Re: Polysaccharides influence human health via microbiota-dependent and -in

[문형철]

Front Nutr

. 2022 Nov 9;9:1030063. doi: 10.3389/fnut.2022.1030063

Polysaccharides influence human health via microbiota-dependent and -independent pathways

Liping Gan 1, Jinrong Wang 1,*, Yuming Guo 2

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PMCID: PMC9682087  PMID: 36438731

Abstract

Polysaccharides are the most diverse molecules and can be extracted from abundant edible materials. Increasing research has been conducted to clarify the structure and composition of polysaccharides obtained from different materials and their effects on human health. Humans can only directly assimilate very limited polysaccharides, most of which are conveyed to the distal gut and fermented by intestinal microbiota. Therefore, the main mechanism underlying the bioactive effects of polysaccharides on human health involves the interaction between polysaccharides and microbiota. Recently, interest in the role of polysaccharides in gut health, obesity, and related disorders has increased due to the wide range of valuable biological activities of polysaccharides. The known roles include mechanisms that are microbiota-dependent and involve microbiota-derived metabolites and mechanisms that are microbiota-independent. In this review, we discuss the role of polysaccharides in gut health and metabolic diseases and the underlying mechanisms. The findings in this review provide information on functional polysaccharides in edible materials and facilitate dietary recommendations for people with health issues. To uncover the effects of polysaccharides on human health, more clinical trials should be conducted to confirm‎ the therapeutic effects on gut and metabolic disease. Greater attention should be directed toward polysaccharide extraction from by-products or metabolites derived from food processing that are unsuitable for direct consumption, rather than extracting them from edible materials. In this review, we advanced the understanding of the structure and composition of polysaccharides, the mutualistic role of gut microbes, the metabolites from microbiota-fermenting polysaccharides, and the subsequent outcomes in human health and disease. The findings provide insight into the proper application of polysaccharides in improving human health.

다당류는 

가장 다양한 분자이며, 

식용 가능한 물질에서 풍부하게 추출할 수 있습니다. 

다양한 물질에서 얻은 다당류의 구조와 구성, 

그리고 그것이 인간의 건강에 미치는 영향을 밝히기 위한 연구가 증가하고 있습니다. 

인간은 

극히 제한된 다당류만 직접 흡수할 수 있으며, 

대부분의 다당류는 원위부 장으로 운반되어 

장내 미생물총에 의해 발효됩니다. 

따라서, 

다당류가 인간의 건강에 미치는 생체 활성 효과의 주요 메커니즘은 

다당류와 미생물총 사이의 상호 작용과 관련이 있습니다. 

Humans can only directly assimilate very limited polysaccharides, most of which are conveyed to the distal gut and fermented by intestinal microbiota. Therefore, the main mechanism underlying the bioactive effects of polysaccharides on human health involves the interaction between polysaccharides and microbiota.

최근 다당류의 다양한 생물학적 활동이 알려지면서 

장 건강, 비만, 관련 질환에 대한 

다당류의 역할에 대한 관심이 높아졌습니다. 

알려진 역할에는 

미생물 군집에 의존하는 메커니즘과 

미생물 군집에서 유래한 대사 산물이 포함된 메커니즘, 

그리고 미생물 군집과 무관한 메커니즘이 포함됩니다. 

이 리뷰에서는 

장 건강과 대사 질환에 대한 다당류의 역할과 

그 근본적인 메커니즘에 대해 논의합니다. 

이 연구의 결과는 

식용 물질에 함유된 기능성 다당류에 대한 정보를 제공하고, 

건강 문제가 있는 사람들을 위한 식이 요법을 권장하는 데 도움이 됩니다. 

다당류가 인체 건강에 미치는 영향을 밝히기 위해서는 

장 질환과 대사 질환에 대한 치료 효과를 확인하기 위한 임상 시험을 더 많이 실시해야 합니다. 

식용 물질에서 다당류를 추출하는 것보다 

직접 섭취하기에 부적합한 식품 가공 과정에서 발생하는 부산물이나 대사 산물에서 다당류를 추출하는 데 

더 많은 관심을 기울여야 합니다. 

이 리뷰에서는 

다당류의 구조와 구성, 

장내 미생물의 공생적 역할, 

미생물 발효 다당류의 대사 산물, 

그리고 인간 건강과 질병에 대한 후속 결과에 대한 이해를 높였습니다. 

이 연구 결과는 

인간 건강을 개선하는 데 

다당류를 적절하게 적용하는 방법에 대한 통찰력을 제공합니다.

Keywords: polysaccharide, microbiota, gut health, metabolic disease, biological activity

Introduction

Polysaccharides, which are composed of more than 10 monosaccharide units connected by glycosidic linkages, are the most abundant types of carbohydrates and are present in various living organisms, including plants, fungi, and marine algae. Depending on their composition of monosaccharides, polysaccharides are classified as either homopolysaccharides, which comprise only one type of monosaccharide (e.g., starch), or heteropolysaccharides, which are composed of two or more different monomeric units (e.g., pectin). Polysaccharides can serve as reserve carbohydrates and/or structural components that contribute to complex physiological processes in plants and other organisms (1). The reserve polysaccharides primally exist in the cytoplasm, whereas the structural polysaccharides are mainly stored in the primary and secondary cell walls. Both serve as carbohydrate sources, provide fibers in human and animal diets, and affect physical function and health (Figure 1) (2).

소개

다당류는

10개 이상의 단당류 단위가

글리코시드 결합으로 연결된 탄수화물의 가장 풍부한 유형이며,

식물, 균류, 해조류를 포함한 다양한 생물체에 존재합니다.

다당류는

단당류의 구성에 따라 단당류 하나(예: 전분)로만 구성된 동종다당류와

두 가지 이상의 다른 단량체 단위(예: 펙틴)로 구성된 이종다당류로 분류됩니다.

다당류는

식물과 다른 유기체의 복잡한 생리학적 과정에 기여하는

예비 탄수화물 및/또는 구조적 구성 요소로 작용할 수 있습니다(1).

예비 다당류는

주로 세포질에 존재하는 반면,

구조적 다당류는 주로 1차 및 2차 세포벽에 저장됩니다.

두 가지 다당류 모두 탄수화물 공급원 역할을 하고,

인간과 동물의 식단에 섬유질을 제공하며,

신체 기능과 건강에 영향을 미칩니다(그림 1)(2).

FIGURE 1.

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The structure of polysaccharides in plant and marine algae. The gray arrows indicate the possibility of extended polymer length.

Polysaccharides are primarily consumed by oral administration and pass through the intestines for further utilization; therefore, polysaccharides have great biological benefits for bowel health (3). Humans and animals can directly process only simple sugars and a certain type of starch; thus, a large portion of polysaccharides (e.g., fiber) reaches the hindgut intact and is fermented by the intestinal microbiota. The microbiota and their derived metabolites have a great impact on human health and physiology (4). Therefore, considerable research has focused on the interaction between polysaccharides and intestinal microbiota as well as on shaping the structure of gut microbiota to determine polysaccharides’ effects on human health (5). Dietary fiber deficiency changes the gut microbiota and leads to gut dysbiosis, which occurs in various diseases, especially metabolic diseases (6). The increased incidence of insulin resistance, obesity, and other metabolic disease is partly due to increased systemic and tissue inflammation caused by increased systemic levels of bacterial endotoxins and DNA (7). Therefore, improving gut health through polysaccharide intervention, which can manipulate gut microbiota, can influence metabolic disease (8).

