Pentosan Polysulphate as a Potential Xylan based Prebiotic: Comparison
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In animal husbandry, prebiotic xylans aid in the maintenance of a healthy gut microbiome. This prevents the colonization of the gut by pathogenic organisms obviating the need for dietary antibiotic supplementation, a practice which has been used to maintain animal productivity but which has led to the emergence of antibiotic resistant bacteria that are passed up the food chain to humans. Seaweed xylan-based animal foodstuffs have been developed to eliminate ruminant green-house gas emissions by gut methanogens in ruminant animals, contributing to atmospheric pollution. Biotransformation of pentosan polysulfate by the gut microbiome converts this semi-synthetic sulfated disease-modifying anti-osteoarthritic heparinoid drug to a prebiotic metabolite that promotes gut health, further extending the therapeutic profile and utility of this therapeutic molecule. Xylans are prominent dietary cereal components of the human diet which travel through the gastrointestinal tract as non-digested dietary fibre since the human genome does not contain xylanolytic enzymes. The gut microbiota however digest xylans as a food source. Xylo-oligosaccharides generated in this digestive process have prebiotic health-promoting properties. Engineered commensal probiotic bacteria also have been developed which have been engineered to produce growth factors and other bioactive factors. A xylan protein induction system controls the secretion of these compounds by the commensal bacteria which can promote gut health or, if these prebiotic compounds are transported by the vagal nervous system, may also regulate the health of linked organ systems via the gut–brain, gut–lung and gut–stomach axes. Dietary xylans are thus emerging therapeutic compounds warranting further study in novel disease prevention protocols.

  • xylan
  • pre-biotics
  • gut microbiome
  • pentosan polysulfate

1. Xylans Are Abundant Plant Carbohydrates

Xylan is the third most abundant naturally occurring carbohydrate biopolymer on Earth after cellulose and chitin [18][1]. Xylan is a component of the secondary cell walls of dicotyledonous plants, all cell walls of cereals and a major structural carbohydrate of seaweeds [19][2]. The human genome does not contain xylanolytic enzymes, and as a consequence, dietary xylans transit through the gastrointestinal tract undegraded. They are a major contributor to the fibre content of foods, serving as a bulking agent which promotes the movement of digested food components through the small and large intestine. The gut microbiota produce a range of xylanolytic enzymes that degrade xylans [20][3] into prebiotic metabolites that regulate the microbiome and significantly contribute to health and well-being [21][4]. The intestinal epithelium is important in the maintenance of T cells in the gut. Intraepithelial CD8α T cells in close contact with intestinal epithelial cells and the underlying basement membrane aid in the detection of invasive pathogens. T cell survival depends on β1 integrin interactions with type IV collagen in the basement membrane. Knock-out of β1 integrin expression in CD8α T lymphocytes decreases levels and the migratory properties of intraepithelial T cells in-vivo and the protective responses they provide against pathogenic bacteria. Type IV collagen interactions with β1 integrins on intraepithelial T cells are not only important for T cell survival but the provision of T-cell protective properties in mucosal immunity [22][5].
The gut microbiome contains 10–100 trillion microorganisms [23][6] that control the digestion of food and regulate the immune [24,25][7][8] and central nervous systems [26][9] and is also linked to other major organ systems like the liver [27][10] and lung [28][11]. Gut dysbiosis is associated with long COVID-19 disease [29][12] and with secondary antibiotic resistant bacterial infections such as Clostridium difficile that have emerged in the COVID-19 pandemic, [30][13] adding a further complication in the treatment of long COVID-19 disease. Some members of the microbiome digest fibre [31][14] and release short-chain fatty acids [32][15], which regulate gut health providing gut barrier properties; prevent weight gain [33][16] and lower cholesterol levels [34][17] and the incidence of diabetes [35][18], heart disease [36][19] and the risk of cancer [37,38,39][20][21][22]. Gut commensal bacteria produce a range of xylanolytic enzymes that allow them to utilise dietary xylans as nutrients [20,40][3][23]. Long-chain xylans are one of the most common dietary fibres in the human gastrointestinal tract that promote the growth of Bifidobacterium pseudocatenulatum [41][24]. Xylo-oligosaccharides are prominently generated from xylans by B. pseudocatenulatum, and these have prebiotic properties that counter gut dysbiosis, [41,42][24][25] reducing the inflammatory response in the gut induced by obesity [43][26]. Methods have been developed to prepare xylans and xylo-oligosaccharides to evaluate their potential health benefits [41,44,45,46,47][24][27][28][29][30]. Nutraceutical supplements are being developed to combat COVID-19 disease [48,49][31][32] and are also of application in the treatment of critically ill patients [50,51,52,53][33][34][35][36].

