Functional Oligosaccharides: The Preparation Methods and Therapy

Mechanism Related to Inflammatory Bowel Disease

Kangjia Jiang

, Minghan Zhao

, Yuting Han

, Le Su

, Xinli Liu

, Qiulin Yue

Song Zhang

, and Lin Zhao

School of Bioengineering Qilu University of Technology Shandong Academy of Sciences, Jinan, 250353, China

yueqiulin88@163.com, zhangsrz@163.com, iahb205@163.com

Keywords: Ulcerative Colitis, Oligosaccharides, Preparation, Mechanism, Inflammatory Bowel Disease.

Abstract: The incidence of inflammatory bowel disease has increased substantially in recent decades. Some studies

have found that oligosaccharides have anti-inflammatory, antioxidant and other physiological activities. This

article summarizes the research progress in the preparation of oligosaccharides and the treatment of colitis in

recent years. The preparation methods of oligosaccharides mainly focus on enzymatic degradation and acid

degradation. In addition, this article summarized the mechanisms of oligosaccharides in IBD, including the

regulation of inflammatory factors, regulation of oxidative stress, regulation of intestinal microbes, and

influence on inflammatory signal pathways. In summary, oligosaccharides have the potential to treat

inflammatory bowel disease, which provides new ideas for the clinical treatment of IBD.

1 INTRODUCTION

Crohn’s disease (CD) and ulcerative colitis (UC) are

two dominant forms of Inflammatory bowel disease

(IBD). In UC, the inflammatory process affects only

the mucosa and extends continuously from the rectum.

The typical symptom of colitis is bloody diarrhea,

which may be accompanied by abdominal pain or

fever(Besednova, Zaporozhets et al. (2020). The

prevalence of IBD is increasing every year worldwide.

Epidemiological studies show that in North America

more than 1.2 million people and 2 million people in

Europe suffer from IBD, and it exceeds 0.3% of the

population in many countries in Oceania, North

America and Europe. It is predicted that in 2025, the

total number of patients with IBD in the world would

be equal to the total population of Western countries,

and the treatment of IBD is imminent (Zhang, Huang

et al. (2019).

https://orcid.org/0000-0003-4117-3226

https://orcid.org/0000-0002-3396-4776

https://orcid.org/0000-0002-4545-0529

https://orcid.org/0000-0003-4794-6138

https://orcid.org/0000-0002-8416-7865

https://orcid.org/0000-0003-3904-3270

https://orcid.org/0000-0001-5160-8321

https://orcid.org/0000-0002-4016-3176

From the current point of view, IBD is thought to

be the result of the interaction of a number of factors.

NF-κB is an important signaling pathway in

inflammatory response, regulation of inflammatory

cytokine expression. Activation by NF-κB induces

the production of immune mediators. In intestinal

immunity in IBD, cytokines are important mediators

between activated cells and non-immune cells.

The intestinal barrier facilitates the separation of

substances and prevents the invasion of pathogenic

antigens(Dong, Li et al. 2020). Intestinal microbe is a

kind of microorganisms that live on the surface of

intestinal mucosa and intestinal lumen for a long time.

Patients with colitis were found to have less diversity

and a change in their gut flora composition. Intestinal

microorganisms can induce regulatory and protective

immune responses(Belkaid and Harrison 2017).

Studies have shown that reactive oxygen and

nitrogen are significantly associated with

Jiang, K., Zhao, M., Han, Y., Su, L., Liu, X., Yue, Q., Zhang, S. and Zhao, L.

Functional Oligosaccharides: The Preparation Methods and Therapy Mechanism Related to Inﬂammatory Bowel Disease.

DOI: 10.5220/0011369100003438

In Proceedings of the 1st International Conference on Health Big Data and Intelligent Healthcare (ICHIH 2022), pages 343-349

ISBN: 978-989-758-596-8

343

inflammatory bowel disease as they regulate the

associated oxidative stress and redox(Korenaga,

Takesue et al. 2002). Oxidative stress in IBD not only

produces excessive ROS/RNS, damages cell lipids

and other components, but also leads to mucosal

damage, dysfunction and inflammation, directly

leading to intestinal injury, and redox signaling

disorders, promoting the overexpression of

inflammatory factors and adhesion

molecules(Grisham and Granger 1988).