Furthermore, the influence of polysaccharides on gut health and metabolic diseases is not limited to mechanisms linked to the intestinal microbiota. Some in vitro studies have shown that polysaccharides can directly modulate the health of humans. Astragalus polysaccharides protected bladder epithelial cells against Escherichia coli infection by upregulating TLR4 expression‎ and subsequently increased the secretion of IL-6 and IL-8 (9). Polysaccharides can activate the B-cell TLR4/TLR2-p38 MAPK signaling pathway to enhance immune response (10). In addition, some polysaccharides, such as the pectin-type polysaccharides from Smilax china L., can be absorbed in the small intestine and are distributed in the liver and kidney (11). Oral absorption constitutes the basis of the direct effect of polysaccharides on human health. The widespread distribution and fundamental function of polysaccharides in plants as well as the extraction of different polysaccharides from various organisms and their positive effects on the health of humans and animals have been reported (12). However, it is unclear whether polysaccharides from different organisms have similar effects on animals and humans or if it is necessary to extract polysaccharides from various plants or other organisms even when their polysaccharide concentration is low. Therefore, this review focuses on how polysaccharides from terrestrial plants, fungi, and marine algae influence human health, especially gut health and metabolic disease. Additionally, it aims to identify the underlying mechanisms of bioactive polysaccharides in gut health and metabolic disease to provide insight for further research and application of polysaccharides in human and animal health.

식물과 해양 조류에 존재하는 다당류의 구조. 회색 화살표는 중합체 길이가 길어질 가능성을 나타냅니다.

다당류는

주로 경구 투여로 섭취되며,

장을 통과하여 추가 활용됩니다.

따라서

다당류는 장 건강에 큰 생물학적 이점을 가지고 있습니다(3).

인간과 동물은

단순당과 특정 유형의 전분만 직접 처리할 수 있습니다.

따라서

다당류(예: 섬유질)의 상당 부분은

온전한 상태로 후장에 도달하여

장내 미생물총에 의해 발효됩니다.

미생물군과 그로부터 파생된 대사 산물은

인간의 건강과 생리학에 큰 영향을 미칩니다(4).

따라서

다당류와 장내 미생물군 간의 상호 작용과 장내 미생물군의 구조 형성에 초점을 맞춘

상당한 연구가 이루어져 왔으며,

이를 통해 다당류가 인간의 건강에 미치는 영향을 파악하고자 합니다(5).

식이섬유 결핍은

장내 미생물총을 변화시키고 장내 미생물 불균형을 유발하는데,

이는 다양한 질병, 특히 대사성 질환에서 발생합니다(6).

인슐린 저항성, 비만, 기타 대사성 질환의 발생률 증가의 일부 원인은

전신 및 조직의 염증 증가로,

이는 전신 내 세균성 내독소와 DNA의 증가로 인해 발생합니다(7).

따라서

장내 미생물총을 조작할 수 있는 다당류를 통해 장 건강을 개선하면

대사성 질환에 영향을 미칠 수 있습니다(8).

또한, 다당류가 장 건강과 대사성 질환에 미치는 영향은 장내 미생물군과 관련된 메커니즘에만 국한되지 않습니다. 일부 체외 연구에 따르면 다당류는 인간의 건강을 직접적으로 조절할 수 있는 것으로 나타났습니다. 황기 다당류는 TLR4 발현을 증가시켜 대장균 감염으로부터 방광 상피 세포를 보호하고, 그 결과 IL-6와 IL-8의 분비를 증가시켰습니다(9). 다당류는 B세포 TLR4/TLR2-p38 MAPK 신호 전달 경로를 활성화하여 면역 반응을 강화할 수 있습니다(10). 또한, Smilax china L.의 펙틴형 다당류와 같은 일부 다당류는 소장에서 흡수되어 간과 신장에 분포할 수 있습니다(11). 경구 흡수는 다당류가 인체 건강에 직접적인 영향을 미치는 기초가 됩니다. 다당류의 광범위한 분포와 식물에서의 근본적인 기능, 그리고 다양한 유기체로부터의 다양한 다당류의 추출과 인간과 동물의 건강에 미치는 긍정적인 영향이 보고되었습니다(12). 그러나, 다양한 유기체로부터 추출된 다당류가 동물과 인간에게 유사한 영향을 미치는지, 아니면 다당류 농도가 낮더라도 다양한 식물이나 다른 유기체로부터 다당류를 추출해야 하는지 여부는 불분명합니다.

따라서 이 리뷰는

육상 식물, 곰팡이, 해양 조류에서 추출한 다당류가

인간의 건강, 특히 장 건강과 대사성 질환에 어떤 영향을 미치는지에 초점을 맞추고 있습니다.

또한 장 건강과 대사성 질환에 대한

생체 활성 다당류의 근본적인 메커니즘을 규명하여

인간과 동물의 건강에 다당류를 적용하고 연구하는 데 필요한

통찰력을 제공하는 것을 목표로 합니다.

Statistical review of the effects of polysaccharides on health

Research on the influence of polysaccharides on human and animal health published during 2013–2022 was ascertained using VOSViewer, and the terms “polysaccharides” and “health or gut health or microbiota or obesity or type 2 diabetes or non-alcoholic fatty liver disease” were searched in the Web of Science. A total of 7,497 records, including 1,590 review articles, 5,799 articles, and 459 other types of documents, were downloaded from the SSCI database of Web of Science. The yearly publication of related topics has been continually increasing (Figure 2), depicting the increased interest in research on the effects of polysaccharides on health. Of note, the number of publications in 2022 (Figure 2) represents those published in the first three quarters of the year, as the search in Web of Science was conducted on 10 September 2022. Therefore, the number of publications on “polysaccharides” and “health” will likely to exceed 1,500 in 2022. Among the countries that have published more than 130 related articles, both China and the USA have the most publications (3,239 and 1,210, respectively; Figure 2A). Furthermore, the number of publications from China has increased dramatically since 2017 (Figure 2B). The increased number of publications on polysaccharides and its effects on human and animal health may be attributable to the Chinese medicinal processing activities as water extraction is the main method that is used to prepare Chinese medicines, and this method is similar to the procedure for the extraction of polysaccharides. The major keywords that were associated with the search terms which appeared more than 100 times were summarized (Figure 2C), and the top 15 keywords are listed in Table 1.

Unsurprisingly, except for “polysaccharides,” “intestinal microbiota” was the most frequently identified keyword in the publications. Intestinal microbiotas play a vital role in the digestion of polysaccharides and exert functions on the health of humans and animals. Furthermore, “antioxidant ability” appeared frequently in the downloaded publications, thereby indicating the biofunctions of polysaccharides as antioxidants. The “sulfated polysaccharides” and “fucoidan” that were found in various species of brown algae have increasingly received attention for their marked antioxidant ability. Moreover, from the occurrences of “extraction,” “structural characterization,” and “purification,” we can infer that, with the development of sequencing and other technologies, scientists have become more interested in obtaining pure polysaccharides to clarify their structural characteristics and functions.

