1Microbial Enzymology Group, Department of Applied Sciences, Ellison Building A, University of Northumbria, Newcastle Upon Tyne NE1 8ST, UK.
2APC Microbiome Ireland and School of Microbiology, University College Cork, Western Road, Cork T12 YT20, Ireland.
Correspondence to: Prof. Douwe van Sinderen, APC Microbiome Ireland and School of Microbiology, University College Cork, Western Road, Cork T12 YT20, Ireland. E-mail: email@example.com ; Dr. Jose Munoz-Munoz, Microbial Enzymology Group, Department of Applied Sciences, Ellison Building A, University of Northumbria, Ellison Building A, Newcastle Upon Tyne, NE1 8ST, UK. E-mail: Jose.Munoz@northumbria.ac.uk
© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
Elements of the human gut microbiota metabolise many host- and diet-derived, non-digestible carbohydrates (NDCs). Intestinal fermentation of NDCs salvages energy and resources for the host and generates beneficial metabolites, such as short chain fatty acids, which contribute to host health. The development of functional NDCs that support the growth and/or metabolic activity of specific beneficial gut bacteria, is desirable, but dependent on an in-depth understanding of the pathways of carbohydrate fermentation. The purpose of this review is to provide an appraisal of what is known about the roles of, and interactions between, Bacteroides and Bifidobacterium as key members involved in NDC utilisation. Bacteroides is considered an important primary degrader of complex NDCs, thereby generating oligosaccharides, which in turn can be fermented by secondary degraders. In this review, we will therefore focus on Bacteroides as an NDC-degrading specialist and Bifidobacterium as an important and purported probiotic representative of secondary degraders. We will describe cross-feeding interactions between members of these two genera. We note that there are limited studies exploring the interactions between Bacteroides and Bifidobacterium, specifically concerning β-glucan and arabinoxylan metabolism. This review therefore summarises the roles of these organisms in the breakdown of dietary fibre and the molecular mechanisms and interactions involved. Finally, it also highlights the need for further research into the phenomenon of cross-feeding between these organisms for an improved understanding of these cross-feeding mechanisms to guide the rational development of prebiotics to support host health or to prevent or combat disease associated with microbial dysbiosis.
Cross-feeding, plant fibre, Bacteroides, Bifidobacterium, gut microbiota, prebiotic
The diverse community of microorganisms that inhabit the human gastrointestinal tract make up the human gut microbiota (HGM). The HGM consists of protozoa, archaea, eukaryotes, viruses and bacteria, and these organisms have evolved to exist symbiotically within the host, exerting various beneficial roles, including but not limited to, energy retrieval, protection from invading pathogens, maintaining gut homeostasis, and modulating the immune system. The HGM is made up of three main phyla: Firmicutes, Bacteroidetes and Actinobacteria [Figure 1].
Figure 1. A diagram representing the most abundant microbial components of the human microbiota in the colonic section of the gut.
Changes in the composition of the gut microbiota can be influenced by various factors, such as type of diet, stress or environment, and may result in a so-called state of dysbiosis, an imbalance in the levels of members of the HGM that has been linked to various diseases. Depletion or overabundance of certain bacterial species throughout (part of) an individual’s lifetime may contribute to gut disorders such as inflammatory bowel disease, which includes Crohn’s disease and ulcerative colitis. In this sense, it has been shown that a gut microbiota imbalance during infancy can provoke the development of diseases (e.g., auto-immune diseases) at a later life stage. Moreover, metabolic products of the gut microbiota may promote diseases such as colorectal cancer and obesity and can affect signalling pathways within the host.
