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The rising incidences of Type 2 Diabetes Mellitus (T2DM) and the associated microvascular and macrovascular complexities is demanding a change in thinking in treatment approaches (1). T2DM is a systemic disorder exhibiting chronic inflammation, metabolic inflexibility, disrupted intestinal barrier, microbial dysbiosis. These modulations carry grave consequences in the form of tissue injuries across multiple organs and can cause serious health complications that range from nephropathy to osteoporosis (1,2).It is believed that T2DM management could be improved through precision nutrition and herbal formulation which could shift the paradigm from single-pathway, single-organ understanding toward multi-target and integrated biology (Figure 1). This paradigm shift for T2DM treatment and management does not require the replacement of the conventional therapies but demanding their expansion for synergies and formulation with natural products as multi-target interventions that may be especially well suited to this complexity and holistic improvement of patient (3) (Figure 1). In this regard, Yang et al. surveyed literature and proposed that T2DM and associated polycystic ovary syndrome could be managed by targeting the gut-ovarymetabolism axis through the synergy of probiotic-metformin (4). We summarize the main findings of the papers collected in this research topic and discuss the emerging enthusiasm toward multi-target treatment strategies for T2DM treatment and management.It is well-known that Gut Microbiome (GM) promote metabolism by cutting down resistant dietary fibers into short-chain fatty acids (SCFAs), which play a key role in regulating in lipid storage and glucose levels (5). Human intestinal barrier is highly selective which is comprised of a single layer of epithelial cells and apical junctional complexes, such as claudins, adherens, occludin, and zonula occludens-1 (6). This equilibrium is disturbed during GM dysbiosis-a state in which microbial diversity is lost, obligate anaerobes decrease in the large intestine, and pathobionts (often facultative anaerobic Enterobacteriaceae) propagate in the bowel (7).GM dysbiosis has been frequently associated with metabolic disorders such as obesity, T2DM and hormonal irregularities. New findings indicate that GM dysbiosis is not just a consequence of T2DM but a driver of insulin resistance (IR) and systemic inflammation (8). Advances in computation models are helping to clearly distinguish IR individuals from T2DM patients based as signature GM clusters. For instance, XGBoost identified Bacteroides and Faecalibacterium as major discriminators for IR severity (9).One of the widely accepted pathways through which GM dysbiosis can cause systemic inflammation is "leaky gut" -a condition in which intestinal barrier damage leading to increase translocation of endotoxins and uremic toxins (e.g. indoxyl sulfate) that can initiate and aggravate systemic inflammation and fuel polycystic ovary syndrome and diabetic kidney disease (8).Graphical illustration of the mono-targeted single-drug approach versus the multitargeted herbal drug approach in the management of diabetes mellitus and its associated comorbidities. Mono-targeted drugs lower systemic blood glucose levels by either enhancing insulin secretion or improving peripheral insulin sensitivity. Whereas multi-target drugs are managing diabetes at multilevel ranging from gut microbiome improvement to lowering inflammation. Beyond primary glycaemic control, multi-targeted herbal drugs also improve secondary condition associated with diabetes. Microsoft publisher was used for generating this plot. No generative AI was used for conceptualization and drafting of this figure.Non-digestible carbohydrates (like β-inulin or resistant starch) could revive the depleted beneficial commensal strains. A clinical trial (TarGut-CKD study) has performed the restoration of GM dysbiosis through prebiotics. Importantly, these prebiotics promote the growth of SCFAproducers (such as Faecalibacterium and Roseburia), that help in healing the leaky gut condition by upregulating tight-junction proteins like Zonula Occludens-1 (ZO-1) (10).Among the collected articles, Liu et al. identified herbal monomers that could regulated PPARγ/LXRα signaling and exert renoprotective function by regulating lipid homeostasis and oxidative stress (11). Another study by Dai et al. explained that Yiqi Huoxue recipe, derived from traditional Chinese medicine (TCM), showed protective abilities in DKD by autophagy, implicating mitochondria-associated endoplasmic reticulum