Bifidobacterium and the intestinal mucus layer
Abstract
Bifidobacterium species are integral members of the human gut microbiota and these microbes have significant interactions with the intestinal mucus layer. This review delves into Bifidobacterium-mucus dynamics, shedding light on the multifaceted nature of this relationship. We cover conserved features of Bifidobacterium-mucus interactions, such as mucus adhesion and positive regulation of goblet cell and mucus production, as well as species and strain-specific attributes of mucus degradation. For each interface, we explore the molecular mechanisms underlying these interactions and their potential implications for human health. Notably, we emphasize the ability of Bifidobacterium species to positively influence the mucus layer, shedding light on its potential as a mucin-builder and a therapeutic agent for diseases associated with disrupted mucus barriers. By elucidating the complex interplay between Bifidobacterium and intestinal mucus, we aim to contribute to a deeper understanding of the gut microbiota-host interface and pave the way for novel therapeutic strategies.
Keywords
INTRODUCTION
Intestinal mucus
The intestine is continually exposed to a multitude of luminal antigens and bacterial components. To protect itself, the intestinal epithelium harbors specialized cells known as goblet cells, which synthesize and secrete mucus. The structure of intestinal mucus is intricately designed to form a protective barrier. The primary structural component of intestinal mucus is a gel-forming glycoprotein called MUC2. MUC2 is a large, heavily glycosylated protein that forms disulfide-bonded dimers. These dimers undergo further polymerization and crosslinking, resulting in the formation of a gel-like network that constitutes the mucus layer.
In addition to the gel-forming MUC2, intestinal mucus contains a diverse array of compounds that contribute to its composition and functionality. Mucus harbors Antimicrobial Peptides (AMPs): small cationic peptides that possess antimicrobial properties. AMPs in the mucus layer help to maintain the balance of microbial populations by inhibiting the growth of pathogenic bacteria and promoting the growth of beneficial commensal bacteria. Immunoglobulin A (IgA) antibodies are also abundant in the mucus layer of the gut. They are produced by specialized immune cells called plasma cells and secreted into the mucus, where they play a crucial role in immune defense by neutralizing pathogens, preventing their adherence to the intestinal epithelium, and promoting their clearance from the gut. In addition to MUC2, goblet cells also secrete trefoil factors, a family of small peptides that contribute to the maintenance of mucosal integrity and repair by promoting epithelial cell migration, enhancing wound healing, and providing protection against injury and inflammation. Other mucus-associated proteins, such as FCGBP, metalloenzyme CLCA1, ZG16, Lypd8, glycosaminoglycans, and chitinases, contribute to the structural organization, hydration, and stability of the mucus layer[1]. These compounds play various roles in shaping the mucus layer and modulating host-microbe interactions within the gut.
The structural organization of intestinal mucus is highly dynamic, exhibiting regional variations along the gastrointestinal tract. In the small intestine, the mucus layer is thinner and less firmly attached to the epithelium, allowing for efficient absorption of nutrients. In contrast, the mucus layer in the colon is thicker and firmly adheres to the epithelial surface, serving as a physical barrier that limits direct contact between luminal contents and the epithelium. In the colon, the mucus layer is stratified, consisting of two distinct regions: the inner mucus layer and the outer mucus layer. The inner mucus layer, also known as the firmly adherent mucus layer, is in direct contact with the intestinal epithelium. It is tightly packed with MUC2, forming a dense and organized matrix that provides a protective barrier against luminal contents. The outer mucus layer, also referred to as the loose mucus layer, is less compact and acts as a reservoir for commensal bacteria and other luminal components. This outer layer is more penetrable and allows for the establishment of symbiotic interactions between the gut microbiota and the host.
