Hemicellulose as an Immune Enhancing Tool

The Impact of Hemicellulose from Plants and Mushroom-Derived Polysaccharides on Immune Function

Hemicellulose isn’t a new thing. In fact, it is as timeless as the plants and fungi that cover the face of our planet. Hemicellulose differs from cellulose in that it is a polysaccharide comprised of various sugars including glucose, mannose, galactose, xylose, and arabinose, whereas cellulose is comprised exclusively of glucose.[1] Structurally, hemicellulose may be branched and is comprised of 500 to 3,000 sugar units while cellulose is unbranched and typically has 7,000 to 15,000 glucose molecules. Within plants, much like cellulose, hemicellulose is structural in function, and the specific types and quantities of the different hemicellulose compounds differ by plant and features (leaf, stem, branch, etc.) of the plant.

Although these hemicellulose compounds, for humans, offer very little to no caloric nourishment,[2],[3] this does not mean they are unimportant. In fact, many of them have numerous important biological properties. Well-known hemicelluloses are xylan, the base molecule from which xylitol and xylooligosaccharides (XOS), a prebiotic fiber that promotes healthy bifidobacteria in the gut,[4] are formed; arabinoxylan, which contains both soluble and insoluble fiber and also delivers a high level of antioxidant activity;[5],[6] and glucomannan, a hemicellulose commonly used in constipation and weight loss formulas due to its high water affinity.[7] Because of these and other medicinal properties, as well as their relative abundance and non-toxicity, hemicellulose products have gained substantial interest in both the pharmaceutical, functional food, and dietary supplement industry.[8]

One property of great interest is the ability of certain hemicellulose compounds to stimulate immune function. Herein, we look at the immune effects of the hemicellulose compound arabinoxylan and the closely related arabinogalactan, as well as the clinical and preclinical research surrounding a particular combination of plant and mushroom-sourced compounds, containing these and other active moieties.

Arabinoxylans

Arabinoxylans are hemicellulose compounds found at high levels in the cell walls of numerous cereal grains including rice, wheat, rye, barley, millet, and maize.[9] Because they are often a by-product of the processing of these grains for various food industry purposes, many have looked at processes to extract them, adding value and reducing waste.

Arabinoxylans are food for the gut bacteria, which degrade them into short chain fatty acids (SCFAs); thus, they are considered a prebiotic.[10],[11] Studies have shown arabinoxylans are a food source for Bifidobacterium spp. and increase levels of butyrate-producing bacteria, although the specific bacteria that are promoted depends in part on the specific arabinoxylan structure.[12] Although certain prebiotics occasionally may aggravate conditions like irritable bowel syndrome (IBS), compared to placebo, rice bran-sourced arabinoxylans were shown in one small clinical study to significantly decrease scores of diarrhea and constipation as well as C-reactive protein (CRP) levels in patients with IBS.[13] In humans, supplementation with arabinoxylans was also shown in a randomized crossover study to increase levels of bifidobacteria and total SCFAs, including butyrate, and reduce levels of dysbiotic bacteria.[14]

Arabinoxylans, due to their structure, are highly bonded to ferulic and other phenolic acids.[15],[16] Rice-sourced arabinoxylans are highly ferulated (containing bound ferulic acid molecules) which contributes to their potent antioxidant activity.[17],[18] Ferulic acid has affinity for biological membranes and prevents lipid peroxidation.[19] Ferulic acids are used in many skin care products for the protection they offer against the damaging effects of UV light.[20],[21] The antioxidant activity and bowel-directed action of ferulated arabinoxylans has also led to their consideration for intestinal conditions associated with inflammation and oxidative stress such as inflammatory bowel disease and colon cancer.[22]

Research suggests rice bran-sourced arabinoxylans enhance macrophage migration, attachment, and phagocytosis,[23] increase natural killer (NK) cell and dendritic cell activity,[24],[25] and induce CD4+ T cell proliferation and cytokine production.[26] However, in lipopolysaccharide (LPS)-stimulated animals, they also have been shown to have anti-inflammatory activity, reducing levels of tumor necrosis factor (TNF)-α and inflammatory cytokines.[27] Numerous other sources of arabinoxylans have been shown to have immunomodulatory effects as well.[28],[29]

