Polysaccharides and inulins: immunostimulants and adjuvants

Inulins and polysaccharides: immunostimulants and adjuvants. Host defense functions are responsive to diet composition. It is known since many years that inulin and oligofructose increase resistance to health challenges. Kelly-Quagliana, K.A., Nelson, P.D., Buddington, R.K. Dietary oligofructose and inulin modulate immune functions in mice. Nutr Res. 2003;23:257–267 The bioavailability of drugs with low aqueous solubility may be enhanced by inulin. Inulin has been used to produce solid dispersions or tablets of various poorly soluble drugs like diazepam. It is used in sprays for pulmonary delivery. Amorij JP, Meulenar J, Hinrichs WL. Rational design of a vaccine powder with sugar glass technology Vaccine, 25, 6447-6457 Inulin stabilizes proteins. MA Mensink. H Frijlink, K van der Voort. Inulin a flexible oligosaccharide. Carbohydrate Polymers. 2015, 154, 418-428. Inulin-derived adjuvants that principally stimulate the innate immune system through their ability to activate the alternative complement pathway have proven ability to induce both cellular and humoral immunity. With their excellent tolerability, long shelf-life, low cost and easy manufacture, they offer great potential for use in a broad range of prophylactic and therapeutic vaccines. Based on successful animal studies in a broad range of species, human trials are about to get underway to validate the use of inulin-based adjuvants in prophylactic vaccines against malaria and other pathogens. Elena Mata, Aiala Salvador, Manoli Igartua, Rosa María Hernández, and José Luis Pedraz. Malaria Vaccine Adjuvants: Latest Update and Challenges in Preclinical and Clinical Research. BioMed Research International. Volume 2013 (2013), Article ID 282913, 19 pages .doi.org/10.1155/2013/282913 The Advax adjuvant produced by Vaxine in Australia enhances CD4+ and CD8 T Cell proliferation. Under certain conditions, inulin-type fructans may improve mineral absorption by their impact on the amelioration of gut health. This has been demonstrated for calcium, magnesium, phosphorus, copper, zinc and iron in animal trials. Scholz-Ahrens KE, Ade P, Marten B, Weber P, Timm W, Açil Y, Glüer CC, Schrezenmeir J Prebiotics, probiotics, and synbiotics affect mineral absorption, bone mineral content, and bone structure. J Nutr. 2007 Mar;137(3 Suppl 2):838S-46S. Inulins are prebiotics, indigestible carbohydrates, and may enhance the effect of probiotics like Lactobacillus or Bifidobacterium a genus of bacteria considered beneficial to health. Monika Roller, Gerhard Rechkemmer and Bernhard Watzl. Prebiotic Inulin Enriched with Oligofructose in Combination with the Probiotics Lactobacillus rhamnosus and Bifidobacterium lactis Modulates Intestinal Immune Functions in Rats. Nutritional Immunology-Research Communication, 2004, 153-156 A 15-g.day-1 dietary addition of oligofructose or inulin led to Bifidobacterium becoming the numerically predominant genus in feces. Thus, small changes in diet can alter the balance of colonic bacteria towards a potentially healthier microflora. Gibson GR, Beatty ER, Wang X, Cummings JH. Selective stimulation of bifidobacteria in the human colon by oligofructose and inulin. Gastroenterology. 1995 Apr;108(4):975-82. The combination of the same pre- and probiotics reduced colon cancer induced by by azoxymethane. Femia AP, Luceri C, Dolara P, Giannini A, Biggeri A, Salvadori M, Clune Y, Collins KJ, Paglierani M, Caderni G. Antitumorigenic activity of the prebiotic inulin enriched with oligofructose in combination with the probiotics Lactobacillus rhamnosus and Bifidobacterium lactis on azoxymethane-induced colon carcinogenesis in rats. Carcinogenesis. 2002 Nov;23(11):1953-60. This was confirmed in a recent review paper. Pool-Zobel BL, Sauer J. Overview of experimental data on reduction of colorectal cancer risk by inulintype fructans. J Nutr 2007;137(11):2580–84. The University of Louvain has shown 15 years ago that inulins inhibit breast cancer and tumor growth. Taper HS, Roberfroid MB. Inhibitory effect of dietary inulin or oligofrutose on the development of cancer metastases. Anticancer Res. 2002; 20(6B): 4291-4 Mireia Hidalgo-Garciaa, Andreu Farran-Codinaa, Evidencia existente sobre la influencia de la ingesta de prebióticos sobre el riesgo de cáncer colorrectal. Rev Esp Nutr Hum Diet. 2013; 17(1): 27 - 33 Gut microbiota also influence the pathogenesis of malaria. Results from a recent study identify the composition of the gut microbiota as a previously unidentified risk factor for severe malaria and modulation of the gut microbiota (e.g., probiotics) as a potential treatment to decrease parasite burden. Villarino, NF., Gary R. LeCleir, Joshua E. Denny, Sarah S. Sloan, Steven W. Wilhelm, and Nathan W. Schmidt. Composition of the gut microbiota modulates the severity of malaria. Proc Natl Acad Sci U S A. 2016 23;113(8):2235-40. Inulin is a dietetic fiber, a polysaccharide and some Artemisia species may contain up to 9% polysaccharides of their dry weight. Capsules of Chinese origin containing Artemisia annua leaf powder also contain inulin. The main reason may be reduction of iron absortion in the intestine. JM Laparra Llopis, Elad Tako, R Glahn, Inulins and mucins in the intestine can reduce iron uptake. FASEB Journal abstract 22/2 MB Zimmermann, Effect of Inulin on iron absortion in humans. Clinical trial.go identifier NCT01483092. Elmar Breuer and Thomas Efferth. Treatment of Iron-Loaded Veterinary Sarcoma by Artemisia annua. Nat Prod Bioprospect. 