다당류가 건강에 미치는 영향에 대한 통계적 검토

2013-2022년 사이에 발표된 다당류가 인간과 동물의 건강에 미치는 영향에 대한 연구는 VOSViewer를 사용하여 확인되었으며, Web of Science에서 “다당류”와 “건강 또는 장 건강 또는 미생물군 또는 비만 또는 제2형 당뇨병 또는 비알코올성 지방간 질환”이라는 용어를 검색했습니다. 총 7,497건의 기록이 Web of Science의 SSCI 데이터베이스에서 다운로드되었습니다. 이 기록에는 1,590건의 리뷰 기사, 5,799건의 기사, 그리고 459건의 기타 유형의 문서가 포함되어 있습니다. 다당류가 건강에 미치는 영향에 대한 연구에 대한 관심이 증가함에 따라 관련 주제의 연간 출판물도 지속적으로 증가하고 있습니다(그림 2). 참고로, 2022년에 발표된 논문 수(그림 2)는 2022년 9월 10일에 Web of Science에서 검색을 진행했기 때문에, 그 해의 첫 3분기 동안 발표된 논문을 나타냅니다. 따라서, 2022년에 발표된 “다당류”와 “건강”에 관한 논문 수는 1,500개를 초과할 것으로 예상됩니다. 관련 기사를 130개 이상 발표한 국가 중 중국과 미국이 가장 많은 기사를 발표했습니다(각각 3,239개와 1,210개, 그림 2A). 또한, 중국의 발표 건수는 2017년 이후 급격하게 증가했습니다(그림 2B). 다당류와 그 다당류가 인간과 동물의 건강에 미치는 영향에 관한 출판물의 수가 증가한 것은 중국 약재 가공 활동 때문일 수 있습니다. 중국 약재를 제조하는 데 주로 사용되는 방법은 물 추출이며, 이 방법은 다당류를 추출하는 절차와 유사합니다. 100회 이상 검색된 검색어와 관련된 주요 키워드를 요약했습니다(그림 2C). 상위 15개 키워드는 표 1에 나열되어 있습니다.

당연히 “다당류”를 제외하고, “장내 미생물군”이 출판물에서 가장 많이 확인된 키워드였습니다. 장내 미생물군은 다당류의 소화에 중요한 역할을 하며, 인간과 동물의 건강에 영향을 미칩니다. 또한, 다운로드된 출판물에서 “항산화 능력”이 자주 등장했는데, 이는 다당류가 항산화제로서의 생물학적 기능을 가지고 있음을 나타냅니다. 갈조류의 다양한 종에서 발견된 “황산 다당류”와 “후코이단”은 항산화 능력이 뛰어나다는 점에서 점점 더 주목을 받고 있습니다. 또한, “추출”, “구조적 특성 분석”, “정제”의 발생을 통해, 과학자들이 시퀀싱 및 기타 기술의 발달과 함께 순수한 다당류를 얻어 그 구조적 특성과 기능을 명확히 하는 데 더 많은 관심을 갖게 되었다는 것을 추론할 수 있습니다.

FIGURE 2.

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Publication analysis of polysaccharides in the last 10 years. (A) Total publications related to polysaccharides and human health from 2013 to 2022. (B) The yearly output from different countries. (C) Network visualization of terms associated with polysaccharides and human health.

TABLE 1.

The top 15 highest occurrences of keywords.

Items

Occurrences

Total link strength

Occurrences

Total link strength

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Interaction between polysaccharides and microbiota

The gastrointestinal tract houses several trillion microbial cells which are strongly associated with human health. Carbohydrates are the main source of energy and nutrients for intestinal microbiota and thus influence microbial composition through the modulation of specific species and their derived metabolites (13). Moreover, the microbiota possesses a larger repertoire of degradative enzymes and is adept at foraging glycans and polysaccharides that are derived from plants, animals, and other sources (14). The mutual dependence between polysaccharides and gut microbiota constitutes an important basis for the participation of polysaccharides in a diverse array of physiological processes in humans.

다당류와 미생물 간의 상호작용

위장관에는

인간의 건강과 밀접한 관련이 있는

수조 개의 미생물 세포가 있습니다.

탄수화물은

장내 미생물의 주요 에너지와 영양소 공급원이기 때문에

특정 종과 그 파생 대사 산물의 조절을 통해 미생물 구성에 영향을 미칩니다(13).

또한,

미생물총은 더 많은 분해 효소를 보유하고 있으며,

식물, 동물, 기타 출처에서 유래된 당류와 다당류를 잘 섭취합니다(14).

다당류와 장내 미생물총의 상호 의존성은

인간이 다양한 생리학적 과정에 참여하는 데 있어

중요한 기반을 형성합니다.

Polysaccharides degradation by microbiota

The huge diversity of polysaccharides has partly resulted from the various component sugar substituents and their linkage patterns, which can be branched at different positions on a single substituent by α- or β-glycosides (15). In addition, polysaccharides can be covalently coupled to other molecules, such as protein, lipids, and even RNA (16), and thereby adopt a secondary structure. At the same time, some studies have revealed the three-dimensional molecular conformation of polysaccharides, such as polysaccharides from Laminaria japonica (17), which inevitably adds complexity to the polysaccharides.

In general, the more complex the polysaccharides are, the greater the number of enzymes that are required in the breakdown process. However, for humans, only 17 enzymes are encoded for the digestion of food glycans, specifically for a certain type of starch (18), whereas gut bacteria can produce hundreds of enzymes with catalytic specificities that range well beyond that of starch (15, 19). The carbohydrate-active enzymes (CAZymes), which are encoded by intestinal microbiota, are required to break down the glycoconjugates and polysaccharides to release fermentable monosaccharides that can be used as an energy source by intestinal cells and/or bacteria. Glycoside hydrolases (GHs) and polysaccharide lyases (PLs) are two main types of CAZymes that cleave glycosidic bonds between carbohydrates and between a carbohydrate and a non-carbohydrate moiety (18). The animal gut harbors trillions of microbes, of which Firmicutes and Bacteroidetes are the most commonly represented phyla. The Bacteroidetes encode more CAZymes than other phyla (18). Bacteroides thetaiotaomicron, a dominant member of human distal gut microbiota, contains more than 261 GHs and PLs (20). Furthermore, the comparative genomic analysis revealed that fully sequenced intestinal Bacteroidetes contain genes that encode sulfatases and the related active enzymes, which are crucial for fermenting sulfated polysaccharides, such as mucin and glycosaminoglycans in mucus, as well as fucoidans in brown seaweeds and carrageenan in red seaweeds (21, 22). With the capacity to utilize an extensive array of dietary and host-derived polysaccharides, the Bacteroidetes are considered glycan-degrading generalists. However, Firmicutes and Actinobacteria appear more specialized with a preference for the reserve polysaccharides of plants (23).

Different phyla have different fermentation mechanisms for processing polysaccharides. The gram-negative Bacteroidetes pack their diverse array of CAZymes into discrete polysaccharides utilization loci (PUL) gene clusters, which have been identified in all intestinal Bacteroidetes and encode substantial numbers of surface proteins that are required for the utilization of polysaccharides. Therefore, the polysaccharides targeted by Bacteroidetes require extracellular hydrolysis before being transported into the cell. The well-studied starch utilization system (Sus) is the first PUL that was described for starch processing in B. thetaiotaomicron (24). However, in contrast to the Bacteroidetes, the gram-positive Firmicutes and Actinobacteria depend more on a diverse array of transporters, such as ABC-transport systems, to import smaller sugars for intracellular processing, which provides an important competitive advantage against the predominant Bacteroidetes (25). The mechanisms of polysaccharide degradation that use either the PUL or Sus system by Bacteroidetes and the ABC system by Firmicutes and Actinobacteria have been described previously (26) and are not covered in depth here. Overall, the microbiota plays a critical role in the host’s digestion of polysaccharides.

미생물 군집에 의한 다당류의 분해

다당류의 엄청난 다양성은

부분적으로 다양한 구성 당의 치환기와 그 결합 패턴에 기인하는데,

이 결합 패턴은 α- 또는 β-글리코시드(15)에 의해

단일 치환기에서 다른 위치에 분지될 수 있습니다.