Given they are a source of soluble and insoluble fiber, their interactions with the gut microbiota, and their antioxidant activity, it is not surprising that arabinoxylans also have numerous metabolic effects. Their impact on metabolism is affected by their structure both directly and indirectly: directly, their viscosity and structure affect their ability to absorb lipids, bile acids, and glucose; indirectly, in addition to the flora balance they favor, they have numerous other metabolism-affecting actions.[30] In humans with impaired glucose tolerance, dietary supplementation with arabinoxylan was shown to positively impact fasting glucose and triglycerides.[31] Acutely, supplementation of arabinoxylan oligosaccharides with carbohydrates consumed in the evening was shown to improve morning measures of insulin sensitivity and SCFA levels in healthy subjects.[32]

Arabinogalactans

By some classifications, arabinogalactans are considered hemicellulose compounds, as simply put, they are plant wall polysaccharides that are not cellulose components;[33],[34] however, by more stringent definitions of hemicellulose that include specifics concerning the molecular backbone of these structures, they are not.[35] Either way, these non-starch polysaccharides serve a similar structural function in plants, and even have similar effects in the human body.

Arabinogalactans are found at high levels in plants such as the larch tree, which we often associate with this compound due to it commonly being the source. Similar to arabinoxylan, other sources of arabinogalactans include cereal grains such as wheat, rye, barley, and spelt.[36] Their molecular size varies not only with their source, but also processing technique, with reported sizes ranging from 16 kDa to more than 100 kDa.[37],[38]

Arabinogalactans also have been shown to serve as prebiotics for the gut bacteria, increasing levels of healthy bacteria such as Bifidobacterium spp., decreasing levels of pathogenic Clostridium perfringens,[39] and enhancing levels of the SCFAs butyrate and propionate.[40] In an intestinal stimulator inoculated with bacteria of an IBD patient, arabinogalactans were also shown to improve parameters related to intestinal permeability and inflammation.[41]

There is considerable research on arabinogalactans as immune-supportive agents. Studies specifically looking at larch-sourced arabinogalactans have shown they enhance NK cell amount, activity, and cytotoxicity,[42],[43] and increase macrophage activity and their production of the infection-fighting mediators hydrogen peroxide and nitric oxide.[44] Animal models have shown arabinogalactans from various botanical sources also have anti-allergic and asthmatic effects, in part by enhancing the Th1 response.[45],[46],[47]

In healthy humans, modest doses (4 to 4.5 g/d) of arabinogalactans have been shown to enhance immune activity,[48] while in adults with recurrent respiratory tract infections, they were shown to significantly decrease the incidence of the common cold, with a trend towards decreased cold duration as well.[49] Supplementation at 1.5 g/d and 4.5 g/d for a prolonged period before vaccination was also shown to significantly increase the antibody response to vaccination with tetanoid toxin and Streptococcus pneumoniae, respectively, when compared to placebo.[50],[51]

Blended hemicellulose compound

A particular blended hemicellulose complex has been the topic of multiple research studies. Comprised of the hemicellulose fraction of Oryza sativa (commonly known as Asian rice), Hordeum vulgare (barley), Dioscorea spp. (Chinese and purple yam), Olea europaea (European olive), and the mushrooms Ganoderma lucidum (reishi), Lentinula edodes (shiitake), Grifola frondosa (hen-of-the-woods), and Schizophyllum commune (split gills), it is perhaps not surprising that this proprietary blend containing a high level of mushroom-derived hemicellulose compounds has been demonstrated to have immune activities. In addition to arabinoxylans and arabinogalactans, it contains numerous other polysaccharides, polyphenols, and fatty acids.