1.1. Dietary Xylans

Xylans are complex polysaccharides classified as (i) glucuronoxylans (GXs), (ii) arabinoxylans (AXs) and (iii) glucuronoarabinoxylans (GAXs) based on their constituent monosaccharides [18,54][1][37]. Xylans are the second most abundant hemicellulose and represent ~25–35% of the carbohydrate biomass of woody tissues of dicotyledonous plants and lignin rich tissues of monocotyledons, comprising up to 50% by dry weight of grasses and cereal grains. [18,54][1][37] Xylans are complex heteropolysaccharides containing a β-(1,4)-glycosidically linked D-xylose backbone, L-arabinose (L-Ara), D-glucuronic acid (D-GlcA), D-GlcA methylated at O-4, or acetyl group [18][1] side chains. These side chains can be further esterified with acetic and ferulic acids [54][37]. The type and frequency of these side chains and their modifications vary with the tissue source of the xylan and determine whether the xylan has gel-forming properties in situ or acts as a structural carbohydrate [55][38]. Xylans in woods and cereal stems are acetylated, and they cross-link cellulose fibres, providing high mechanical support to these tissues [56][39]. Arabinoxylan in the cereal endosperm has water retention properties and maintains the hydration of the seed head [55][38]. Seaweed xylans occur as 1,3-β-D-xylans; 1,3:1,4-β-D-xylans and 1,4-β-D-linked xylans, and these are assembled into triple-helical microfibrillar structures that have similar supportive properties to the cellulose fibres found in terrestrial plants [57][40]. Xylans thus have a variable structure and function depending on their tissue of origin. AX is a prominent gel-forming xylan in the endosperm of cereal seed heads and its hydration properties ensure the viability of the embryo in the aleurone layer is maintained [55][38]. GAX in the secondary plant cell wall of the cereal stem has a mechanically supportive role and is acetylated and substituted with ferulic acid to variable degree [56][39]. In addition, ferulic acid esters derived from lignin are also found attached to O-5 of L-Ara in wood xylans and form a linkage group for the xylan to cellulose fibres. Stem and wood xylans also contain α1–2 or α1–3 linked D-GlcA and 4-O-methylated D-GlcA as well as α L-Ara furanose (α L-Araf) and O-acetyl groups attached to the xylan main chain. Wood xylans are more heavily substituted with acetyl and ferulic acids compared to cereal xylans [58][41].

1.2. Pentosan Polysulfate, a Therapeutic Semi-Synthetic Sulfated Xylan

Pentosan polysulfate (PPS) is a semi-synthetic sulfated xylan produced from beech wood xylan. PPS is heavily sulfated and is referred to as a heparinoid; however, it has a higher charge density than both heparin and heparan sulfate (HS), is less heterogeneous and is a small molecular weight drug (4–6 kDa). PPS is a potent disease modifying osteoarthritic drug (DMOAD) [59,60[42][43][44],61], has been used to treat cystitis and painful bowel disorder in humans and has anti-viral properties and potential anti-SARS Cov-2 activity [62,63,64,65][45][46][47][48]. Approximately one in every ten residues of PPS has a 4-O-methylated D-GlcA side chain linked O-2 to the xylan backbone, but PPS is devoid of the other xylan modifications mentioned above [66][49].

