What Is the Use of D Mannose Powder?

Mannose is a diastereomer of glucose at the C-2 position, with the molecular formula C₆H₁₂O₆. It primarily exists in the form of the sweet-tasting α-isomer (67%) or the bitter-tasting β-isomer (33%) of the pyranose sugar [1-2]. Mannose is widely distributed in body fluids and tissues, such as nerves, skin, testes, retina, liver, and intestines. The free mannose concentration in mammalian plasma is 50–100 μmol/L [3], which is only 1/50 of the blood glucose concentration. Mannose is primarily transported into mammalian cells via hexose transporters, specifically glucose transporters, located on the cell membrane, through facilitated diffusion. Within cells, mannose is phosphorylated by hexokinase to form 6-phosphate mannose, which can be metabolized by mannosephosphate isomerase (MPI) or enter N-glycosylation via the action of phosphomannose mutase.

In recent years, the various regulatory effects of mannitol powder have gradually attracted the attention of scholars. Among them, the FimH protein is a type I fimbriae adhesin in Escherichia coli, and mannitol can inhibit the colonization of pathogenic microorganisms by binding to it [4]. Researchers have utilized these characteristics to develop drugs that highly bind to the FimH protein for the treatment of urinary tract infections [5]. Additionally, researchers have combined mannose with conventional chemotherapy to enhance therapeutic efficacy by leveraging its inhibitory effect on tumor cell glucose metabolism [6]. Furthermore, mannose can suppress inflammatory responses by regulating host immune cells and gut microbiota [7]. Given the multifaceted regulatory roles of mannose, this review summarizes the latest advances in mannose medical research and highlights its potential for clinical applications.

1. Antimicrobial Activity

Urinary tract infections (UTIs) are the most common bacterial infections in women, with incidence rates increasing after menopause [8]. Approximately 20%–30% of female UTIs recur. Recurrent UTIs (rUTIs) are defined as at least three UTIs within 12 months or at least two episodes within six months. UTIs are one of the most common causes of antibiotic use worldwide, and the growing problem of antibiotic resistance underscores the importance of identifying non-antibiotic alternatives for the prevention and treatment of UTIs [9]. The latest European Association of Urology guidelines recommend non-antimicrobial approaches for preventing urinary tract infections. In response, Scribano et al. [10] proposed a “uropathogenic Escherichia coli (UPEC) diet,” including mannose and other natural compounds, which have been proven to be a safe and effective clinical method for preventing UTI recurrence while limiting the adverse effects of long-term antibiotic use.

Many studies have shown that mannitol powder can significantly improve the characteristic symptoms of urinary tract infections [11–12]. Most UTIs are caused by UPEC [13]. UPEC adheres to the bladder surface by binding the FimH protein on its fimbriae to mannitol [4]. UPEC then proliferates further, leading to a UTI outbreak. Spalding et al. [5] utilized the characteristic that the FimH protein can bind to mannose to modify mannose into mannose glycoside, which has an affinity for the FimH protein that is 100,000 times higher than that of mannose. Compared with control mice, oral administration of mannitol glycoside significantly reduced the amount of UPEC in the intestines and bladder of mice.

Furthermore, researchers have utilized the binding properties of mannose with UPEC to develop targeted cytotoxic drugs against UPEC. Polyethyleneimine (PEI) is a highly cytotoxic compound. Liu et al. [14] modified PEI with mannose, and the results showed that the bactericidal rate of mannitol-modified polyethyleneimine copolymer particles with a mass ratio of 100:36 PEI to mannitol reached 100%, while the bactericidal rate was only 10% at a mass ratio of 100:0. When mannitol-modified PEI copolymer particles and PEI were used to treat cervical cancer HeLa cells, the results indicated that the former caused less harm to HeLa cells. This suggests that mannitol-modified PEI copolymer particles exhibit higher selectivity toward Escherichia coli and lower cytotoxicity toward cells.

Therefore, by leveraging the ability of mannitol to bind to the FimH protein, various drugs can be developed to target UPEC, causing them to detach from the bladder surface or die directly. By developing efficient and safe non-antibiotic therapies targeting the pathogenic mechanisms of UPEC, it is anticipated that antibiotic use can be replaced or reduced, thereby lowering the emergence of antibiotic-resistant UPEC.