Multiple studies with this blended hemicellulose complex have shown it to have immune-enhancing effects. Specifically, the combination stimulated murine macrophage phagocytosis, nitric oxide production, and proliferation by 65%, 517%, and 155% respectively.[52] In a pilot study of healthy individuals, supplementation of the blended hemicellulose complex at a dose of 3 g/d for two weeks significantly increased NK cell cytotoxicity, with no adverse effects being seen.[53] A larger human study, in which the complex was taken at a dose of only 250 mg twice daily for eight weeks, showed a significant increase in circulating total lymphocyte levels.[52] While there were increases in T-cell, B-cell and NK cells subsets, increases were not statistically significant. Further lending weight to the findings of this trial was the fact that individuals in this study with impaired immunity (due to HIV, hepatitis C, or cancer) experienced improvements as well.  

As we look to enhance our body’s natural protection against infection, it is important to consider the many different factors that impact our immune function and overall health. Essential vitamins and minerals, traditional botanicals like echinacea and elderberry, the immunoglobulins and protective factors found in colostrum, and even melatonin are other important considerations. Looking at the natural hemicellulose found in things we consume as a part of a whole foods diet, we are reminded of the fact that mother earth may provide everything we need to remain healthy, physically wealthy, and wise.

Dr. Carrie Decker graduated with honors from the National College of Natural Medicine (now the National University of Natural Medicine) in Portland, Oregon. Prior to becoming a naturopathic physician, Dr. Decker was an engineer, and obtained graduate degrees in biomedical and mechanical engineering from the University of Wisconsin-Madison and University of Illinois at Urbana-Champaign respectively. Dr. Decker continues to enjoy academic research and writing and uses these skills to support integrative medicine education as a writer and contributor to various resources. Dr. Decker supports Allergy Research Group as a member of their education and product development team.

References:


[1] Gibson LJ. The hierarchical structure and mechanics of plant materials. J R Soc Interface. 2012 Nov 7;9(76):2749-66.

[2] Annison G, et al. Low-calorie bulking ingredients: nutrition and metabolism. In: Low-calorie foods and food ingredients 1993 (pp. 53-76). Springer, Boston, MA.

[3] Capuano E, et al. Role of the food matrix and digestion on calculation of the actual energy content of food. Nutr Rev. 2018 Apr 1;76(4):274-89.

[4] Finegold SM, et al. Xylooligosaccharide increases bifidobacteria but not lactobacilli in human gut microbiota. Food & Function. 2014;5(3):436-45.

[5] Izydorczyk MS, Dexter JE. Barley β-glucans and arabinoxylans: Molecular structure, physicochemical properties, and uses in food products–a Review. Food Res Int. 2008 Nov 1;41(9):850-68.

[6] Malunga LN, Beta T. Antioxidant capacity of water‐extractable arabinoxylan from commercial barley, wheat, and wheat fractions. Cereal Chemistry. 2015 Jan;92(1):29-36.

[7] Keithley J, Swanson B. Glucomannan and obesity: a critical review. Altern Ther Health Med. 2005 Nov-Dec;11(6):30-4.

[8] Liu X, et al. Hemicellulose from plant biomass in medical and pharmaceutical application: A critical review. Current Med Chem. 2019 Apr 1;26(14):2430-55.

[9] Niño-Medina G, et al. Feruloylated arabinoxylans and arabinoxylan gels: structure, sources and applications. Phytochem Rev. 2010 Mar 1;9(1):111-20.

[10] Mendis M, Simsek S. Arabinoxylans and human health. Food Hydrocolloids. 2014 Dec 15;42:239-43.

[11] Pham T, et al. In Vitro Fermentation Patterns of Rice Bran Components by Human Gut Microbiota. Nutrients. 2017 Nov 12;9(11):1237.

[12] Chen Z, et al. Arabinoxylan structural characteristics, interaction with gut microbiota and potential health functions. J Func Foods. 2019 Mar 1;54:536-51.

[13] Kamiya T, et al. Therapeutic effects of biobran, modified arabinoxylan rice bran, in improving symptoms of diarrhea predominant or mixed type irritable bowel syndrome: a pilot, randomized controlled study. Evid Based Complement Alternat Med. 2014;2014:828137.