The complex structural variation of dietary polysaccharides, such as arabinoxylan, arabinogalactan or pectin, is determined by the monosaccharide composition, type of glycosidic linkage, side chains and substitutions. Due to the high degree of structural diversity found among non-digestible carbohydrates (NDCs) that are part of the human diet, efficient metabolism of dietary and host-derived polysaccharides requires an array of highly specific enzymes, that all belong to the so-called Carbohydrate active enzymes (CAZymes). Host-derived polysaccharides such as mucins or glycosaminoglycans, and diet-derived polysaccharides, which include glucans, xylans, fructans, mannans and galactans, are mostly resistant to degradation by human enzymes and therefore they form fermentable substrates for members of the gut microbiota, especially in the colon. Fermentation of dietary fibre by the gut microbiota typically produces short-chain fatty acids (SCFAs), such as acetate, propionate and butyrate, which are taken up by the host and used primarily as an energy source, thereby benefitting host health[8,9]. In addition, Bifidobacterium species produce lactate, as a major metabolic end-product, while some species generate 1,2-propanediol from fucose metabolism, and both of these metabolites can in turn be converted into SCFAs by other gut microbiota members. These metabolites affect various biological processes; in the intestinal lumen SCFAs lower the intestinal pH, which may inhibit the growth of pathogens, while this is also believed to influence the composition of the wider microbial community. In intestinal epithelial cells, butyrate regulates cell proliferation, differentiation and gene expression in a manner associated with antineoplastic transformation. Systemically, propionate and acetate activate the free fatty acid receptors GPR41 and GPR43, which are expressed by enteroendocrine cells lining the gut and are present in other tissues, including adipocytes; these receptors may help to activate anti-inflammatory signalling pathways, control metabolism, and influence appetite and mood. The ability of the resident bacteria in the gut to efficiently metabolize these otherwise indigestible glycans means that they share a symbiotic relationship with the host and with one another as these bacteria must effectively compete for carbohydrate nutrition and so have co-evolved efficient glycan-harvesting strategies.
The Gram-negative Bacteroidetes is one of the main phyla that make up the HGM. A large proportion of the genome of these organisms is dedicated to the metabolism of complex glycans, making them primary glycan degraders in the HGM. Although several Bacteroides species are known to degrade a variety of distinct polysaccharides, there is not a single known species capable of metabolising all main dietary, complex glycans, such as starch, pectin, xylan or beta-glucan. The degradation of such complex carbohydrates is performed by CAZymes, whose encoding genes are arranged into clusters known as polysaccharide utilisation loci (PULs). These PULs encode, in addition to the above mentioned CAZymes [represented by glycoside hydrolases (GHs), polysaccharide lyases and carbohydrate esterases], various other proteins involved in glycan degradation, including cell surface glycan-binding proteins, TonB-dependent transporters, and sensors, which regulate PUL transcription. For example, the first described PUL was the starch utilisation system (Sus-system) of Bacteroides thetaiotaomicron VPI-5182, which has been extensively studied. The cell surface-associated proteins SusE and SusF bind the polysaccharide substrate, thereby facilitating the initial starch degradation by SusG - an amylase enzyme, which is also located at the bacterial cell surface, and which hydrolyses the large polymeric substrate into smaller oligosaccharides. These oligosaccharides are then transported into the periplasmic compartment by the SusC/SusD complex (a TonB-dependent transporter), where they are further degraded into monosaccharides by SusA and SusB glycosidases [Figure 2].
Figure 2. (A) A schematic overview of the PUL required for starch utilisation (Sus) in B. thetaiotaomicron VPI-5182. The substrate is bound by lipoproteins at the cell surface, where it is initially degraded to oligosaccharides and then transported to the periplasm, where it is further hydrolysed to monosaccharides which can then be transported into the cytoplasm of the cell. (B) Genomic content of B. thetaiotaomicron VPI-5182 PUL in its action on starch. PUL: Polysaccharide utilisation loci.
Firmicutes and Actinobacteria are the other two main phyla that are resident in the human gut. These phyla represent Gram-positive bacteria that possess different mechanisms for glycan degradation. Gram-positive PULs (gpPULs) have a similar gene content to the PUL systems present in Bacteroidetes. However, gpPULs are devoid of the SusC/D-encoding gene pair that characterises an archetypical PUL. The gpPULs encode proteins such as transporters (commonly ABC-type transporters), regulatory proteins (typically LacI-type regulators) and glycan-degrading enzymes (mostly GHs), and large glycans (i.e., those that have a DP of > 6-7 monosaccharidic moieties) must be degraded by extracellular (or cell envelope-bound) glycoside hydrolases. The resulting oligosaccharides are then typically bound by solute binding proteins associated with an ABC uptake system which internalizes them to be further degraded into monosaccharides.