2. Degradation of Xylans in the Gastrointestinal Tract

2.1. The Xylan Regulon and Production of Xylanolytic Enzymes

The xylan regulon [79][50] is a cluster of genes in commensal bacteria that encode for a number of xylanolytic enzymes. These genes of the xylan regulon are activated by dietary xylan. Gut commensal bacteria produce a number of endo β-D-xylanase glycohydrolases (GH 30, 10, 11 and 30) which internally cleave β1–4 glycosidically linked xylopyranose residues of the xylan backbone releasing xylo-oligosaccharides. These xylo-oligosaccharides then act as substrates for a family of β-D-xylosidases which release D-xylose monosaccharide units from the non-reducing termini of xylotriose and xylobiose. Other side chain components (depending on xylan source) are released from the xylan backbone by α-L-arabinofuranosidases (GH 43, 51, 54, 62), acetyl esterases (CE 1–7, 12) and α-D-glucuronidases (GH 67,115); GH 1O endoxylanase (Xyn A1) releases arabinoxylobiose, arabinoxylotriose, xylobiose, xylotriose and methylglucuronoxylotriose from glucuronoarabinoxylans (GAXs). Gut commensal bacteria utilize the released monosaccharides as a nutritional source.

2.2. Metabolism of GAGs in the Gut Microbiome and the Essential Roles They Play in Gut Homeostasis

Glycosaminoglycans (GAGs) are constant components in the gut and are present as proteoglycans or as free GAG forms. Some members of the gut microbiome produce GAG depolymerizing enzymes that allow GAGs to be used as nutrient sources by the gut microbiome [80][51]. Gut bacteria produce a range of sulfatases which are used in the degradation of GAGs including heparin and HS, sulfated neurotransmitters such as serotonin and dopamine, and the hormones melatonin, estrone, dehydroepiandrosterone, and thyroxine [81,82,83][52][53][54]. GAGs have essential roles in the regulation of the colonization and proliferation of beneficial symbiont bacterial populations and the prevention of gut colonization by pathogenic bacteria [84][55]. Digestion of GAGs such as CS, HS, HA and dietary xylans by the microbiome generates short chain fatty acids that improve gut health [84,85,86,87][55][56][57][58]. GAGs are one of the most important host glycans that are continuously and abundantly present in the intestine through continuous shedding of proteoglycan from the gut epithelium [88][59]. In murine gut models, CS disaccharides alter the microbiota increasing the prevalence of Bacteroides acidifaciens [86][57], a bacterial strain that inhibits pathogenic colonization in the gut via induction of IgA production [89][60]. Oral administration of other GAGs also elicits beneficial gut responses promoting growth of Lactobacillus bacteria which ensures gut homeostasis [90,91][61][62]. Oral HS administered as enoxaparin, a low molecular weight heparin, improves mucosal healing in a murine colitis model [92][63]. Dietary HS also improves recovery of renal functions in nephrectomized rats [93][64]. Low molecular weight HA produced by depolymerization of high molecular weight HA has also been shown to reduce membrane permeability associated with colitis [94][65].
The Bacteroidetes are the second-most abundant bacterial phylum capable of catabolizing a diverse range of polysaccharides, including GAGs, which is attributable to the diverse range of carbohydrate metabolizing enzymes (CAZymes) in their genomes [95,96,97][66][67][68]. Proteus vulgaris, a component of a healthy gut microbiome [98][69], produces two well-characterized chondroitinase enzymes that are not encoded in the human genome; thus, GAGs are of limited nutritive value to mammalian cells but can be utilized by members of the gut microbiome [99,100,101][70][71][72]. Unlike the Bacteroides, the ability to degrade GAGs is not widely prevalent in other gut phyla. Salyers et al. [102][73] showed 154 faecal strains of Firmicutes and Bifidobacteria (Actinobacteria) were incapable of metabolizing CS, HA and heparin. Crociani and colleagues [103][74] also demonstrated that 239 strains of Bifidobacterium were incapable of metabolizing heparin, CS, HA and polygalacturonate, and therefore, the abundant Bacteroidetes with GAG-degradative properties have particularly important roles to play in the maintenance of gut homeostasis.
Pathogenic bacteria can colonize gut tissues using GAGs and PGs as a site of entry to infect host cells [104][75]. Enteric pathogens such as Toxoplasmosis gondii, E. coli O157:H7 [104][75] and opportunistic pathogenic Streptococci [105][76] can utilise GAGs as entry points to infect intestinal cells. Antibiotics used to treat these gastrointestinal pathogens detrimentally affect beneficial gut bacteria and may cause gut dysbiosis. It is therefore essential that beneficial gut bacteria be maintained as dominant symbionts to ensure that pathogenic bacteria do not obtain a niche to colonise the gut microbiome.
Experiments with radiosulfate-labelled PPS (Elmiron) showed it was metabolised into lower molecular weight forms of lower sulfation, with ~50% of orally-administered PPS absorbed and excreted in the faeces; 11% of radiolabelled PPS was excreted by the kidneys, and ~3% of the PPS was discharged in the urine as intact 4–6 kDa PPS [106][77]. PPS has efficacy in the treatment of cystitis [107][78] and urinary tract infections, [108][79] indicating that sufficient bioactive levels of intact PPS were present in the urinary tract to provide a therapeutic effect in urinogenital infections. However, as already discussed, based on the known GAG degrading capability and xylanolytic enzymes produced by gut microbiota members, PPS would also be expected to be converted to prebiotic xylo-oligosaccharides, with roles in the maintenance of gut health extending the therapeutic profile of PPS.
Sodium alginate is a sulfated polymer commonly used as a food additive in Asian cuisines. An analysis of the human gut microbiota for bacteria capable of degrading alginate into its mannuronic and guluronic acid components also revealed specific members of the Bacteroides genus with this capability [109][80]. Additionally, the sulfate-reducing bacterium Desulfovibrio piger, which colonizes the gut of ∼50% of all humans, would also be expected to contribute to alginate degradation [110,111,112,113,114][81][82][83][84][85]. Mammalian cells also produce a number of sulfatases that degrade GAGs and sulfated cerebrosides. These include N-sulfoglucosamine sulfohydrolase, N-acetylglucosamine-6-sulfatase, iduronate 2-sulfatase, N-acetylgalactosamine-4-sulfatase, cerebroside sulfatase and N-acetylgalactosamine-6-sulfatase [115][86].