[14] Hald S, et al. Effects of Arabinoxylan and Resistant Starch on Intestinal Microbiota and Short-Chain Fatty Acids in Subjects with Metabolic Syndrome: A Randomised Crossover Study. PLoS One. 2016 Jul 19;11(7):e0159223.

[15] Mandalari G, et al. Fractionation and characterisation of arabinoxylans from brewers’ spent grain and wheat bran. J Cereal Sci. 2005 Sep 1;42(2):205-12.

[16] Yadav MP, et al. Phenolic acids, lipids, and proteins associated with purified corn fiber arabinoxylans. J Agri Food Chem. 2007 Feb 7;55(3):943-7.

[17] Rao RS, Muralikrishna G. Water soluble feruloyl arabinoxylans from rice and ragi: changes upon malting and their consequence on antioxidant activity. Phytochemistry. 2006 Jan;67(1):91-9.

[18] Yuwang P, et al. Phenolic compounds and antioxidant properties of arabinoxylan hydrolysates from defatted rice bran. J Sci Food Ag. 2018 Jan;98(1):140-6.

[19] Srinivasan M, et al. Ferulic acid: therapeutic potential through its antioxidant property. J Clin Biochem Nutri. 2007;40(2):92-100.

[20] Saija A, et al. Ferulic and caffeic acids as potential protective agents against photooxidative skin damage. J Sci Food Ag. 1999 Mar 1;79(3):476-80.

[21] Lin FH, et al. Ferulic acid stabilizes a solution of vitamins C and E and doubles its photoprotection of skin. J Invest Derm. 2005 Oct 1;125(4):826-32.

[22] Mendez-Encinas MA, et al. Ferulated Arabinoxylans and Their Gels: Functional Properties and Potential Application as Antioxidant and Anticancer Agent. Oxid Med Cell Longev. 2018 Aug 16;2018:2314759.

[23] Ghoneum M, Matsuura M. Augmentation of macrophage phagocytosis by modified arabinoxylan rice bran (MGN-3/biobran). Int J Immunopath Pharmacol. 2004 Sep;17(3):283-92.

[24] Pérez-Martínez A, et al. Arabinoxylan rice bran (MGN-3/Biobran) enhances natural killer cell–mediated cytotoxicity against neuroblastoma in vitro and in vivo. Cytotherapy. 2015 May 1;17(5):601-12.

[25] Kim HY, et al. A polysaccharide extracted from rice bran fermented with Lentinus edodes enhances natural killer cell activity and exhibits anticancer effects. J Medic Food. 2007 Mar 1;10(1):25-31.

[26] Ghoneum M, Agrawal S. Activation of human monocyte-derived dendritic cells in vitro by the biological response modifier arabinoxylan rice bran (MGN-3/Biobran). Int J Immunopathol Pharmacol. 2011 Oct-Dec;24(4):941-8.

[27] Son HJ, et al. Effects of arabinoxylan rice bran and exercise training on immune function and inflammation response in lipopolysaccharide-stimulated rats. Journal of Applied Biological Chemistry. 2012;55(1):41-6.

[28] Chen Z, et al. Arabinoxylan structural characteristics, interaction with gut microbiota and potential health functions. J Func Foods. 2019 Mar 1;54:536-51.

[29] Mendis M, et al. Arabinoxylans, gut microbiota and immunity. Carbohydr Polym. 2016 Mar 30;139:159-66.

[30] Chen Z, et al. Arabinoxylan structural characteristics, interaction with gut microbiota and potential health functions. J Func Foods. 2019 Mar 1;54:536-51.

[31] Garcia AL, et al. Arabinoxylan fibre consumption improved glucose metabolism, but did not affect serum adipokines in subjects with impaired glucose tolerance. Horm Metab Res. 2006 Nov;38(11):761-6.

[32] Boll EV, et al. Effects of wheat bran extract rich in arabinoxylan oligosaccharides and resistant starch on overnight glucose tolerance and markers of gut fermentation in healthy young adults. Eur J Nutr. 2016 Jun;55(4):1661-70.