2 Antitumor Effects

2.1 Mannose Inhibits Tumor Growth

Existing studies have identified various metabolic changes in tumor cells, including enhanced glucose uptake, a typical metabolic alteration observed in many tumors, known as the Warburg effect [15–16]. This metabolic characteristic reveals the vulnerability of tumor cells. Targeting this metabolic characteristic, Gonzalez et al. [6] found that after treating tumor cells with mannose, it accumulates in tumor cells in the form of 6-phosphate mannose, inhibiting hexokinase and phosphofructokinase, thereby inhibiting glycolysis and suppressing cell growth. Compared to other hexoses such as galactose, fructose, fucose, and glucose, mannose is more effective in inhibiting tumor cell growth. Additionally, the researchers confirmed that tumor cells' responsiveness to mannose depends on their MPI levels. Cells with low MPI levels are sensitive to mannose, while those with high levels exhibit resistance. MPI levels also vary significantly among different patients and tumor types, suggesting that MPI levels can serve as a biomarker to guide successful mannose administration. Importantly, oral doses of mannose at effective concentrations have no significant impact on animal weight or health [6].

Additionally, Yao et al. [17] first explored the relationship between MPI and immune infiltration, gene expression, and clinical characteristics in head and neck squamous cell carcinoma using bioinformatics analysis. The results showed that patients with lower MPI expression had higher survival rates, and increased MPI expression was a response to DNA damage. Mannose can synergistically inhibit oral squamous cell carcinoma by interacting with ataxia-telangiectasia mutated kinase inhibitors, CD8+ T cells, and bone marrow-derived inhibitory cells. Thus, mannitol can target the metabolic vulnerabilities of tumor cells to effectively inhibit their growth, making it a promising simple and safe therapeutic option for various types of tumors.

2.2 Mannose enhances the efficacy of radiotherapy and chemotherapy

Tumor cells interact with other cells such as fibroblasts, vascular endothelial cells, and immune cells, forming a unique extracellular environment known as the tumor microenvironment (TME) [18]. Tumors can regulate immune suppression in the TME through immune modulators such as regulatory T cells (Treg), tumor-associated macrophages (TAM), transforming growth factor β (TGF-β), and soluble proteins like interleukin (IL)-10, forming a robust immune suppression network. This leads to tumor immune escape, limiting T lymphocyte infiltration and function. Additionally, the physical environment, such as excessive lactic acid production by tumor cells causing TME acidification, not only promotes the transformation of macrophages from pro-inflammatory M1 phenotype to anti-inflammatory M2 phenotype, driving tumor progression and metastasis [19], but also becomes one of the factors affecting the efficacy of chemotherapy drugs [20]. Furthermore, one of the main drawbacks of traditional tumor therapy is the lack of selectivity, necessitating the development of targeted drug delivery systems to achieve selective killing of tumor cells [21].

In terms of regulating the acidic tumor microenvironment, since mannose can interfere with glucose metabolism in tumor cells, some researchers have speculated that it may weaken drug resistance caused by TME acidification resulting from tumor cell glycolysis. Results confirmed that when mannitol was combined with cisplatin or doxorubicin to treat mouse tumors, the efficacy was superior to that of chemotherapy alone [6]. In terms of regulating the tumor immune microenvironment, Zhang et al. [22] found that mannitol could significantly improve the efficacy of breast cancer by degrading the programmed cell death ligand 1 (PD-L1). The mechanism is that mannose-mediated PD-L1 degradation promotes T cell activation and tumor cell killing. The combination of mannose and programmed cell death protein-1 (PD-1) blockade therapy significantly inhibits tumor growth and prolongs the lifespan of tumor-bearing mice. Additionally, mannose-induced PD-L1 degradation leads to instability of messenger RNA associated with DNA damage repair genes, thereby increasing breast cancer cells' sensitivity to ionizing radiation therapy and enhancing the efficacy of radiotherapy in breast cancer mice. Thus, mannose can regulate the tumor microenvironment (TME) through multiple mechanisms to enhance the efficacy of chemotherapy and radiotherapy.

In addition to the aforementioned mechanisms, mannose can also enhance the targeted cytotoxic effects of chemotherapy drugs on tumor cells. The mannose receptor CD206 is a type I transmembrane protein primarily expressed on immune cells (macrophages and dendritic cells) and lymphocytes, and is also overexpressed on the surface of many malignant tumor cells [23].