또한,

다당류는

단백질, 지질, 심지어 RNA(16)와 같은 다른 분자와 공유 결합될 수 있으며,

이로 인해 2차 구조를 채택할 수 있습니다.

동시에, 일부 연구에서는 다당류의 입체적인 분자 구조를 밝혀냈는데,

라미나리아 자포니카(17)에서 추출한 다당류와 같은 다당류는 불가피하게 복잡성을 더합니다.

일반적으로 다당류가 복잡할수록

분해 과정에서 필요한 효소의 수가 많아집니다.

그러나

인간의 경우,

음식의 글리칸을 소화하는 데 필요한 효소는 17개뿐이고,

그중에서도 특정 유형의 전분(18)을 소화하는 데 필요한 효소만 17개입니다.

반면,

장내 세균은

전분(15, 19)을 훨씬 능가하는 촉매 특이성을 가진

수백 가지의 효소를 생산할 수 있습니다.

장내 미생물 군집에 의해 암호화되는 탄수화물 활성 효소(카자임)는

장 세포 및/또는 박테리아가 에너지 원으로 사용할 수 있는

발효 가능한 단당류를 방출하기 위해 당화합물과 다당류를 분해하는 데 필요합니다.

글리코시다아제(glycoside hydrolases, GHs)와

다당류 분해효소(polysaccharide lyases, PLs)는

탄수화물 사이와 탄수화물과 비탄수화물 부분 사이에서 글리코시딕 결합을 절단하는

두 가지 주요 유형의 카자임입니다(18).

동물 장에는 수조 개의 미생물이 서식하고 있으며,

그 중에서도 피막균과 박테로이데테스가

가장 흔하게 나타나는 문입니다.

박테로이드테스는

다른 문(phylum)보다 더 많은 카자임(CAZymes)을 암호화합니다(18).

인간 장내 미생물 군집의 지배적인 구성원인

박테로이드테스 테타이오타오미크론(Bacteroides thetaiotaomicron)은 261개 이상의

GH와 PL을 포함하고 있습니다(20).

또한, 비교 유전체 분석 결과,

장내 Bacteroidetes의 완전한 염기서열에는

황산염 다당류를 발효하는 데 중요한 역할을 하는

설파타제 및 관련 활성 효소를 암호화하는 유전자가 포함되어 있는 것으로 밝혀졌습니다.

이러한 효소는

점액의 뮤신 및 글리코사미노글리칸,

갈조류의 후코이단,

홍조류의 카라기난과 같은 황산염 다당류를 발효하는 데

중요한 역할을 합니다(21, 22).

다양한 종류의 식이 및 숙주 유래 다당류를 활용할 수 있는 능력을 가진 박테로이데테스는

당분해성 다재다능한 것으로 간주됩니다.

그러나, 피막균과 방선균은

식물의 예비 다당류를 선호하는 것으로 보아

좀 더 전문화된 것으로 보입니다(23).

다양하고 다른 진핵생물은 다당류를 처리하는 데 있어서 다른 발효 메커니즘을 가지고 있습니다. 그람 음성균인 박테로이데테스는 다양한 종류의 카자임(CAZymes)을 분리된 다당류 이용 유전자좌(PUL) 유전자 클러스터에 집어넣는데, 이 유전자 클러스터는 모든 장내 박테로이데테스에서 확인되었으며, 다당류의 이용에 필요한 상당수의 표면 단백질을 암호화합니다.

따라서, 박테로이데테스가 표적으로 삼는 다당류는 세포 내로 운반되기 전에 세포 외 가수분해가 필요합니다. 잘 연구된 전분 이용 시스템(Sus)은 B. thetaiotaomicron(24)의 전분 처리에 대해 설명된 최초의 PUL입니다. 그러나, Bacteroidetes와는 달리, 그람 양성 Firmicutes와 Actinobacteria는 세포 내 처리를 위해 더 작은 당을 수입하기 위해 ABC 수송 시스템과 같은 다양한 수송체에 더 의존하는데, 이것은 지배적인 Bacteroidetes에 대한 중요한 경쟁 우위를 제공합니다(25). 박테로이드테스(Bacteroidetes)의 PUL 또는 Sus 시스템과 펩토코쿠테스(Firmicutes) 및 액티노박테리아(Actinobacteria)의 ABC 시스템을 사용하는 다당류 분해 메커니즘은 이전에 설명된 바 있으며(26), 여기에서는 자세히 다루지 않습니다. 전반적으로, 미생물총은 숙주의 다당류 소화에 중요한 역할을 합니다.

Influence of polysaccharides on microbiota

The exceptional diversity of dietary polysaccharides has a profound influence on the composition and structure of intestinal microbiota (27). Different microbial species have different preferences for glycans, which determine the structure and monosaccharide composition of polysaccharides and have a great impact on intestinal microbiota. Wu et al. (28) reported that okra pectic-polysaccharides with different structures selectively changed the composition of intestinal microbiota (27). Enteromorpha polysaccharide enriched the abundance of Bacteroides, which helps to break down the polysaccharides (29). At the same time, several studies that focused on the capacity of gut bacteria to catabolize marine algal polysaccharides, such as porphyran and agarose, have revealed the geographic distribution of intestinal microbiota (30–32). B. plebeius, which contains genes that encode porphyranases and agaroses, has been isolated from Japanese individuals whose diet typically includes seaweed. However, the gut metagenome analyses from North American individuals showed the absence of porphyranases and agaroses (31). Furthermore, a study of Desulfobulbus and Methanosarcina indicated that the spatial distribution of microbial communities significantly correlated with geographic distance (32).

The abovementioned studies indicated that the sources of polysaccharides directly influence the composition of intestinal microbiota. Moreover, the inclusion of pea fiber in the diet of gnotobiotic mice that were cloned with a defined consortium of human-gut-derived bacteria significantly increased the abundance of B. thetaiotaomicron. In addition, the richness of B. cacccae in the model revealed the pronounced effects of high-molecular weight inulin on the composition of the microbiota (33). Polysaccharides can directly encourage the expansion of certain bacterial species by serving as nutrient sources for their growth. Another study that involved the incubation of different human gut-derived bacteria with different glycans in vitro showed that some species and strains from Bacteroides and Parabacteroides exhibited the ability to bind one or more specific glycans, thereby indicating that different glycans are responsible for the expansion of different bacterial species or strains (34). Furthermore, microbiota that has limited metabolic capacities for processing complex polysaccharides must rely on other organisms that are capable of fermenting polysaccharides through microbe–microbe interactions, such as commensalism, mutualism, and competition (26, 33, 35, 36). Therefore, many types of complex polysaccharides help to confer additional diversity to the gut microbiota partly through the interactions among microbes.

Different types of polysaccharides enable rational manipulation of the microbiota based on the species’ metabolic capacity. The CAZymes (e.g., extracellular β-2,6 endo-fructanase) that are encoded by intestinal bacteria enable the metabolic processing of β-2,6-linked fructan levan. Therefore, dietary involvement of β-2,6-linked fructan levan enriches the abundance of B. thetaiotaomicron (37). Genome analysis coupled with efforts to culture human gut microorganisms is constantly aiding the elucidation of the mechanisms underlying mutualistic behavior, which has long been attributed to human gut microbes in the processing of dietary fiber polysaccharides (15, 23, 34, 38). The interaction between microbiota, polysaccharides, and their subsequent metabolites are highly correlated with human health and physiological process.