In the HGM, the phylum Actinobacteria is largely represented by the Bifidobacterium genus. Members of this genus mainly produce lactate, acetate and formate (and sometimes 1,2-propanediol) as products of sugar fermentation in the gut. Analysis of the genomes of Bifidobacterium longum subspecies infantis and Bifidobacterium bifidum show that they encode glycosyl hydrolases that are utilised in the degradation of human milk oligosaccharides. Bifidobacterium species, however, typically degrade glycans with a lower degree of polymerisation than those utilized by Bacteroidetes members.
As mentioned above, Bifidobacterium species are generally able to metabolize a range of oligomeric and rather simple carbohydrates, commonly being unable to metabolise more complex polysaccharides that require extracellular GHs. Studies have reported evidence of cross-feeding behaviour between members of the Bifidobacterium genus with other organisms, thereby allowing the complete metabolism of certain complex glycans. An example of this is the interspecies cross-feeding relationship between Bifidobacterium bifidum and Bifidobacterium breve when co-cultured on sialyllactose. This study showed how Bi. breve was able to cross feed on sialic acid, the product of 3’-sialyllactose degradation by Bi. bifidum. Bifidobacterium species have also been shown to produce metabolites, such as 1,2-propanediol, that can be used by other HGM members, e.g., Lactobacillus spp. or Eubacterium hallii, for cross-feeding purposes[20,21].
This review will focus on the molecular mechanisms underpinning cross-feeding interactions between members of Bacteroides and Bifidobacterium pertinent to the metabolism of dietary glycans, such as arabinoxylans. We selected these two genera because they are extensively studied as primary and secondary degraders of these glycans. Members of the genus Bacteroides have been shown to be glycan generalists that metabolize complex polysaccharides, generating extracellular oligosaccharides, which may be shared with other microbial members in the gut, such as particular Bifidobacterium species. The latter bacteria have been shown to generally act as specialists in the metabolism of oligosaccharides rather than complex intact polysaccharides. In addition, as we stated above, bifidobacteria are considered to represent beneficial microbes supporting human health. Arabinoxylans are present in commonly consumed cereals, like wheat or corn, and the cross-feeding behaviour between these two groups of bacteria demonstrates how they have co-evolved to utilise a varied range of diet and host-derived carbohydrate sources. We will explore both intra- and inter-genus interactions among members of these two genera. Although other metabolites have been shown to be involved in the cooperation or inhibition of different members of gut microbiota, such as 1,2-propanediol or methane, this review will focus on carbohydrates and their metabolic end products.
Microbial communities have evolved a balanced and dynamic network of metabolic interactions, which enable them to adapt and thrive within the human gastrointestinal tract (GIT). The competition for nutrients between members of the HGM has resulted in the evolution of ecological feeding strategies that increase the efficiency of glycan utilisation. Although there are various distinct definitions describing such interactions in literature, Smith et al. have defined bacterial metabolic cross-feeding as “an interaction between bacterial strains in which molecules resulting from the metabolism of one strain are further metabolised by another strain”. The term “microbial syntrophy” is a closely related term to cross-feeding, which describes the obligately mutualistic metabolism of microorganisms whereby processes are carried out through metabolic interactions between organisms that are mutually dependent upon one another. These syntrophic interactions can result in the metabolism of complex molecules, which would otherwise be unable to be degraded by the action of just one organism.
