+ values has been observed in diabetic mice.^29,90

Furthermore, polyphenols are bioactive compounds that attenuate metabolic disorders by various mechanisms. Polyphenolic compounds, including epigallocatechin-3-gallate, epicatechin-3-gallate, and epigallocatechin, have been demonstrated to augment insulin secretion via an elevation in GLP-1 levels.⁶¹ Notably, epigallocatechin-3-gallate (EGCG) has exhibited the potential to ameliorate autoimmune disease symptoms in animal models. Mice administered with EGCG showed a significant increase in Treg cells within the lymph nodes and spleen, coupled with an attenuated T-cell response. Furthermore, a clinical investigation by Morais et al elucidated that EGCG’s role in mitigating insulin resistance and hepatic TG concentrations can be ascribed to its effect in decreased lipid uptake and lowering pro-inflammatory cytokine levels.⁴⁶ EGCG was also claimed to modulate the immune system through the modulation of cytokine production and T lymphocyte proliferation, as well as its enhancement of lymphocyte, monocyte, IL-1α, and IL-1β production.⁵¹

Isoflavones and their metabolites from soy influence the signaling and functional mechanisms of natural killer (NK) cells. Specifically, genistein attenuates the production of interferon-gamma (IFN-γ) induced by interleukin (IL)-12/IL-18 compared to control groups. Comprehensive cellular studies reveal that genistein mitigates IFN-γ production triggered by IL-12/IL-18 in human NK cell subsets without consistently affecting their cytotoxic capabilities. In terms of intracellular signaling, genistein reduces both the total tyrosine phosphorylation and the phosphorylated components of the MAPK pathway elicited by IL-12/IL-18 stimulation.⁷⁶

Conclusion

This review reveals potential synergistic effects in which the same plants that improve metabolic markers also enhance immune response modulation. The comprehensive analysis of thirty-six studies investigating the impact of plant-based diets and phytochemicals on metabolic disorders substantiates the significant role of plant-based diet interventions in mitigating various conditions related to metabolic disorders. The evidence indicates that plant-based foods with an abundant content of phytochemicals confer notable improvements in glycemic control, lipid profiles, weight management, blood pressure, and inflammatory markers. Furthermore, numerous studies demonstrate that phytochemicals from a diverse range of plants and herbal preparations exert multifunctional therapeutic effects which have been associated with improved insulin resistance, reduced LDL-cholesterol, decreased levels of inflammatory markers, and enhanced insulin sensitivity, offering promising avenues for the management of DM and CVD. Additionally, the correlation between the immune system and metabolic disorders is increasingly recognized, with corroborations suggesting that plant-based interventions can exert immunomodulatory effects. Plants such as Boswellia serrata, Cinnamomum cassia, Citrus bergamia, Coffea arabica, Ficus racemosa, Momordica charantia, Morus alba, Trigonella foenum graecum, and many others, could affect multiple biochemical pathways which correspond to the relationship between metabolic health and immune function.