3. Xylans Promote a Healthy Human Microbiome and Linked Organ Systems

Digestion of xylans by the microbiome maintains stable health promoting bacterial symbionts in the gut [116][87]. Carbohydrate epitopes released from dietary polysaccharides by the microbiota educate the human immune system in infancy, aiding in the provision of tolerance to food types and minimising the development of food allergies in later life [117,118,119,120,121][88][89][90][91][92]. The microbiota of the gastrointestinal tract have a close symbiotic relationship with the human host with roles in health maintenance, metabolism of indigestible dietary fibre and synthesis of some vitamins and neurotransmitters [122][93]. The prevalence of beneficial symbiont species in the gut prevents the colonization of the gut by harmful pathogenic cell populations. The human microbiota of the large intestine are dominated by the Firmicute and Bacteroidetes phyla which represent >90% of the total microbial community [123][94]. Roseburia intestinalis, a butyrate-producing Firmicute, is also important in gut health [116][87]. Metagenomic and transcriptomic studies have identified distinctive signatures in gut microbiota in neural disorders such as autism and bipolar disorders [124,125,126][95][96][97]. Machine learning techniques are also now being applied to the diagnosis of diseases from dynamic changes in the gut microbiome [127][98]. The gut microbiota produce bioactive fragments of polysaccharides that undergo fermentation in the gut, which educate the immune system in infancy [128][99], and immunomodulatory responses that subsequently develop in later life [129][100], such as development of immune tolerance to food groups and prevention of food allergies [130][101]. This is a rapidly evolving area of intensive investigation using powerful technologies across multiple research disciplines. The FLEXIGUT rationale is an integrated -omics data analysis framework designed to understand exposomic associations with food substances that result in chronic low-grade gut inflammation [131][102]. FLEXIGUT aims to characterize human life-course environmental exposures to specific substances and how they impact on gut inflammation and resultant instructive immune responses. Available evidence shows gut metabolites impact on cell populations in vivo affecting cellular responses to fat storage, hypolipidemia, hypoglycaemia, appetite and disease processes [131][102].
A human study comparing the impact of diet versus drugs on the control of cellular metabolism found that diet had as strong an impact as drugs on many cellular processes and diseases such as obesity, diabetes, heart disease and neurological diseases [126,132,133,134,135,136][97][103][104][105][106][107]. Diet is a powerful medicine, involving nutrient-signalling pathways effecting the gut microbiome [137][108]. The formation of a healthy microbiome in early childhood is important for the establishment and maintenance of human health in later life. The full impact of the gut microbiome on the attainment of tolerance to certain foods and the neurological pathways that train innate immune responses and how these impact on allergic and autoimmune disorders however is incompletely understood [117,118,119,120,121][88][89][90][91][92].

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