The ability of various Bacteroides species to utilise polysaccharides has been well documented. Initial Bacteroides processing of complex NDCs typically results in the extracellular release of polysaccharide breakdown products (PBPs) which then become available to other organisms that are unable to directly metabolise the complex NDC. Rakoff-Nahoum et al. proposed this notion in 2014 and found that various Bacteroides species are able to degrade different plant-derived polysaccharides to varying degrees, thus producing varying amounts of PBPs. Interestingly, they observed that B. ovatus ATCC 8483 and B. vulgatus ATCC 8482 released only oligosaccharide PBPs from xylan breakdown, which contradicts the findings of Salyers et al. in 1981, who previously described the production of xylose on the breakdown of xylan by these organisms. They then performed growth experiments showing that these PBPs were not universally utilised by the non-polysaccharide-utilising organisms meaning that the use is dependent upon the producer strain as well as the PBPs produced. The ability of the non-utilising strains to grow on these PBPs suggests that they possess PULs that encode CAZymes required to metabolise the breakdown products. The observation of amylopectin breakdown in extracellular zones suggests that, as a consequence of releasing PBPs by the utilising strains, GH and PL CAZymes are also secreted. Communication between Gram-negative bacteria via outer membrane vesicles (OMVs) allows for the secretion of enzymes to extracellular regions where polysaccharide degradation can take place. This was demonstrated in using western immunoblot analysis, which revealed that GH and PL enzymes were present in OMVs from B. ovatus ATCC 8483 and that their release supported the growth of B. vulgatus ATCC 8482 on inulin. This evidence is supported by a further study by Rakoff-Nahoum et al. in 2016, which found that there is a co-operation between B. ovatus ATCC 8483, as primary degrader, in the breakdown of inulin releasing two GH enzymes (BACOVA_04502 and BACOVA_04503) that are not necessary for its metabolism. It is thought that
Bifidobacterium species have also been known to interact with one another to cooperatively break down carbohydrates. The differing abilities of strains to utilise glycans have been thought to result in the evolution of cross-feeding activities between bifidobacterial strains. Studies have shown that Bifidobacterium species are able to secrete GH enzymes. It is predicted that 10.9% of the GH enzymes encoded by Bifidobacterium are extracellular, of which 24% are predicted to be of the GH43 family, which act as
In addition to cross feeding on plant-derived glycans, certain members of the Bifidobacterium genus are involved in the metabolism of host-derived glycans and human milk oligosaccharides (HMOs)[19,30]
Research has shown that Bacteroides and Bifidobacterium have a cross-feeding relationship in the utilisation of certain dietary and host-derived carbohydrates. The sharing of partially degraded oligosaccharides, intermediary molecules, and genes by lateral gene transfer, contributes to the metabolic flexibility of the HGM. In 2010, Hehemann et al., proposed that Bacteroides plebeius, a gut bacterium mainly present in the Japanese population, acquired genes from the marine bacterium Zobellia galactanivorans needed for the degradation of an algal polysaccharide, porphyran. This gene transfer was explained because seaweed is a common component of the Japanese diet, and bacteria associated with this nutrient may have been the route by which the novel CAZymes were acquired by Bacteroides plebeius. Bacteroides species often act as primary degraders of complex carbohydrates in the gut, releasing oligosaccharides that then become available for secondary degrader organisms. Such cross-feeding activities are believed to allow less dominant organisms such as Bifidobacterium to utilise glycans as a source of nutrition without becoming completely out-competed by bacterial strains that are present in the gut in much higher numbers.
An investigation into the interactions between members of the Bacteroides and Bifidobacterium genera in the utilisation of different carbon sources was carried out by Rios-Covian et al.. They cultured different combinations of two strains of Bacteroides and two strains of Bifidobacterium using exopolysaccharide, inulin or glucose as the sole carbon source. They found that Bi. longum NB677 and Bi. breve IPLA2004 are able to utilise glucose as a carbon source; however, neither grew on more complex polysaccharides. Conversely, B. thetaiotaomicron DSM 2079 and B. fragilis DSM 2151 were able to utilise all tested carbon sources. The authors found that the growth of B. thetaiotaomicron DSM 2079 on glucose was inhibited by the presence of Bi. breve IPLA2004, suggesting that the interaction between these organisms, when grown on this simple sugar, is not mutualistic. B. fragilis DSM 2151, on the other hand, was shown to increase the fitness of Bi. longum NB677. These results emphasized that the behaviour of co-cultures of different species is not universal and very much depends on the specific bacterial strain/species combination and particular carbon source.