membranes, and calcium homeostasis (12). In addition, several other studies have reported beneficial abilities of natural compounds and TCM formulae (such as Lycium, icariin, jiaogulan, barbarum polysaccharide, Dendrobium officinale polysaccharides, Gastrodia elata water extract, cumin infusion) that could help in regulating glucose and lipids; reinstate the GM diversity and composition; and lower down inflammation which eventually benefit other organs (13)(14)(15)(16)(17).The beneficial role of the TCM in improving GM composition and alleviating associated disease is well-explained by Yin et al (18). The review proposed that PCOS-induced IR and hyperandrogenism could be treated with TCM by restoring microbial balance, reducing low grade inflammation, and improving IR.TCM model is based on holistic improvement of the body, which is aligning well with systems biology, providing an efficient alternative treatment and managing strategy for complex diseases such as metabolic syndromes, cardiovascular diseases, and neurodegenerative disorders (19). The diverse constituents of the TCM formulae target various a wide range of drug receptors. In addition, TCM is a rich source of prebiotics (e.g. non-digestible carbohydrates, oligosaccharides, and polyphenols) that promote the growth of beneficial microbes (e.g. Bifidobacterium and Lactobacillus) in colon and consequently provide beneficial effects on the host (20). Furthermore, GM also serve as a metabolic mediator and biotransforms hydrophobic TCM components into smaller, more bioavailable, and efficient active metabolites. TCM-GM establishes a bidirectional relationship, in which, TCM improve the gut health by remodelling GM, and the beneficial bacteria improve TCM bioavailability and efficacy.TCM could serve as effective alternative strategy for the management of diabetes mellitus and its secondary complications (e.g. DKD and chronic wounds). TCM derived prebiotics could resolve the root of diabetic complications through the gut-pancreas axis. According to He et al. there are compelling evidence that certain GM clusters are associated with IR-related clinical measures (9). Dendrobium officinale is another TCM herbs know for T2DM management. Wan et al. summarized the available literature and proposed that Dendrobium officinale polysaccharides, the major bioactive constituent of this herb, should be developed as prebiotic for remodelling GM that could eventually improve intestinal permeability and ameliorate T2DM symptoms (21).T2DM and metabolic dysfunction-associated steatohepatitis are tightly linked chronic metabolic diseases that exacerbate each other and creating a dangerous cycle of lipid and glucose dysregulation (22,23). It is noticed that during diabetes mellitus hepatic glucose is increased that cause lipid accumulation, which contribute to accelerated progression of metabolic dysfunction-associated steatohepatitis toward liver fibrosis and steatohepatitis (24). In a comprehensive review, Li et al. established a firm causal association between visceral adipose tissue accumulation and DKD which is govern through a multi-channel pathophysiological network (25).GM play a key role in progression of T2DM complicated by MASLD. Therefore, modulation of the gut microbiota has emerged as a key strategy for managing MASLD in patients with T2DM (26). Several studies have reported that Zhaqu Compound (comprised of eight TCM ingredients) alleviate MASLD and T2DM by remodelling GM and their metabolites, which consequently improve hepatic glucose and lipid metabolism (27)(28)(29). Liu et al. identified that Zhaqu compound serve as prebiotic for key genera like Bacteroides, Mucispirillum, Lactobacillus that through secretory metabolites (like SCFAs) improve the hepatocytes metabolic function through PPARγ-related pathways (11). In addition, Lycium barbarum polysaccharide have also shown to improve glycolipid profile and protection against glucotoxicity-induced organ injury. Yao et al. proposed that Lycium barbarum polysaccharidebased supplement should be developed and prescribed for efficient management of T2DM and associated disease conditions (30). In addition, Huang et al. evaluated Sanghuangporus vaninii-based formulation for anti-T2DM effects through network analysis and observed that apigenin and tangeritin were the most potent constitute of the formula associating with decreased level of M3G (hepatic metabolite) (31).Gut-kidney axis is a relatively a new farmwork through which dysbiosis implicate in the onset and progression of diabetic kidney disease (DKD) and chronic kidney disease (CKD). The interaction between GM and kidneys