다당류가 미생물 군집에 미치는 영향

다당류의 식이 다양성은 장내 미생물 군집의 구성과 구조에 큰 영향을 미칩니다(27). 미생물 종마다 선호하는 당질이 다르며, 이는 다당류의 구조와 단당류 구성을 결정하고 장내 미생물 군집에 큰 영향을 미칩니다. Wu et al. (28)은 구조가 다른 오크라 펙틴 다당류가 장내 미생물 군집의 구성을 선택적으로 변화시킨다고 보고했습니다(27). Enteromorpha polysaccharide는 Bacteroides의 풍부함을 강화하여 다당류를 분해하는 데 도움이 됩니다(29). 동시에, 포르피란과 아가로스와 같은 해양 조류 다당류를 분해하는 장내 세균의 능력에 초점을 맞춘 여러 연구에서 장내 미생물 군집의 지리적 분포가 밝혀졌습니다(30-32). B. plebeius는 포르피라나아제와 아가로스를 암호화하는 유전자를 포함하고 있으며, 주로 해조류를 섭취하는 일본인 개체군에서 분리되었습니다. 그러나 북미 개체군의 장내 메타게놈 분석 결과, 포르피라나아제와 아가로스가 존재하지 않는 것으로 나타났습니다(31). 또한, Desulfobulbus와 Methanosarcina에 대한 연구에 따르면 미생물 군집의 공간적 분포는 지리적 거리와 상당한 상관관계가 있는 것으로 나타났습니다(32).

위에서 언급한 연구들은 다당류의 공급원이 장내 미생물 군집의 구성에 직접적인 영향을 미친다는 것을 보여줍니다. 또한, 인간 장에서 유래된 박테리아의 특정 집합체로 복제된 고토바이오틱 마우스의 식단에 완두콩 섬유질을 포함시켰을 때, B. thetaiotaomicron의 수가 크게 증가했습니다. 또한, 모델에서 B. cacccae의 풍부함은 고분자량 이눌린이 미생물 군집의 구성에 미치는 뚜렷한 영향을 보여주었습니다(33). 다당류는 특정 박테리아 종의 성장을 위한 영양 공급원 역할을 함으로써 박테리아 종의 확장을 직접적으로 촉진할 수 있습니다. 체외에서 다른 글리칸을 가진 다른 장내 박테리아의 배양을 포함한 또 다른 연구에 따르면, 박테로이드(Bacteroides)와 파라박테로이드(Parabacteroides)의 일부 종과 균주가 하나 이상의 특정 글리칸에 결합하는 능력을 나타냈으며, 이는 다른 글리칸이 다른 박테리아 종 또는 균주의 확장을 담당한다는 것을 나타냅니다(34). 또한, 복잡한 다당류를 처리할 수 있는 대사 능력이 제한적인 미생물은 공생, 공생, 경쟁과 같은 미생물 상호 작용을 통해 다당류를 발효할 수 있는 다른 유기체에 의존해야 합니다(26, 33, 35, 36). 따라서 많은 종류의 복잡한 다당류는 부분적으로 미생물 간의 상호 작용을 통해 장내 미생물에 추가적인 다양성을 부여하는 데 도움이 됩니다.

다양한 종류의 다당류는 종의 대사 능력에 따라 미생물 군집을 합리적으로 조작할 수 있게 해줍니다. 장내 세균에 의해 암호화되는 CAZymes(예: 세포 외 β-2,6 엔도프럭탄아제)는 β-2,6-연결된 프럭탄 레반의 대사 처리를 가능하게 합니다. 따라서, β-2,6-연결된 프럭탄 레반의 식이 섭취는 B. thetaiotaomicron(37)의 풍부함을 증가시킵니다. 인간 장내 미생물을 배양하려는 노력과 결합된 게놈 분석은 식이 섬유 다당류의 처리 과정에서 인간 장내 미생물이 오랫동안 기여해 온 공생 작용의 기전을 밝혀내는 데 지속적으로 도움을 주고 있습니다(15, 23, 34, 38). 미생물군, 다당류, 그리고 그 후속 대사 산물 간의 상호 작용은 인간의 건강과 생리적 과정과 밀접한 관련이 있습니다.

Polysaccharides play vital roles in the physiological status of humans

Dietary polysaccharides have diverse, crucial influences on human health. Interactions with microbiota partly explain the underlying mechanisms as polysaccharides are predominantly administered via the oral route, and therefore, exert functions for improving human health through their absorption. Due to the lack of methods and technologies to detect polysaccharides, some researchers consider that polysaccharides have poor intestinal absorption after oral administration. However, with improved detection technology, studies have found that after oral administration, polysaccharides can be absorbed into the circulatory system even if they have high molecular weight and complicated structures (11, 39, 40). Moreover, the oral absorption mechanisms of polysaccharides and the factors influencing them are well-reviewed by Zheng et al. (41) and are accordingly not covered in depth here. Overall, direct gut absorption and the interaction with intestinal microbiota are key aspects for understanding the mechanisms of polysaccharide function in human intestinal and metabolic health.

다당류는 인간의 생리적 상태에 중요한 역할을 합니다.

식이 다당류는 인간의 건강에 다양하고 중요한 영향을 미칩니다. 미생물총과의 상호작용은 부분적으로 다당류가 주로 경구로 투여되기 때문에 근본적인 메커니즘을 설명할 수 있으며, 따라서 흡수를 통해 인간의 건강을 개선하는 기능을 발휘합니다. 다당류를 검출하는 방법과 기술이 부족하기 때문에 일부 연구자들은 다당류가 경구 투여 후 장내 흡수율이 낮다고 생각합니다. 그러나 검출 기술이 향상됨에 따라 연구에 따르면 다당류는 분자량이 크고 구조가 복잡하더라도 경구 투여 후 순환계로 흡수될 수 있다는 사실이 밝혀졌습니다(11, 39, 40). 또한, 다당류의 경구 흡수 메커니즘과 그 메커니즘에 영향을 미치는 요인에 대한 연구는 Zheng et al. (41)에 의해 잘 검토되어 있으므로, 여기에서는 자세히 다루지 않겠습니다. 전반적으로, 직접적인 장 흡수와 장내 미생물과의 상호 작용은 인간의 장과 대사 건강에서 다당류의 기능 메커니즘을 이해하는 데 중요한 측면입니다.

Polysaccharides influence intestinal health

A functional intestine and an intact intestinal barrier, which permit nutrient transport from the lumen into the blood and simultaneously restrict the passage of potentially harmful microorganisms and toxins, constitute an integral regulator of human health (7, 42). Observational findings that have been accumulated during the last 10 years suggest that polysaccharides have profound biological benefits for bowel health, including anti-inflammation, gut epithelial barrier protection, and immune modulation through both microbiota-dependent and -independent mechanisms (3, 12). Most polysaccharides pass through the small intestine intact and can successfully reach the large bowel, where they can be either fermented by the microbiota or excreted in the stool. Due to their capacity for water retention, polysaccharides in the large bowel could attract water and add bulk to the digesta which increases intestinal peristalsis and softens the stool, thus diluting toxin concentrations, increasing the frequency of defecation, and preventing constipation and its associated problems, such as hemorrhoids (3, 43, 44). Moreover, dietary ingestion of high concentrations of non-starch polysaccharides (NSP) is associated with increased stool weight and a decreased risk of bowel cancer (45). In addition, polysaccharides enhance bowel health by promoting the immune system and reducing inflammation. Polysaccharides from astragalus that mainly contained rhamnose, glucose, galactose, and arabinose ameliorated dextran sulfate sodium (DSS)-induced colitis and increased the colon length by inhibiting NF-κB activation, and thus downregulating TNF-α, IL-1β, and IL-6 expression‎ and subsequently reducing proinflammatory responses (46). Similarly, Scutellaria baicalensis Georgi polysaccharides, which are mainly composed of mannose, ribose, glucuronic acid, glucose, xylose, and arabinose, suppressed DSS-induced colitis through inhibition of NF-κB and NLRP3 inflammasome activation, and thereby decreasing pro-inflammatory cytokines secretion in mice and macrophages (47). There is increasing evidence that Peyer’s patches hold the key to how polysaccharides enhance intestinal immune status. Polysaccharides from molokhia (Corchorus olitorius L.) leaves could increase bone marrow cell proliferation as well as immunoglobulin A and cytokine production via Peyer’s patches (48), which is consistent with the hypothesis of Han (49) who states that polysaccharides could enter Peyer’s patches to trigger immune responses even without entering the blood circulation. Moreover, polysaccharides from Coptis chinensis Franch. (50), Atractylodes lancea (51), and Lavandula angustifolia Mill. (52) could be taken up by Peyer’s patches and stimulate the immune cells inside it to regulate cytokine secretion. Therefore, polysaccharides can exert immune-enhancing functions without absorption into the bloodstream, which benefits gut health by improving the immune status of the gut. Furthermore, polysaccharides, such as α-D-glucan, could enhance the intestinal barrier function by increasing the expression‎ of tight junction proteins (53, 54).