Elsewhere Rogowski et al., 2015 showed that bifidobacterial growth on xylooligosaccharides (XOS) may be supported by Bacteroides species. Notably, Bi. adolescentis ATCC 15703 was unable to utilise xylans, although it can degrade simple XOS such as linear arabino-xylooligosaccharides. These authors showed that xylans can be divided into complex xylan, such as corn bran (CX), which contains several different linkages and distinct monosaccharides, or simple xylan, such as wheat arabinoxylan (WAX), which consists of a smaller number of different monosaccharides and linkages. WAX was degraded by B. ovatus ATCC 8483 using two PULs [Figure 3A and B], and some of the resulting breakdown products were then further metabolised by Bi. adolescentis ATCC 15703. However, this glycan sharing was not observed with CX. The authors of this study suggested that Bi. adolescentis ATCC 15703 lacked the machinery to degrade the PBPs released by B. ovatus ATCC 8483 from CX due to the complexity of these oligosaccharides. Specifically,
Figure 3. (A) A schematic representation of the glucoronoarabinoxylan utilisation system in B. ovatus ATCC 8483. The substrate is bound by lipoproteins at the cell surface where it is primarily degraded to oligosaccharides and then transported to the periplasm where it is further hydrolysed to monosaccharides which can then be transported to the cytoplasm of the cell. (B) Genomic content of
Further study into the utilisation of XOS by Bacteroides and Bifidobacterium strains in co-culture supported the findings of the previous study by Zeybek et al.. Mono and co-culture fermentation experiments were carried out with various xylans as substrate; Bi. bifidum, Bi. breve, Bi. longum subspecies infantis and Bi. longum subspecies longum were unable to utilise XOS in monoculture; however, Bifidobacterium animalis subsp. lactis was able to grow on XOS but no other xylans. In monoculture, two Bacteroides strains, B. ovatus ATCC 8483 and B. xylanisolvens XB1A, showed good growth on xylose, XOS, beechwood xylan and corncob xylan. In co-culture, in the presence of the Bacteroides strains, Bi. animalis subsp. lactis, showed growth on beechwood and corncob xylans. Bi. bifidum, Bi. breve, Bi. longum subspecies infantis and Bi. longum subspecies longum showed no growth on any of the substrates in co-culture. These results highlight the differences in xylan-type polysaccharide fermentation abilities of different bifidobacterial species as is the case in the degradation of inulin-type fructans observed by Falony et al.. The observed growth of Bi. animalis subsp. lactis, in co-culture, provides evidence for a cross feeding relationship between this species and the Bacteroides. This is likely due to the release of XOS as a PBP on the extracellular hydrolysis of xylan by the Bacteroides species. This released XOS is subsequently utilised by Bi. animalis subsp. lactis. This also provides an explanation for the lack of growth of other Bifidobacterium species in co-culture as they are unable to utilise XOS.
Cross-feeding behaviour between B. cellulosilyticus DSM 14838 and certain bifidobacterial strains was analysed previously, where interactions between the assessed strains were observed during cultivation on plant-derived Larch Wood arabinogalactan (LW-AG, Figure 4). This study demonstrated how
Figure 4. Molecular interactions between B. cellulosilyticus DSM 14838 PRL 2010 and Bi. breve UCC2003 when act on larch wood arabinogalactan. B. cellulosilyticus employs a GH43_24 on its surface to break down the complex polymer into smaller oligosaccharides releasing beta-1,3-galactobiose and beta-1,3-galactotriose and rhamnose into the medium. Bi. breve can use these galactooligosaccharides as carbon source degrading them to galactose using a specific GH2 in its cytoplasm. Galactose is later incorporated into the central catabolism of the cell.