One feature of mucus that makes it amenable to microbe interactions is the structure of the mucin proteins. The MUC2 protein is extensively O-glycosylated with branched oligosaccharides[2-7]. O-glycans are attached at serine and threonine residues in the MUC2 protein and consist of core structures of α- and β-linked
Bifidobacteria and mucus
Among the bacteria found in the gut microbiota, Bifidobacterium species are known to reside within the intestinal mucus layer[8-14] and exert multiple beneficial effects on the host[15-20]. Bifidobacteria are Gram-positive anaerobic bacteria from the phylum Actinobacteria that can have a rod or a distinctive bifid (i.e., Y) shape. There are currently 55 recognized species and subspecies of Bifidobacterium[21-23]. These species can be grouped into seven phylogenetic clusters: B. longum, B. adolescentis, B. pseudolongum, B. boum,
Bifidobacteria are predominant in the healthy breast-fed infant gut due to the presence of human milk oligosaccharides (HMOs), which these bacteria are adept at utilizing[24-27]. Studies have suggested that Bifidobacterium species make up ~80% of a breast-fed infant gut microbiota[28-32]. The benefits of Bifidobacterium strains are especially pronounced in early life, encompassing epithelial maturation, immune cell activation, and gut-brain-axis crosstalk[33-39]. Upon the introduction of solid food and weaning, the level of intestinal bifidobacteria continually decreases until adulthood, at which point bifidobacteria are maintained at a relative abundance of about ~10% throughout adult life[31,40-42]. In the elderly, the level of bifidobacteria further diminishes to about 0%-5% relative abundance[42]. This reduction in bifidobacteria levels in the elderly has been linked to age-related alterations in lifestyle and environment. Interestingly, this decline in Bifidobacterium abundance coincides with a simultaneous decrease in the thickness of intestinal mucus and an increase in its permeability[43-45]. It remains uncertain whether there is a direct link between decreased Bifidobacterium and decreased mucus, but this interesting observation suggests a relationship. Independent of age, Bifidobacterium species can be found in both the small intestine and colon, although they exhibit a higher abundance in the colon. Several Bifidobacterium species have been observed to interact with intestinal mucus, colonize the mucus layer, consume mucus glycans, and exert strain-specific modulatory effects on the mucus layer. This review covers the existing literature for the following Bifidobacterium-mucus interactions: (1) mucus adhesion; (2) mucin glycan degradation; (3) positive modulation of goblet cell cells; (4) goblet cell retention during inflammation; and (5) suppression of pro-inflammatory cytokines and production of anti-inflammatory IL-10.
MUCUS ADHESION BY BIFIDOBACTERIUM SPECIES
Multiple studies have demonstrated the ability of Bifidobacterium species to adhere to mucus [Table 1].
Literature review of mucus adhering Bifidobacterium species and strains
Bifidobacterium species | Mucus type | Ref. |
B. animalis subsp. Bb12 | Human stool mucus | [41] |
Bifidobacterium 420 | ||
Bifidobacterium BF1100 | ||
Bifidobacterium 913 | ||
B. adolescentis JCMI275T | Human stool mucus | [46] |