Additionally, the interaction of polysaccharides and intestinal microbiota plays a crucial role in gut health. A deficiency of dietary polysaccharides leads to gut dysbiosis. As the microbiota mostly relies on polysaccharides as a nutrient source, the absence of these nutrients in the diet forces the microbiota to transition toward the use of indigenous host glycans, which causes the expansion of pathogenic organisms and decreased abundance of probiotics and the linked metabolites. Evidence has revealed that the microbiota can erode the colonic mucus layer in the absence of dietary polysaccharides, thus accelerating enteric pathogen invasion and intestinal disease progression when challenged with the pathogen Citrobacter rodentium (15, 55). Low concentrations of dietary polysaccharides induced inflammation and increased intestinal permeability that led to increased pathogen invasion into other tissues, which is highly associated with the onset of obesity and other metabolic diseases (56) (Figure 3). Comparatively, the dietary inclusion of polysaccharides is important for supporting the function and stability of gut microbiota and, eventually, for maintaining gut health. Polysaccharides derived from Lentinula edodes encouraged the expansion of B. acidifaciens (57). In addition, polysaccharides from Flammulina velutipes improved colitis by shaping the structure of the colonic microbiota and inflammatory responses. Bacteria-derived polysaccharides, including glucorhamnan, which are synthesized and secreted by Ruminococcus gnavus, influence intestinal health via the regulation of intestinal inflammatory states (58). Furthermore, the microbiota-derived metabolites, such as short-chain fatty acids (SCFAs) (59), enhanced the intestinal fermentation of diverse polysaccharides and have profound effects on bowel health. SCFAs can be used directly as energy sources by colonic epithelial cells, support their proliferation, and enhance the epithelial barrier function (60). Polysaccharides from Cistanche (61), Vigna radiata L. skin (62), enriched probiotic bacteria and SCFA in the intestine of mice. In addition, both in vivo and in vitro studies indicated that polysaccharides from soybean or marine algae could enhance the abundance of probiotic bacteria whereas inhibiting pathogens in the intestine (19, 63, 64). Thus, polysaccharides are crucial for intestinal health, which further benefits the health of the body.

FIGURE 3.

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The inclusion of polysaccharides has a profound impact on gut health. Polysaccharide-based interventions increased microbiota-derived metabolites, such as short-chain fatty acids (SCFA) and vitamins (Left). SCFAs can bind to receptors on L cells and subsequently induce the secretion of glucagon-like peptide 1 (GLP-1), which can affect energy expenditure (132). Polysaccharides are highly associated with increased stool volume, frequency, and fat and bile acid concentrations (45, 46, 133), which reinforce gut health. Moreover, the intestinal immune system is enhanced by polysaccharides, as indicated by the increased secretion of immunoglobulin A (sIgA) levels. However, when the diet contains very low concentrations of polysaccharides, the balance between the gut microbiota and immunity will be disrupted (Right), resulting in decreased diversity of microbiota with an increased abundance of pathogens, which elicit gut inflammation and subsequent bowel disease.

The relationship between polysaccharides and obesity

The preval‎ence of obesity has been increasing dramatically worldwide, and the progression and maintenance of obesity include genetic and environmental factors, diet (e.g., high availability of high-energy foods with less dietary fiber), and lifestyle (e.g., sedentary ways of life) that leads to excess peripheral and visceral lipid accumulation (65). Moreover, dysbiosis of intestinal microbiota acts both as a cause and a consequence of obesity (66–68). Notably, obesity is associated with systemic low-grade inflammation and various health issues, such as type 2 diabetes (due to insulin resistance), fatty liver disease, short life expectancy, and so on (69). Therefore, identifying efficient strategies to prevent or ameliorate obesity is important for the health of people who are overweight or obese. Recently, interest in the role of polysaccharides in preventing obesity has increased, and the anti-obesity properties and mechanisms of polysaccharides have been reported by several studies (70–72) (Figure 4).

FIGURE 4.

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Mechanisms by which polysaccharides alleviate obesity. A polysaccharide-rich diet contributes to the maintenance of a healthy gut and reduces inflammation of the liver and adipose tissue (Right). Intestinal microbiota composition is associated with obesity, of which low diversity, reduced abundance of Akkermansia and Alistipes, and enhanced Firmicutes-to-Bacteroidetes ratio were observed in obese individuals. However, polysaccharide supplementation can reverse the microbiota changes in obese situations, along with increased glucagon-like peptide 1 (GLP-1) levels, which is positively related to energy expenditure.

Most polysaccharides cannot be digested to directly provide energy to animals. Therefore, the dietary inclusion of polysaccharides could reduce calorie intake. Moreover, due to their complex special structure, polysaccharides are characterized by great fat-binding capacities, which leads to the increased excretion of dietary or endogenous fatty acids (73). Polysaccharides can bind bile acids in the intestine to enhance its excretion, thus enabling new bile acid synthesis in the liver and consuming more cholesterol (74). Consistent results were obtained in research on xyloglucan and inulin supplementation, which increased the fecal total bile acid concentration (75). Decreasing the energy intake as well as increasing fatty acids and cholesterol excretion is of great importance for decreasing lipid accumulation, and thus could benefit overweight individuals. Besides this, enhancing energy expenditure is another mode of action that actualizes the anti-obesity property of polysaccharides. Lyophyllum decastes polysaccharides enhance energy expenditure in diet-induced obese mice, which might be due to the upregulation of the secondary bile acids-activated TGR5 pathway (74). Furthermore, the enhanced brown tissue activity by polysaccharides (74, 76) could explain the energy expenditure property of polysaccharides to some extent.