Although no cross-feeding interactions were observed, a study by Liu et al. showed how certain Bacteroides and Bifidobacterium species are involved in the breakdown of polysaccharides in co-culture. Three polysaccharide mixtures, made up of different combinations of AX, xyloglucan, β-glucan and pectin, were used as the sole carbon source to perform co-cultivation experiments involving five different bacterial species, including B. ovatus ATCC 8483 and Bi. longum subsp. longum ATCC 15707. Size-exclusion chromatography showed that the observed degradation of the polysaccharides was carried out by B. ovatus ATCC 8483 and Bi. longum subsp. longum ATCC 15707, and the other bacterial species did not utilise these carbohydrates. Further analysis identified the release of oligosaccharides by B. ovatus ATCC 8483 on the hydrolysis of β-glucan; however, these glucooligosaccharides were not utilised by any of the other species in the co-culture. It was found that B. ovatus ATCC 8483 played a key role in the production of the SCFA succinate, which was utilised in the formation of propionate by other members of the co-culture, supporting the claim that Bacteroides species act as primary degraders of polysaccharides. This was also the case in the production of lactate by both B. ovatus ATCC 8483 and Bi. longum subsp. longum ATCC 15707, which was utilised by the other organisms. This study, along with previous studies discussed, highlights how the microorganisms in the human GIT can cooperatively interact in the breakdown of polysaccharides and benefit one another through PBPs and SCFA production as well as providing benefit to the human host.
The abilities of various Bacteroides and Bifidobacterium species to utilise different polysaccharides have been highlighted in this review. The identification of polysaccharide utilisation loci in the dominant gut phyla, Bacteroides, has helped to increase knowledge of the complex system in which glycan molecules are broken down. It has also allowed for further research into these utilisation mechanisms as well as the ongoing characterisation of carbohydrate-active enzymes that are produced by all glycan-degrading bacteria, including Bifidobacterium. Understanding of enzyme function is essential to fully understand NDC utilisation and may help us predict the production of postbiotics, either SCFA or other bioactive compounds such as vitamins, from a given substrate. Enzymology also contributes to our understanding of the interactions between bacteria in the context of the complex community that is the human gut microbiota.
In the case of Bacteroides and Bifidobacterium, there is evidence for glycan-sharing and cross feeding activities between certain members of these two genera, particularly during the breakdown of dietary fibre. As has been discussed in this review, interactions between these two genera have previously been studied. However, it is likely that many other cross-feeding activities exist that have yet to be discovered. Interaction between Bacteroides and Bifidobacterium in the breakdown of arabinoxylan has been observed in a small number of studies; however, there is little to no literature available on possible cross-feeding activities on other dietary glycans, such as β-glucan, arabinogalactan, arabinan. Future research should investigate the interaction, if any, between Bacteroides and Bifidobacterium in the metabolism of dietary β-glucan and its effect on the human host. In addition, there are numerous other gut commensals, less dominant in the human large intestine such as Lactobacillus reuteri, which can be studied for their cross-feeding activities with Bifidobacterium (either involving dietary fibres or released mon-/oligo-saccharides), but also for the conversion of metabolic end products of one species (e.g., 1,2-propanediol, lactate) into other metabolites (propionate, butyrate). The experimental proof of the conservation of polysaccharide utilisation loci involved in β-glucan degradation specifically, amongst the Bacteroides would allow us to identify the enzymes involved in the metabolism of these molecules, which would then provide a starting point to investigate whether Bifidobacterium has a role in the breakdown of this polysaccharide. Due to the extremely complex nature of the human gut microbiota as well as the complexity and variation in carbohydrate structure, much more research is required for us to fully understand the roles of each of the members of the human gut microbiota.
Writing - original draft preparation: Fernandez-Julia P
Writing - review, editing, and conceptualization: Commane DM, van Sinderen D, Munoz-Munoz J
All authors contributed to the article and approved the submitted version.Availability of data and materials
Not applicable.Financial support and sponsorship
Munoz J received financial support from an internal grant in Northumbria University. van Sinderen D is a member of APC Microbiome Ireland which received financial support from Science Foundation Ireland, through the Irish Government’s National Development Plan (SFI/12/RC/2273-P1 and SFI/12/RC/2273-P2).Conflicts of interest
All authors declared that there are no conflicts of interest.Ethical approval and consent to participate
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© The Author(s) 2022.
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