Currently, the drugs used in clinical treatment of

IBD include glucocorticoids, immunosuppressants

and biological agents. The main purpose is to relieve

the acute onset of inflammation, but personalized

treatment plans are still adopted in clinical

practice(Ramos de Mattos, Gracindo Garcia et al.

2015). However, their use is often harmful and has

side effects. Amino Salicylates can cause patients to

experience nausea and vomiting or other intestinal

side effects. Glucocorticoids can lead to osteoporosis,

hypertension, obesity, type 2 diabetes.

Glucocorticoids should not be used as long-term

treatment(Ramos de Mattos, Gracindo Garcia et al.

2015). Methotrexate in the treatment of IBD showed

a good anti-inflammatory effect, but nausea, vomiting,

and certain renal toxicity. Some heart conditions,

allergic or infectious complications and skin lesions

are side effects of anti-TNF-alpha drugs(Nielsen

2014).

Because of the severe side effects of traditional

drug therapy, an important way to improve the

clinical symptoms of IBD is to find new sources of

drugs. Oligosaccharides are attracting more and more

attention as prebiotics functional food ingredients.

Methods of obtaining include extraction from various

biological sources, or obtaining by enzymatic and

acid digestion of polysaccharides, or synthesis by

enzymatic transfer reactions using simple

oligosaccharides(Rastall 2010). Recently, other

physiological functions of oligosaccharides have

been found. For example, short-chain fatty acids, a

metabolite that provides energy to cells in the

intestine, can also accelerate cell renewal(Courtois

2009).

Many oligosaccharides in recent studies,

including fructo-oligosaccharides(Winkler, Butler et

al. 2007) and lacto-oligosaccharides(Algieri,

Rodriguez-Nogales et al. 2014), can alleviate damage

to the intestinal barrier. This article summarizes the

possibility of using oligosaccharides extracted from

natural substances or degraded by polysaccharides as

drugs or functional food products to prevent and treat

inflammatory bowel disease.

2 TYPES AND PREPARATION

OF OLIGOSACCHARIDES

2.1 Oligosaccharides Derived from

Plants

2.1.1 Oligogalacturonic Acid

Oligogalacturonic acid (OGA) is a polymer

consisting of 2~10 galacturonic acids attached by α-

1, 4-glycosidic bond(Huang, Huang et al. 2018).

Oligomeric isomalturonic acid esters (OGA) from

citrus pectin hydrolysed by microbial pectinases can

be used as food emulsifiers and have shown

antioxidant capacity and the ability to inhibit lipid

oxidation., and had bactericidal effect on foodborne

pathogens(Huang, Lu et al. 2011). The literature

reports that OGA fragments can prevent the

multiplication of human cancer cells (Wu, Li et al.

2014).

2.1.2 Xylo-oligosaccharides

Xyloglucan (XOS) is a common oligosaccharide

consisting of xylose(Seesuriyachan, Kawee-ai et al.

2017). XOS is mainly obtained by physical, chemical

and enzymatic degradation of xylan in corn cob,

bagasse and other agricultural Enzymatic method is

the main method for industrial production of xylo-

oligosaccharide due to its mild reaction conditions,

easy control, high conversion rate and environmental

friendliness(Chapla, Pandit et al. 2012). Adding XOS

to the diet to show the effect of XOS

probiotics(Karlsson, Schmitz et al. 2018). They can

significantly increase beneficial intestinal bacteria

and thus relieving the damage to the intestinal

tract(Christensen, Licht et al. 2014).

2.1.3 Fructose-oligosaccharides

FOS is an indigestible carbohydrate, chemically

composed mainly of a fructose unit chain and a

glucose unit connected by the glycoside bond beta -

(2-1) (Table 1). Their structure is formed by the

repeated combination of disaccharides such as

sucrose(Flores-Maltos, Mussatto et al. 2016). A few

articles have proposed new bioprocesses that can

integrate the production of inulin endosynthesis, FOS

fermentation and impurity removal into a single

reactor, left-handed disaccharide, which can

significantly improve the yield of FOS(Wang, Li et al.