Inhibition of lipogenesis and promotion of lipolysis/fatty acid oxidation are very important to restrict fat accumulation. Peroxisome proliferator-activated receptor gamma (PPARγ) is a transcriptional factor that directs the differentiation of adipocytes, whereas PPARα is a key transcriptional factor for fatty acid oxidation (77). In addition to dietary sources, endogenous fatty acid production from de novo lipogenesis in mammalian tissues, including liver, white adipose tissue, and brown adipose tissue, has been identified in both healthy and obese individuals. Polysaccharides inhibit hepatic lipogenesis and lipogenesis in white adipose tissues, (78, 79), mainly through the inhibition of core enzymes, such as acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), in the lipogenic process (80). Moreover, PPARγ expression‎ could be inhibited by dietary polysaccharides in the liver and adipose tissues of diet-induced obese mice (81). In vitro experiments using 3T3-L1 cells demonstrated the direct inhibition of adipocyte differentiation by quinoa polysaccharide through PPARγ inhibition (79, 82, 83), and activation of the AMPK/PPARα pathway by polysaccharides was observed in obese mice, which implies increased fatty acids oxidation and energy expenditure. Therefore, polysaccharides could prevent obesity and/or ameliorate obesity by inhibiting lipogenesis while enhancing lipolysis. Although polysaccharides with anti-obesity properties have different sources, structure, and composition, they have similar modes of actions in ameliorating diet-induced obesity.

The fundamental influence of polysaccharides on intestinal microbiota explains its primary mechanism in reducing obesity, which has been studied in many research articles (70, 71, 84, 85) and reviews (86, 87). High-weight molecular polysaccharides isolated from Ganoderma lucidum reduced body weight and fat accumulation in obese mice by altering the intestinal microbiota composition, as indicated by the decreased Firmicutes-to-Bacteroidetes ratios and improved gut barrier function. Research on HG-type pectin, derived from Ficus pumila L. fruits, increased the abundance of Akkermansia and Alistipes in obese mice. The subsequent metabolites, myristoleic acid, and pentadecanoic acid, are negatively associated with serum lipid concentration and contribute to decreased fat concentration (88). A fucoidan from Sargassum fusiform has similar effects, which restored Alistipes abundance (89). The microbiota species enriched by polysaccharides in obese animals correlated with a reduction of obesity, thus providing insights to guide the development of probiotics and functional prebiotics to prevent obesity in clinical practice.

Interestingly, xyloglucan compounded with arabinoxylan or inulin supplementation activated intestinal or hepatic G protein-coupled 5 (TGR5) of mice that were fed a high-fat diet (75). TGR5 signals in enteroendocrine L-cells induce glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) excretion, thereby attenuating food consumption rate, improving liver and pancreatic function, and promoting glucose metabolism, as well as activating TGR5 in adipose and muscle tissues to increase energy expenditure (90). TGR5 activation by polysaccharides prevents diet-induced obesity through attenuation of energy intake and increased energy expenditure. Therefore, dietary inclusion of more of the abovementioned polysaccharides is considered a good strategy to alleviate obesity.

Polysaccharides and control of type 2 diabetes

Diabetes mellitus comprises a group of metabolic diseases characterized by chronic hyperglycemia, along with many complications, such as diabetic nephropathy and cardiovascular disease. Usually, diabetes can be divided into two main broad categories: type 1 diabetes and type 2 diabetes mellitus (T2DM), which account for the majority (∼90%) of total diabetes preval‎ence (91, 92). Known as non-insulin-dependent diabetes mellitus, T2DM is largely induced by insulin resistance and dysfunction of insulin-producing β cells, which decreases the tissue sensitivity to insulin and has insufficient biological effects, thereby leading to hyperglycemia (91). However, unlike type 1 diabetes, which is not preventable with the current knowledge, effective approaches are available to prevent T2DM and its complications (93). Increasing evidence has shown that polysaccharides exhibit antidiabetic effects. Considering the growing reports on polysaccharides as therapy for T2DM and their popularity as dietary supplements, this subsection is designed to clarify the various mechanisms of such therapeutic applications.

The application of polysaccharides in the diet- and/or drug-induced T2DM animal models ameliorated glucose tolerance (94), inhibited insulin resistance (95), protected damaged pancreatic islets (96), improved β cell function (95), enhanced lipid metabolism thus increasing insulin sensitivity in the liver (97), and reduced oxidative stress and inflammatory response (98) to relieve T2DM. Polysaccharides from Anoectochilus roxburghii could inhibit the key gluconeogenesis enzymes, thereby increasing glucose absorption (99), which explains the function of polysaccharides in decreasing fasting blood glucose levels. Echinops spp. polysaccharide B could increase muscle and liver glycogen content (100), which lowers the blood glucose level in T2DM. Polysaccharides from Sphacelotheca sorghi (Link) Clint (101) and Auricularia auricula-judae (102) enhanced the hepatic health of T2DM by activating the PI3K/Akt signaling pathway. Echinops spp. polysaccharide B increased the number of insulin receptors in the liver and muscles, thus decreasing insulin resistance in T2MD (100). Besides their use as a dietary source, polysaccharides can be used to protect insulin that is administered orally. The ability to improve the permeability via transcellular and/or paracellular pathways and even selectivity for targeted delivery of insulin through nano- and microencapsulation of polysaccharides is considered an important technological strategy to protect insulin against the harsh conditions of the gastrointestinal tract (103).

In addition to the abovementioned functions, polysaccharides can affect T2DM by influencing the structure of intestinal microbiota and their derived metabolites, the composition of which plays pivotal roles in the pathogenetic process of T2DM (104). Patients with T2DM have increased relative abundances of the phyla Firmicutes and Actinobacteria and decreased relative abundances of Bacteroidetes. Consistently, Lactobacillus and Eubacteria were significantly enriched (104), whereas abundances of Bifidobacterium were decreased in T2DM patients (105). Inulin supplementation increased the abundance of Bifidobacterium and increased the integrity of the gut barrier, which was negatively correlated with T2DM (75, 105). Apocynum venetum polysaccharides reversed the gut microbiota dysbiosis in diabetic mice by increasing probiotic abundances, such as Odoribacter, Parasutterella, Lactobacillus, and Akkermansia, whereas decreasing Enterococcus and Aerococcus levels, which are correlated with improved liver glycogen contents and reduced insulin resistance (95, 106, 107). Dietary polysaccharides enriched the SCFA-producing strains in the intestine, including Bifidobacterium and Romboutsia, thus enhancing SCFAs concentrations, inhibiting the growth of other detrimental bacteria, and benefiting T2DM patients (104, 108). The bacteria-derived SCFAs have been shown to decrease proinflammatory cytokines and inhibit lipolysis in adipose, which is responsible for glucose disposal of T2DM patients by regulating free fatty acids in blood (109). Butyrate was reported to improve hepatic fatty acid oxidation and activate the AMPK-acetyl-CoA carboxylase pathway, thereby regulating glucose metabolism and inhibiting insulin resistance in the liver (95, 110). Meanwhile, acetate intervention in obese mice improved the expression‎ of genes involved in oxidative and glucose metabolism and glucose transporter in skeletal muscle, enhancing glucose disposal for which skeletal muscle accounts for 85% of postabsorptive blood glucose (111). Collectively, considering the high price as well as the indistinct safety property of the drug used in T2DM patients currently, polysaccharides with anti-diabetes features can be used as promising ingredients for T2DM patients.