[33] Selvendran and O’Neill (1985). Isolation and analysis of cell walls from plant material. In Methods of Biochemical Analysis, Vol 32 (D Glick ed), John Wiley & Sons, pp. 25-123.

[34] Thompson NS. Hemicellulose. Kirk‐Othmer Encyclopedia of Chemical Technology. 2000 Dec 4.

[35] O’Neill and York (2003) The composition and structure of plant primary walls. In The Plant Cell Wall (JKC Rose ed), Blackwell, pp. 1-54.

[36] Van den Bulck K, et al. Isolation of cereal arabinogalactan-peptides and structural comparison of their carbohydrate and peptide moieties. J Cereal Sci. 2005 Jan 1;41(1):59-67.

[37] Saeed F, et al. Arabinoxylans and arabinogalactans: a comprehensive treatise. Crit Rev Food Sci Nutr. 2011 May;51(5):467-76.

[38] Dion C, et al. Does larch arabinogalactan enhance immune function? A review of mechanistic and clinical trials. Nutr Metab (Lond). 2016 Apr 12;13:28.

[39] Terpend K, et al. Arabinogalactan and fructo-oligosaccharides have a different fermentation profile in the Simulator of the Human Intestinal Microbial Ecosystem (SHIME ®). Environ Microbiol Rep. 2013 Aug;5(4):595-603.

[40] Aguirre M, et al. The gut microbiota from lean and obese subjects contribute differently to the fermentation of arabinogalactan and inulin. PloS one. 2016 Jul 13;11(7):e0159236.

[41] Daguet D, et al. Arabinogalactan and fructooligosaccharides improve the gut barrier function in distinct areas of the colon in the Simulator of the Human Intestinal Microbial Ecosystem. J Funct Foods. 2016 Jan 1;20:369-79.

[42] Hauer J, Anderer FA. Mechanism of stimulation of human natural killer cytotoxicity by arabinogalactan from Larix occidentalis. Cancer Immunol Immunother. 1993;36(4):237-44.

[43] Currier NL, et al. Effect over time of in-vivo administration of the polysaccharide arabinogalactan on immune and hemopoietic cell lineages in murine spleen and bone marrow. Phytomedicine. 2003 Mar;10(2-3):145-53.

[44] Choi EM, et al. Immunomodulating activity of arabinogalactan and fucoidan in vitro. J Med Food. 2005 Winter;8(4):446-53.

[45] Furuya K, et al. The effect of arabinogalactan from coffee beans in an allergic mouse model. 22nd International Conference on Coffee Science, ASIC 2008, Campinas, SP, Brazil, 14-19 September, 2008.

[46] Peters M, et al. Arabinogalactan protects mice from allergic asthma via modulation of dendritic cell function. Pneumologie. 2011 Feb;65(02):A5.

[47] Peters M, et al. Arabinogalactan isolated from cowshed dust extract protects mice from allergic airway inflammation and sensitization. J Allergy Clin Immunol. 2010 Sep;126(3):648-56.e1-4.

[48] Nantz M, et al. Evaluation of arabinogalactan’s effect on human immunity. FASEB J. 2001;15(4):633.

[49] Riede L, et al. Larch arabinogalactan effects on reducing incidence of upper respiratory infections. Curr Med Res Opin. 2013;29(3):251–8.

[50] Udani JK. Immunomodulatory effects of ResistAid: a randomized, double-blind, placebo-controlled, multidose study. J Am Coll Nutr. 2013;32(5):331–8.

[51] Udani JK, et al. Proprietary arabinogalactan extract increases antibody response to the pneumonia vaccine: a randomized, double-blind, placebo-controlled, pilot study in healthy volunteers. Nutr J. 2010;9:32.

[52] Weeks BS, Perez PP. The hemicellulose preparation, Natramune (PDS-2865), increases macrophage phagocytosis and nitric oxide production and increases circulating human lymphocytes levels. Med Sci Monit. 2009 Feb;15(2):BR43-46.

[53] Chavoustie SE, et al. Pilot study: effect of PDS-2865 on natural killer cell cytotoxicity. JANA. 2003;6(2):39-42.