2016). Fructo-oligosaccharides have low calorific

value, help intestinal absorption of ions, reduce lipid

and cholesterol levels, and stimulate Bifidobacteria.

ICHIH 2022 - International Conference on Health Big Data and Intelligent Healthcare

344

Because of its potential health benefits, purified linear

fructose oligomers are added to a variety of

foods(Bali, Panesar et al. 2015).

Table 1: Types and molecular structure of functional

oligosaccharides.

Oligosaccharide Structure

Xylooligosaccharides

(

XOS

)

(Xylβ-1,4)n Xyl; n =1 ～ 4

Fructooligosaccharides

(FOS)

Glcα-1,2(Fruβ-1,2/β-1,6)n

Fru; n =1 ～ 3

Isomaltooligosaccharid

es (IMO)

Glcα-1,6 Glcα-1,6 Glc;

Glcα-1,4 Glcα-1,6 Glc

lactosucrose Galβ-1,4Glcα-1,2Fru

lactulose Galβ-1,4Fru

2.1.4 Oligomeric Mannose

Mannan oligosaccharide (MOS) consists of mannose

residue fragments attached by beta-1,4-mannose, and

is further characterized as galactomannan,

galactomannan, and galactomannan. They are usually

found in the endosperm of legumes(Singh, Singh et

al. 2018). At present, it mainly adopts physical

method, chemical method and enzyme method MOS

was prepared by degradation of mannan(Malgas, van

Dyk et al. 2015).

2.1.5 Oligomeric Maltose

Isomalto Oligosides (IMO) are functional

oligosaccharides with a degree of 2-10, consisting of

glycosylated units with α-1,6-glucosidic

bonds(Zhang, Wang et al. 2019). In general, IMO is

produced by the conversion of starch hydrolysates by

α -glucosidase in conventional industrial

processes(Huang, Li et al. 2018). IMO is a natural

functional oligosaccharide that regulates the

intestinal flora. For example, after using IMO, the

levels of Bifidobacteria and Lactobacilli are

increased(Shi, Hou et al. 2016).

2.1.6 Alginate Oligosaccharides

Alginic acid consisting of alpha-1, 4-glycosidic bonds

between manuronic acid and guluronic acid. AOS is

the depolymerization of alginate by enzymolysis

(Table 2), acid hydrolysis and oxidative degradation.

Alginate lyase is an important tool enzyme in the

production of AOS(Zhu, Ni et al. 2021). Alginate

oligosaccharide treatment can regulate intestinal

microbial community and significantly reduce the

expression of inflammatory markers, which has good

anti-inflammatory effect(Wang, Li et al. 2020).

2.1.7 Agarose Oligosaccharides

Agarose oligosaccharides (AGOs) are produced by

the hydrolysis of agarose. The structure and

biological activity of AGO have been extensively

studied(Chen and Yan 2005). AGOs has repeated

agarose units consisting of non-reducing d-galactose

and reducing 3, 6-dehydrogen-L-galactose

(Higashimura, Naito et al. 2014).

2.2 Oligosaccharides from Animals

2.2.1 Galactose Oligomeric

Galactosyl oligosaccharides (GOS) are formed by 1

to 10 galactosyl units connected to a terminal

glucose(Dai, Lyu et al. 2017), or formed from

galactose-based units only. β-galactosidase can

catalyze galactose acylation to produce galactose

oligosaccharides(You, Zhang et al. 2017). GOS

reduces the incidence of intestinal diseases and a

significant increase in the SCFAs concentration was

found. One study found that GOS has significant

potential to improve intestinal health and body

immunity(Wang, Zhu et al. 2020).

2.2.2 Oligo-chitosan

Chitosan is a polysaccharide with varying degrees of

n-acetylation. It is obtained from the degradation of

chitosan and is the n-deacetylated form of chitin.

Chitosan has been prepared by various enzymatic and

acid hydrolysis methods. In contrast, COS, the

hydrolysis product of chitosan, consisting of beta-1,4-

glycosidic bonds linking 2-amino-2-deoxy-D-

glucopyranose. The short chain of D-glucosamine

units in COS and the small number of free amino

groups make it more soluble under physiological

conditions(Lodhi, Kim et al. 2014).