is bidirectional -the exacerbated uremia in CKD and chronic hyperglycaemia in DKD can remodel the GM diversity and composition and similarly the dysbiosis-induced decrease in the anti-inflammatory metabolites (e.g. butyrate) and increase in endotoxins (LPS) could cause renal decline (32).Diabetic nephropathy, also known as DKD, is a progressive renal dysfunction of the major microvascular triggered chronic diabetes mellitus. While conventional medication is failing to provide therapy for DKD, TCM is progressing through systemic approach to mitigate intraglomerular hypertension. Yiqi Huoxue Recipe is considered one of such approaches that could efficiently regulate DKD. Dai et al. identified that Yiqi Huoxue recipe protect kidneys by targeting the mitochondria-associated endoplasmic reticulum membranes complex (VAPB-PTPIP51) that triggers autophagy, a key cellular cleanup process that safeguards podocytes from hyperglycaemic damage (12). Yao et al. explored the underlying mechanism of Shenqi compound in NS-1 cells and reported that Shenqi compound protective effect is operating through NOD1/RIP2 signaling pathway and favour the maturation of insulin secretory vesicles (30). Sun et al. proposed that gut microbiota-gut-kidney axis hold a profound importance in DKD management and should be explored through precision nutrition (33). Through comprehensive bibliometric analysis, Cui et al. established that herbal intervention against DKD is rapidly growing and highlighted that deeper mechanistic research needs to be conducted to strengthen the confidence of herbal medication into evidence-based therapies (34). Wu et al. have explained that TCM monomers hold great potentials for managing DKD by regulating cholesterol efflux (35).Wu et al. explained the concept of metabolism-senescence axis, an axis through which diabetic wounds are sustain by inflammation and impair process which is driven by hyperglycaemia and IR (36). During the diabetic wounds mitochondrial is dysfunctional, oxidative stress and glycation is higher, and senescent cells are aggregated. The metabolismsenescence axis well-explain why multifunctional TCM is an emerging approach in treating diabetic wound than agents with potency against a single node (36).Through a systemic review, Yang et al. summarized T2DM and polycystic ovary syndrome are linked through GM dysbiosis and IR (4). They proposed that polycystic ovary syndrome could be managed by targeting the gut-ovary-metabolism axis through the synergy of probioticmetformin. In another study, Yin et al. advocating that TCM hold strong footing for restoring the GM dysbiosis, reducing inflammation, and improving IR (18). They listed TCM formulae that strengthen the intestinal barrier by promoting the growth of SCFAs producing bacteria that are consequently lowering systemic and ovarian inflammation. Zhang et al. highlighted the importance of TCM for the treatment of another condition, known as diabetic gastroparesis, which is commonly noticed with diabetic autonomic neuropathy, and is described by abnormal and delayed gastrointestinal movement (37). Moreover, Jia et al. explored the role of Gastrodia elata Blume (G. elata), an edible medicinal plant, for its therapeutic abilities against osteoporosis in streptozotocin-induced diabetic rats (38). Apart from TCM, Aslam et al. developed a carbohydrate-controlled diet in combination with Cuminum cyminum, a member of the Apiaceous family, can provide support for glycaemic control and lipid metabolism (39).In conclusion, the articles compiled within this research topic underscore the paradigm shift in the treatment of T2DM therapy from pancreas-and-glucose management toward a new paradigm of holistic, multi-organ approach through by harnessing the complexity of the natural products through the network pharmacology and targeting system biology of the GM-organ axis. The published articles in this research issue illustrated those herbal products -ranging from singular traditional monomers to complex herbal formulations -engage in a bidirectional crosstalk with the host's internal microenvironment. Herbal products hold great potentials beyond simple glucose management toward tissue repair and the treatment of chronic secondary conditions of T2DM. Since this research is currently in the preclinical phase, the translation of the findings to large-scale is the next critical next step in validating the findings. Future research should be conducted to overcome the limitation of bioavailability and efficacy and the development of synbiotics could be one of such innovative targeted systems.
Imran Khan (Wed,) studied this question.