Modifying the surface of nanocarriers with mannose enhances their specific cellular uptake through binding with specific receptors and nanomedicine systems, thereby selectively delivering drugs. Mannose holds promise for targeting anticancer drugs to cells with up-regulated receptor expression [21]. Methotrexate (MTX) was initially used to treat acute leukemia [24]. Fan et al. [25] synthesized carrier-free nanoparticles composed of MTX and mannose, with mannose linked to MTX via an ester bond. When these nanoparticles enter lysosomes via endocytosis, the ester bond between MTX and mannitol hydrolyzes, releasing MTX to kill tumor cells. Sheikhzadeh et al. [26] used mannitol-modified poly(lactic-co-glycolic acid) nanoparticles in a mouse model of breast cancer, successfully inducing antitumor immunity, altering the immune-suppressive microenvironment of the tumor microenvironment (TME), and effectively inhibiting breast cancer growth.

In summary, mannose can inhibit tumor cell glucose metabolism and suppress tumor cell growth. Additionally, when combined with radiotherapy and chemotherapy, it enhances the selectivity and cytotoxicity of drugs toward cancer cells, achieving effective targeted killing of tumors while protecting the safety of host tissue cells.

3 Immunomodulatory effects

Glucose plays a central role in energy production, storage, and regulation within cells. Mannose is a C-2 isomer of glucose, naturally present in many plants and fruits, particularly cranberries. However, the physiological blood concentration of mannose is only one-fiftieth that of glucose, and it has not received widespread attention [27]. However, recent studies have shown that in some inflammatory diseases, a phenomenon similar to the Warburg effect observed in tumors, characterized by a significant increase in glycolysis, may occur. This metabolic feature holds promise as a target for mannose's immune regulatory effects [28].

The application of mannose in autoimmune diseases and inflammatory conditions has also gradually gained attention. Studies have shown that in models of autoimmune diabetes and airway inflammation, oral administration of mannose can promote the production of reactive oxygen species (ROS) by increasing fatty acid oxidation, thereby activating TGF-β and inducing CD4+ T cells to produce regulatory T cells (Treg), thus inhibiting immune pathological responses [29]. This conclusion was further validated in an experimental autoimmune encephalomyelitis (EAE) model. Hwang et al. [30] found that oral mannitol can delay the onset of EAE and reduce disease severity by inducing Treg cell differentiation, preventing EAE recurrence. Liu et al. [31] also found that mannitol can promote cortical bone volume and trabecular microarchitecture in ovariectomized mice by inducing Treg cell proliferation and reshaping the gut microbiota, while inhibiting the expression of osteoclast-related cytokines in bone marrow, thereby alleviating estrogen deficiency-induced bone loss. Thus, mannitol can suppress the body's inflammatory response by inducing Treg cells and inhibiting effector T cells.

Mannose can also regulate the expression of inflammatory factor IL-1β by inhibiting its expression, thereby suppressing lipopolysaccharide (LPS)-induced macrophage activation and inhibiting the progression of colitis in mice induced by sodium glucuronate. Its mechanism involves the accumulation of intracellular 6-phosphogalactose, which inhibits the activation of hypoxia-inducible factor (HIF) IV-1α, ultimately reducing LPS-induced IL-1β expression. Lin et al. [33] found that autophagy activation, delayed IL-1β-induced rat chondrocyte degeneration and inhibited sodium iodate-induced osteoarthritis progression. Zhou et al. [34] also confirmed that mannose can inhibit IL-1β-induced chondrocyte ferroptosis in a HIF-2α-dependent manner, thereby alleviating osteoarthritis progression.

In addition to its direct regulatory effects on immune cells, Guo et al. [35] found that human periodontal ligament stem cells (hPDLSC) pretreated with mannitol can inhibit T cell proliferation and promote T cell differentiation toward Treg cells by suppressing IL-6 expression in hPDLSC. In summary, based on its multifaceted regulatory effects on immune cells, mannose holds promise as a safe, simple, and effective adjunctive therapeutic strategy for autoimmune diseases and inflammatory conditions.

4 Conclusions and Prospects

Mannose possesses multiple biological effects, including interfering with pathogen colonization, inhibiting glucose metabolism pathways, and mediating mannose receptor-mediated phagocytosis. These characteristics have been utilized to develop various drugs that safely and effectively exert antibacterial, antitumor, and immunomodulatory effects. Although mannose shows great potential for application in various diseases, whether it can effectively prevent or treat periodontal disease, dental caries, and autoimmune oral mucosal diseases through its antibacterial and immunomodulatory functions remains to be investigated. In the future, it is hoped that by gaining a deeper understanding of the mechanisms of action of mannose, it can play a more active and important role in clinical treatment.