3 ANTI - INFLAMMATORY

EFFECT AND MECHANISM OF

OLIGOSACCHARIDES

3.1 Effects on Cytokines

Inflammatory bowel disease (IBDs) is a debilitating

condition in which chronic inflammation leads to

intestinal damage. The cytokines produced by the

immune cells are involved in colitis due to the large

number of immune cells that infiltrate the

colon(Francescone, Hou et al. 2015). Tumour

Functional Oligosaccharides: The Preparation Methods and Therapy Mechanism Related to Inﬂammatory Bowel Disease

345

necrosis factor (TNF) has been reported to influence

cell proliferation, differentiation and apoptosis, and

has also been associated with inflammation and

cancer development(Liu 2005). Different target cells

are triggered by Il-6, to affect pro-inflammatory

functions(Kim, Keku et al. 2008). Studies have

shown that Il-1 β indirectly activates endothelial cells

and angiogenesis by regulating pro-inflammatory and

pro-angiogenic molecules(Carmi, Dotan et al. 2013).

Ferulic acid oligosaccharides can significant

reduction IL-23 and IL-6 in dendritic cells (DCs) in

vivo and in vitro, enhance the secretion of TGF-β1,

and regulate colitis in mice(Xia, Zhu et al. 2019).

Glucosamine oligomers reduced pro-inflammatory

factors in mouse serum and effectively alleviated

clinical signs of colitis in mice(Azuma, Osaki et al.

2015).

3.2 Effects on Inflammatory Signaling

Pathways

3.2.1 Effects on NF-κB Signaling Pathway

One way in which gene expression of inflammatory

cytokines is elevated is through NF-κB signaling

pathway(Atreya, Atreya et al. 2008). In the DSS-

induced mouse colitis model, NF -κB p65 protein

expression was suppressed because of galactose

intervention(Dai, Feng et al. 2018). Sucrose (LS)

significantly reduced the levels of TLR-2 protein and

NF-κB pathway protein. Therefore, LS has potential

as a nutritional intervention for colitis(Zhou, Ruan et

al. 2015).

3.2.2 Influence on MAPK Signaling Pathway

A variety of serine and threonine kinases make up the

mitogen-activated protein kinase (MAPK)(Wang,

Pan et al. 2019). It was found that fructose-

oligosaccharides can down-regulate the expressions

of Jun and JNK proteins in d-galactose induced rat

aging model, suggesting that fructose-

oligosaccharides may improve lung inflammation

and fibrosis in aging rats by inhibiting the activation

of JNK/Jun pathway, and has obvious anti-

inflammatory effect(Yeh, Wu et al. 2014).

3.3 Regulation of Oxidative Stress

Oxidative stress injury was significantly correlated

with the onset and severity of IBD(Rezaie, Parker et

al. 2007). Infiltrates of immune cells, especially

neutrophils, are histologic features of IBD. The

excessive production of ROS in host tissues

exacerbates oxidative damage and may damage the

mucosa of the intestine. Neutrophil-myeloperoxidase

(MPO), a granulocyte enzyme, increases the levels of

more potent ROS. Biomarkers of intestinal mucosal

damage appear significantly increased in patients

(Chami, Martin et al. 2018). Lactulose can prevent

and suppress intestinal inflammation, which can

significantly reduce myeloperoxidase activity, TNF-

α and leucotriene B4 concentration in colon(Algieri,

Rodriguez-Nogales et al. 2014). Hame oxygenase-1

(HO-1) has a significant antioxidant effect. A mouse

macrophage inflammation model (RAW264.7 cells)

was constructed with LPS and HO-1 expression was

upregulated by chitosan (COS) intervention(Hyung,

Ahn et al. 2016).

Table 2: Common preparation methods of oligosaccharides.

Polysaccharide Method Oligosaccharide Mechanism

Xylan Xylanase

Xylo-

oligosaccharides

The endonuclease cleaves the xylan chain at specific

cleavage sites to produce different oligosaccharides

(Karlsson, Schmitz et al. 2018).