The role of polysaccharides in non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease characterized by excess triglyceride accumulation in hepatocytes due to both increased inflow of free fatty acids and de novo hepatic lipogenesis, which affects a high proportion of the world’s population (112). Mechanistic insights into fat accumulation, subsequent hepatocyte injury, and the roles of the immune system and gut microbiome are unfolding (113). The inflow of lipids accumulated in livers mainly originates from three processes namely, de novo lipogenesis (DNL), dietary sources, and circulating esterified-fatty acids. Moreover, approximately 40% of the lipids derive from DNL and dietary sugars and fats, whereas the remaining 60% arise from lipolysis of dysfunctional adipose tissues (114, 115). Furthermore, the diacylglycerol intermediates, accumulated during the above-described process, impair hepatic insulin signaling by activating protein kinase Cε (PKCε) (116). Hepatocyte insulin resistance promotes hyperglycemia and enhances more compensatory insulin production, which prompts DNL by activation of carbohydrate-response element binding protein (ChREBP) and sterol regulatory element binding protein-1c (SREBP-1c) (113). ChREBP and SREBP-1c synergistically induce FAS and ACC expression‎, which catalyzes fatty acid synthesis, and are complexly regulated by various nuclear receptors, such as PPARα and farnesoid X receptor (FXR) (117–119) (Figure 5). Reduced hepatic fatty acid oxidation was reported among the pathophysiological changes of NAFLD (120). Accumulated fatty acids inside hepatocytes impose a strain on mitochondria, leading to the dysfunction of mitochondria and the production of ROS. The ROS and subsequent activation of Jun N-terminal kinase (JNK) in turn result in mitochondrial damage, which adds to the stress on the endoplasmic reticulum and further inhibits β oxidation of fatty acids. Moreover, hepatic inflammation, which is triggered by fatty acids, bacterial endotoxins, and ROS, exacerbates hepatocyte damage (113, 119, 121).

FIGURE 5.

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Effects of polysaccharides on the non-alcoholic fatty liver disease (NAFLD). NAFLD is characterized by increased lipid accumulation within hepatocytes, mainly through the uptake of chylomicron processed from dietary fat, circulating free fatty acids (FFA) from lipolysis of adipose tissues, and elevated de novo lipogenesis (DNL) (119, 123) (Right Panel), leading to high levels of triglycerides (TG), total cholesterol (TC), and low-density lipoprotein-cholesterol (LDL-C), as well as low levels of high-density lipoprotein-cholesterol (HDL-C) in the serum. High-fat diet induces high levels of chylomicron storage in the hepatocytes, which contributed to high FFA levels in hepatocytes. An intermediate metabolite in triglyceride synthesis, diacylglycerol (DAG), induces insulin resistance, which further enhances the lipolysis of adipose tissues and the subsequent high FFA concentrations. FA synthesis is catalyzed by acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), and their expression‎ can be induced by sterol-response-binding-protein-1c (SREBP-1c) and be inhibited by farnesoid X receptor (FXR). Under NAFLD conditions, SREBP-1c expression‎ was enhanced with enhanced DNL (Right Panel). Polysaccharide application enhanced the expression‎ of FXR and reduced DNL. Lipid accumulation within hepatocyte was limited, and FA oxidation was enhanced via improved β-oxidation and GLP-1 function to ensure healthy hepatic lipid metabolism (Left Panel).

To date, there are no effective medical interventions to completely reverse NAFLD other than diet/lifestyle modification. However, polysaccharides that target the hepatocytic DNL, inflammation of the liver, and intestinal microbiota currently have been under investigation to develop promising pharmacological therapies for the treatment of NAFLD. Ginkgo biloba leaf polysaccharides (GBLP) are mainly composed of galactose (32.21%), mannose (20.82%), glucose (9.39%), arabinose (6.71%), rhamnose (14.76%), and galacturonic acid (16.11%), which markedly reduced the serum levels of TC, triglycerides, LDL-C, and free fatty acids and significantly increased HDL-C concentrations in NAFLD rats induced by a high-fat diet. Levels of hepatic triglycerides and lipids decreased after GBLP administration in NAFLD rats (122). As increased DNL is a distinct characteristic of NAFLD (123), it is important to impede the process by using functional ingredients. Guar gum supplementation in chicken diet markedly increased SCFA concentrations, leading to increased GLP-1 levels, activation of mitogen-activated protein kinase (MAPK) pathways in hepatocytes, and subsequent suppression of lipid accumulation in hepatocytes by inhibiting SREBP1 and ACC activities (124). Chicory polysaccharides inhibited DNL through the inhibition of genes related to DNL in hepatocytes, whereas the β-oxidation and anti-inflammatory factors were enhanced in NAFLD rats (125). Based on the serum metabolomic analysis, chicory polysaccharides inhibited fatty acid biosynthesis and enhanced β oxidation of very long-chain fatty acids, which implies the probable mechanisms for alleviating NAFLD (126). Ganoderma amboinense polysaccharides enhance hepatic fat transport and mitochondrial function in NAFLD mice. MDG-1, an insulin-like β-fructan polysaccharide extracted from Ophiopogon japonicus, decreased the activity of PPARγ and upregulated the expression‎ and phosphorylation of AMPK, SREBP-1c, and ACC-1, thus improving lipid metabolism in high-fat diet mice and reducing the pathogenesis of NAFLD (127). Targeting intestinal microbiota is another strategy to prevent NAFLD. MDG significantly increased the diversity of microbiota, of which Akkermansia muciniphila was highly abundant following MDG intervention in NAFLD mice (128). However, most trials eval‎uating the function of polysaccharides were conducted in animal or cell models and further research is needed to identify whether polysaccharides have therapeutic effects on NAFLD patients, and more clinical trials should be conducted.

Limitations and perspectives

Due to the natural source and low toxicity of polysaccharides, considerable efforts have been focused on discovering polysaccharides that can be used as novel therapeutics in various diseases (129). Polysaccharides can be used as carriers to protect some labile drugs and facilitate their survival in hostile gastrointestinal tract environment (103). Interestingly, most polysaccharides exhibit positive effects on human health although they have different compositions and structures. Moreover, publications on polysaccharides are steadily increasing for various reasons. First, as polysaccharides exist in almost all living systems, it is reasonable to infer that thousands of different polysaccharides can be extracted. Furthermore, the extracted polysaccharides usually are not composed of one pure substrate but comprise a mixture of a series or different kinds of polysaccharides with diverse chain lengths and dissimilar branches or linkages. Therefore, the extraction conditions will highly influence the composition and the structure of the polysaccharides, which might induce different consequences when applied under different conditions. However, as the functional ingredients can be directly obtained from the diet, the extraction of polysaccharides from edible plant or organisms that needs considerable energy expenditure is not recommended. Furthermore, Han et al. (130) reported that the functional ingredients of N-methylserotonin from orange fibers by-products were released by intestinal microbiota, which might be disposed of in the extraction process. Therefore, additional efforts are needed to identify functional polysaccharides from non-edible dietary by-products.

Additionally, the polysaccharide-interaction-based approach to promote health is unlikely to elicit consistent effects across individuals (131). The large molecular weight and complex structure of polysaccharides limit their usage in tissues other than the intestine, as the majority of polysaccharides cannot be digested in the small intestine or absorbed by the intestinal epithelium. Most of the functions of polysaccharides in other tissues are mediated through metabolites obtained via fermentation by microbiota. However, the gut microbes varied among different individuals, which explains why the interindividual variation in the gut microbiome is usually linked to differential effects of polysaccharides on the host metabolic phenotypes. Experiments for detecting the function of polysaccharides in different health conditions are warranted, and more clinical trials should be conducted to enable the application of polysaccharides as therapeutic drugs. However, the development of more efficient and economic approaches for the preparation and modification of polysaccharides and elucidation of the structure-activity relationship remain as significant challenges.

Author contributions

LG, JW, and YG wrote the manuscript. JW had primary responsibility for final content. All authors read and approved the final manuscript.

Funding

This work was supported by the National Key Research and Development Program of China (grant number 2021YFD1300300), the National Natural Science Foundation of China (grant number 32202696), the Scientific Research Startup Project of Henan University of Technology (grant number 31401405), and the Innovative Funds Plan of Henan University of Technology (grant number 2020ZKCJ25).

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be eval‎uated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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