Reference

[ 1]Stewart RA , Carrico CK , Webster RL , et al. Physicochemical stereospecificity in  taste  perception  of  αD-mannose  and β-D-mannose[ J]. Nature , 1971 , 234(5326) :220.

[2]Bunn HF , Higgins PJ. Reaction of monosaccharides with proteins : Possible  evolutionary  significance [ J ]. Science ,   1981 ,  213(4504) :222⁃224.

[3]Alton G , Hasilik M , Niehues R , et al. Direct utilization of man-nose for mammalian glycoprotein biosynthesis [ J ]. Glycobiology , 1998 , 8(3) :285⁃295.

[4]Krogfelt KA , Bergmans H , Klemm P. Direct evidence that the FimH protein is the mannose⁃specific adhesin of Escherichia coli type 1 fimbriae[ J]. Infect Immun , 1990 , 58(6) : 1995-1998.

[5]Spaulding CN , Klein RD , Ruer S , et al. Selective depletion of uropathogenic E. coli from the gut by a FimH antagonist [ J]. Na⁃ture , 2017 , 546(7659) :528⁃532.

[ 6]Gonzalez PS , O'Prey J , Cardaci S , et al. Mannose impairs tumour growth and enhances chemotherapy [ J ].  Nature ,  2018 ,  563(7733) :719⁃723.

[7]Zhang W , Cheng H , Gui YY , et al. Mannose treatment: A promis⁃ing novel strategy to suppress inflammation [ J ]. Front Immunol , 2021 , 12 :756920.

[8]Caretto M , Giannini A , Russo E , et al. Preventing urinary tract infections after menopause without antibiotics [ J ].  Maturitas , 2017 , 99 :43⁃46.

[9]Sihra N , Goodman A , Zakri R , et al. Nonantibiotic prevention and management of recurrent urinary tract infection[ J]. Nat Rev Urol , 2018 , 15(12) :750⁃776.

[10]Scribano D , Sarshar M , Fettucciari L , et al. Urinary tract infec⁃tions: Can we prevent uropathogenic Escherichia coli infection with dietary intervention? [ J]. Int J Vitam Nutr Res , 2021 , 91(5/6) : 391 ⁃395.

[11]Domenici L , Monti M , Bracchi C , et al. D ⁃mannose : a promising support for acute urinary tract infections in women. A pilot study [ J]. Eur Rev Med Pharmacol Sci , 2016 , 20(13) :2920⁃2925.

[12]Vicariotto F. Effectiveness of an association of a cranberry dry extract , D ⁃mannose , and the two microorganisms Lactobacillus plan⁃tarum LP01 and Lactobacillus paracasei LPC09 in women affected by cystitis : A pilot study [ J ]. J Clin Gastroenterol ,  2014 ,  48 ( Suppl 1) : S96-S101 .

[13]Yamamoto S , Tsukamoto T , Terai A , et al. Genetic evidence sup⁃porting the fecal⁃perinealurethral hypothesis in cystitis caused by Escherichia coli[ J]. J Urol , 1997 , 157(3) : 1127-1129.

[14]Liu M , Li J , Li BX. Mannose⁃modificated polyethylenimine : A specific and effective antibacterial agent against Escherichia coli [ J]. Langmuir, 2018 , 34(4) : 1574-1580.

[15]Hanahan D , Weinberg RA. Hallmarks of cancer: The next genera⁃tion[ J]. Cell , 2011 , 144(5) : 646⁃674.

[ 16]Pavlova NN , Thompson CB. The emerging hallmarks of cancer metabolism[ J]. Cell Metab , 2016 , 23(1) :27⁃47.

[17]Yao YF , Liu W , Li J , et al. MPI⁃based bioinformatic analysis and coinhibitory  therapy  with mannose  for oral squamous cell carcinoma[ J]. Med Oncol , 2021 , 38(9) : 1 -11 .

[18]Reina⁃Campos M , Moscat J , Diaz⁃Meco M. Metabolism shapes the tumor microenvironment [ J ]. Curr Opin Cell Biol , 2017 , 48 : 47⁃53.