Pectin Polygalacturonase

Oligogalacturonic

acid

Polygalacturonase catalyzes the cleavage of pectin

molecule poly-α-(1,4)-polygalacturonic acid and

participates in the degradation of pectin(Li, Coffman et

al. 2015).

Mannan Mannanase

Mannose

oligosaccharides

β-Mannanase randomly cleaves the backbone to produce

shorter beta-1,4-mannan oligomers. It is very important

in the preparation of mannans(Liu, Ning et al. 2020).

Sucrose

α-amylase、α-

glucosidase

Isomalt

oligosaccharide

The receptor reaction catalyzed by glucose glucosidase

can generate branched imo or glucose oligosaccharides

(GOSs) from sucrose(Goffin, Delzenne et al. 2011).

ICHIH 2022 - International Conference on Health Big Data and Intelligent Healthcare

346

Alginate Alginate lyase

Alginate

oligosaccharide

Glycosidic bonds within alginate polymers are cleaved by

alginate lyase to produce unsaturated oligosaccharides,

while exonuclease can degrade the oligosaccharides

ain to become monomers

(

Zhu, Ni et al. 2021

)

Agar Agarase

Agaro

oligosaccharides

Breakage of the alpha-1,3-glycosidic bond of agarose by

alpha-agarase(Jiang, Cheng et al. 2021).

Lactose β-galactosidase

Galacto

oligosaccharide

Galacto oligosaccharides are produced by the conversion

of lactose through glycosylation and can be catalyzed by

many enzymes. It includes two processes: glycosylation

and de

cos

lation

(

Gao, Wu et al. 2019

)

Chitosan Chitosanase

Chitosan-

oligosaccharide

Chitosanase can hydrolyze the bata-(1-4)-sugar-silicic

acid bond of chitosan(Liu, Jiang et al. 2009).

3.4 Repair of the Intestinal Barrier

There are many factors that affect intestinal health

and the intestinal barrier is a very significant part. The

composition of the intestinal barrier includes the

mucus layer and the intestinal epithelium. The

mucosal barrier consists of gel formation and

transmembrane mucin. It prevents the entry of

pathogens. Therefore, the intestinal barrier is

implicated in IBD(Johansson, Sjovall et al. 2013). It

was found that in mice with acetic acid-induced

colitis, COS infusion reduced the inflammatory

response and restored intestinal barrier

damage(Yousef, Pichyangkura et al. 2012).

Interestingly, another study showed that COS can

promote T84 cell tight-knit assembly(Muanprasat,

Wongkrasant et al. 2015).

3.5 Influence on Intestine Flora

Intestinal microbe is a kind of microorganisms that

live on the surface of intestinal mucosa and intestinal

lumen for a long time. It was found that altered

intestinal flora diversity in UC patients, and the group

was transformed(Frank, Amand et al. 2007). In the

colon, AG and FOS exhibit different fermentation

properties (FOS in the proximal end, AG in the distal

end). These two fibers can repair the intestinal barrier

and effectively reduce inflammation(Daguet,

Pinheiro et al. 2016). Konjac oligosaccharide can

significantly relieves inflammatory symptoms of

experimental acute colitis induced by TNBS, and

improve intestinal flora structure. Therefore, the

mechanism is at least involved in the improvement of

intestinal microflora structure and anti-inflammatory

effect(Liu, Li et al. 2016).

4 CONCLUSIONS

In recent decades, the research on oligosaccharides

has been the focus of research at home and abroad.

The preparation methods of functional

oligosaccharides mainly include chemical method,

enzymatic method and physical method. Among them,

enzymatic preparation is green, efficient, and the

most promising method for application.

Oligosaccharides have a positive impact on the relief

of other intestinal disorders, but they are effective in

the intervention of oligosaccharides. With further

research into the mechanism of action of

oligosaccharides in reducing inflammation, high-

efficiency and non-toxic oligosaccharide anti-

inflammatory drugs will be screened.

ACKNOWLEDGMENTS

This work was supported by Science Foundation of

China (31501396) and Shandong Taishan leading

talent project (grant number LJNY202015,

tscy20180507).

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