2014 Apr; 4(2): 113–118. doi: 10.1007/s13659-014-0013-7 Polysaccharides may enhance the production of NO, through a potent macrophage/monocyte activation. This has been demonstrated for acidic polysaccharides from Artemisia tripartita Gang Xie, Igor A. Schepetkin, Daniel W. Siemsen, Liliya N. Kirpotina, James A. Wiley, and Mark T. Quinn Fractionation and Characterization of Biologically-active Polysaccharides from Artemisia tripartita. Photochemistry, 2008, 69, 1359-71 from Tanacetum vulgare Gang Xie, Igor A. Schepetkin, and Mark T. Quinn. Immunomodulatory Activity of Acidic Polysaccharides Isolated from Tanacetum vulgare L Int Immunopharmacol 2007, 7, 1639-50 from mushrooms Volman JJ, Helsper JP, Wei S, Baars JJ, van Griensven LJ, Sonnenberg AS, Mensink RP, Plat J. Effects of mushroom-derived beta-glucan-rich polysaccharide extracts on nitric oxide production by bone marrow-derived macrophages and nuclear factor-kappaB transactivation in Caco-2 reporter cells: can effects be explained by structure? Mol Nutr Food Res, 2010, 54, 268-76 But the polysaccharide with the strongest stimulation of NO synthesis is inulin Koo HN, Hong SH, Seo HG, Yoo TS, Lee KN, Kim NS, Kim CH, Kim HM. Inulin stimulates NO synthesis via activation of PKC-alpha and protein tyrosine kinase, resulting in the activation of NF-kappaB by IFN-gamma-primed RAW 264.7 cells. J Nutr Biochem. 2003 Oct;14(10):598-605. The production of NO and activation of NF-kB by inulin plays a key role. Bahmani F, Tajadadi-Ebrahimi M, Kolahdooz F, Mazouchi M, Hadaegh H, Jamal AS, Mazroii N, Asemi S, Asemi Z. The Consumption of Synbiotic Bread Containing Lactobacillus sporogenes and Inulin Affects Nitric Oxide and Malondialdehyde in Patients with Type 2 Diabetes Mellitus: Randomized, Double-Blind, Placebo-Controlled Trial. J Am Coll Nutr. 2016 Aug;35(6):506-513. and may explain the antimicrobial and tumoricidal activity. This explains why current research is directed to develop inulin as an adjuvant for influenza vaccines, hepatitis B vaccines, malaria vaccines and anti-tumour drugs. Inulin can induce better humoral response against several antigens than alum adjuvant. Gamma-inulin has been shown to be a potent activator of the alternative pathway of complement and thus can cause direct activation of B cells. N. Mahalaksmi, R Aparnaa, P Kaliraj. Evaluaation of immune response eleicited by inulin as an adjuvant with filarial antigens in mice model. Experimental Immunology 2014, doi : 10.1111/sji.12208 Cooper PD, McComb, Steele EJ. The adjuvanticity of Algammulin, a new vaccine adjuvant. Vaccine, 1991, 9, 408-15. Inulin induces NO release to specific parasite antigens in proximity to the parasite Rajan TV, Porte P, Keefer L, Role of nitric oxide in host defense against an extracellular metazoan parasite. Brujia Malayi Infect Immun. 1996 64, 3351-3 Polysaccharides are known for their immunomodulatory and therapeutic properties Hayakawa Y, Hayashi T, Hayashi T, Niiya K, Sakuragawa N. Selective activation of heparin cofactor II by a sulfated polysaccharide isolated from the leaves of Artemisia princeps. Blood Coagul. Fibrinolysis. 1995;6:643–649. Hwang JS, Chung HK, Bae EK, Lee AY, Ji HJ, Park DW, Jung HJ, Cho CW, Choi HJ, Lee DS, Lee KR, Youn HJ. The polysaccharide fraction AIP1 from Artemisia iwayomogi suppresses apoptotic death of the mouse spleen cells in culture. Arch. Pharm. Res. 2003;26:294–300 So far, the presence of polysaccharides in Artemisia annua has been barely covered in the scientific literature. The reason may be that they are only soluble in water and most of the Artemisia extracts for research are obtained by organic solvents. Polysaccharides are polymeric carbohydrates of high molecular weight. They have probably been overlooked in the research on Artemisia annua. The presence of polysaccharides in other medicinal plants has been more extensively studied. They represent a very large part of the extracts. Pamela Weathers (personal communication) found 0.46 g/100g in dried leaves and 0,84 g/100g of Artemisia annua stems by the Petrovka and Deven method. It is thus fortunate that a very recent paper studied the polysaccharides of Artemisia afra and found that their immunomodulating properties probably contribute significantly to the health-promoting effects of this medicinal plant. Braünlich PM, Inngjerdingen KT, Polysaccharides from the South African medicinal plant Artemisia afra: Structure and activity studies. Fitoterapia. 2017 Nov 15. pii: S0367-326X(17)31374-6. They stimulate the intestinal microbiota and reduce the pro-inflammatory cytokines like IL-8 in CaCo2 cells Melillo de Magalhães, P., et al. Anti-inflammatory effect and modulation of cytochrome P450 activities by Artemisia annua tea infusions in human intestinal Caco-2 cells. Food Chemistry (2012), doi.org/10.1016/j.foodchem.2012.02.195 All safety and toxicity studies suggest that polysaccharide products are well tolerated. Jane E Ramberg, Erika D Nelson, and Robert A Sinnott. Immunomodulatory dietary polysaccharides: a systematic review of the literature Nutr J. 2010; 9: 54. doi: 10.1186/1475-2891-9-54