[19]Qing S ,  Lyu CL , Zhu L , et al. Biomineralized bacterial outer membrane vesicles potentiate safe and efficient tumor microenvi⁃ronment reprogramming for anticancer therapy [ J ]. Adv Mater, 2020 , 32(47) :e2002085.

[ 20]Wojtkowiak JW , Verduzco D , Schramm KJ , et al. Drug resistance and cellular adaptation to tumor acidic pH microenvironment [ J]. Mol Pharm , 2011 , 8(6) :2032⁃2038.

[21]Dalle Vedove E , Costabile G , Merkel OM. Mannose and mannose⁃6⁃phosphate receptor⁃targeted drug delivery systems and their ap⁃plication in cancer therapy [ J ]. Adv Healthc Mater, 2018 , 7(14) :e1701398.

[22]Zhang RN , Yang YJ , Dong WJ , et al. D ⁃mannose facilitates im⁃munotherapy and radiotherapy of triplenegative breast cancer via degradation of PD⁃L1[ J]. Proc Natl Acad Sci USA , 2022 , 119(8) :e2114851119.

[23 ]Hu J , Wei P , Seeberger PH , et al. Mannose⁃functionalized nanoscaffolds for targeted delivery in biomedical applications[ J]. Chem Asian J , 2018 , 13(22) : 3448⁃3459.

[24]Djerassi I , Farber S , Abir E , et al. Continuous infusion of metho-trexate in children with acute leukemia [ J ]. Cancer, 1967 , 20(2) :233 ⁃242.

[ 25]Fan ZX , Wang YQ , Xiang SJ , et al. Dual⁃self⁃recognizing, stimu⁃lus⁃responsive and carrier⁃free  methotrexate⁃mannose  conjugate nanoparticles with highly synergistic chemotherapeutic effects[ J].J Mater Chem B , 2020 , 8(9) : 1922-1934.

[26]Sheikhzadeh S , Delirezh N , Hobbenaghi R. Mannosylated polylac⁃tic⁃co⁃glycolic acid ( MN⁃PLGA) nanoparticles induce potent anti⁃tumor immunity in murine model of breast cancer [ J ]. Biomed Pharmacother, 2021 , 142 : 111962.

[27]Sharma V , Ichikawa M , Freeze HH. Mannose metabolism : More than meets the eye [ J]. Biochem Biophys Res Commun , 2014 , 453(2) :220⁃228.

[28]Zhu LN , Zhao QJ , Yang T , et al. Cellular metabolism and macro-phage functional polarization [ J ]. Int Rev Immunol , 2015 , 34(1) : 82-100.

[ 29]Zhang DF , Chia C , Jiao X , et al. D ⁃mannose induces regulatory T cells and suppresses immunopathology [ J ]. Nat Med , 2017 , 23(9) : 1036-1045.

[30]Hwang D , Boehm A , Rostami A , et al. Oral D ⁃mannose treatment suppresses  experimental  autoimmune  encephalomyelitis  via induction of regulatory T cells [ J ].  J  Neuroimmunol ,  2022 , 362 :577778.

[31]Liu H , Gu RL , Zhu Y , et al. D ⁃mannose attenuates bone loss in mice via Treg cell proliferation and gut microbiota⁃dependent anti⁃inflammatory  effects [ J ].  Ther  Adv  Chronic  Dis ,   2020 ,11 :2040622320912661 .

[32]Torretta S , Scagliola A , Ricci L , et al. D ⁃mannose suppresses macrophage IL-1β production [ J ].  Nat Commun ,  2020 ,  11(1) : 6343.

[33]Lin ZM , Miao JN , Zhang T , et al. D ⁃Mannose suppresses osteoar⁃thritis development in vivo and delays IL-1β⁃induced degeneration in vitro by enhancing autophagy activated via the AMPK pathway [ J]. Biomed Pharmacother, 2021 , 135 : 111199.

[ 34]Zhou XM , Zheng YC , Sun WT , et al. D ⁃mannose alleviates osteo⁃arthritis progression by inhibiting chondrocyte ferroptosis in a HIF⁃2α⁃dependent manner[ J]. Cell Prolif, 2021 , 54(11) :e13134.

[35]Guo LJ , Hou YN , Song L , et al. D ⁃mannose enhanced immuno⁃modulation of periodontal ligament stem cells via inhibiting IL⁃6secretion[ J]. Stem Cells Int , 2018 , 2018 :7168231 .