B. adolescentis JCM7042 | ||
B. adolescentis JCM7046 | ||
B. angulatum JCM7096T | ||
B. animalis JCM 1190T | ||
B. animalis JCM 1253 | ||
B. animalis JCM 7117 | ||
B. animalis JCM 7124 | ||
B. bifidum JCM 1254T | ||
B. bifidum JCM 1255 | ||
B. bifidum JCM 7004 | ||
B. breve JCM1192T | ||
B. breve JCM7016 | ||
B. catenulatum ATCC 27675 | ||
B. catenulatum JCM 7131T | ||
B. infantis JCM 1210 | ||
B. infantis JCM 1222T | ||
B. infantis JCM 1272 | ||
B. animalis subsp. BbI2 | ||
B. lactis JCM 10140T | ||
B. longum JCM 127F | ||
B. longum JCM 7052 | ||
B. longum JCM 7054 | ||
B. pseudocatenulatum JCM 1200T | ||
B. animalis sbusp. lactis Bb12 | Human stool mucus | [47] |
B. adolescentis JCM 2701T | Human stool mucus | [48] |
B. angulatum ATCC 27678 T | ||
B. longum subsp. infantis JCM 1222 T | ||
B. pseudocatenulatum JCM 1200 T | ||
B. bifidum JCM 1255 T | ||
B. breve JCM 1192 T | ||
B. catenulatum JCM 1194 T | ||
B. longum subsp. longum JCM 1217 T | ||
B. animalis subsp. lactis Bb12 | ||
B. bifidum TMC3115 | ||
B. bifidum TMC3103 | ||
B. bifidum TMC3104 | ||
B. bifidum TMC3108 | ||
B. bifidum TMC3110 | ||
B. bifidum TMC3112 | ||
B. bifidum TMC3116 | ||
B. bifidum TMC3119 | ||
B. bifidum TMC3120 | ||
B. bifidum TMC3121 | ||
B. bifidum TMC3122 | ||
B. animalis subsp. lactis Bb12 | Human stool mucus | [49] |
B. lactis Bb12 | Human stool mucus | [50] |
B. lactis Bb12 | Human stool mucus | [51] |
B. longum BIF9s | Colonic tissue mucus | [52] |
B. longum BIF12s | ||
B. longum BIF13s | ||
B. catenulatum BIF31s | ||
B. breve 99 (DSM 13692) | Colonic tissue mucus | [54] |
B. lactis Bb12 (DSM 10140) | ||
B. breve 99 (DSM 13692) | Colonic tissue mucus | [55] |
B. bifidum M6 | Colonic tissue mucus | [56] |
B. bifidum A1 | ||
B. infantis BIR-0304 | Colonic tissue mucus | [57] |
B. infantis BIR-0307 | ||
B. infantis BIR-0312 | ||
B. catenulatum BIR-0324 | ||
B. bifidum BIR-0326 | ||
B. infantis BIR-0349 | ||
B. breve BIR-0350 | ||
B. longum BIR-BPD1 | ||
B. longum BIR-BPD3 | ||
B. longum BIR-BPG1 | ||
B. longum BIR-BPG4 | ||
B. bifidum M6 | Colonic tissue mucus | [58] |
B. bifidum M6dCo | ||
B. bifidum PBT | ||
B. bifidum PBTdOx | ||
B. animalis IPLA 658 | ||
B. animalis 658dOx | ||
B. bifidum A8 | ||
B. bifidum A8dOx | ||
B. bifidum A1 | ||
B. bifidum A1dOx | ||
B. longum NIZO B667 | ||
B. longum B667dCo | ||
B. animalis IPLA 4549 | ||
B. animalis 4549dCo | ||
B. animalis 4549dOx | ||
B. bifidum DSM20456 | Colonic tissue mucus, Caco-2 cells | [53] |
B. bifidum MIMBb75 | ||
B. animalis subsp. lactis Bb12 | Porcine intestinal mucus | [71] |
B. dentium ATCC 27678 | Germ-free mouse cecal mucus, HT29-MTX cells | [18] |
B. longum subsp. infantis ATCC 15697 | ||
B. longum subsp. longum ATCC 55813 | ||
B. breve ATCC 15698 | ||
B. longum BIF 53 | Porcine stomach mucus | [70] |
B. lactis Bb 12 | ||
B. longum BB 536 | ||
B. longum NCC 2705 | ||
B. longum W 11 | ||
B. longum SP 07/3 | ||
B. longum NCIMB 8809 | ||
B. longum ATCC 15707 | ||
B. longum BIR 324 | ||
B. longum BIF 53 | ||
B. animalis subsp. lactis IPLA4549 | HT29-MTX cells | [60] |
B. animalis subsp. lactis 4549dOx | ||
B. animalis subsp. lactis A1 | ||
B. animalis subsp. lactis A1dOx | ||
B. animalis subsp. lactis A1dOx-R1 | ||
B. longum NB667 | ||
B. longum 667Co | ||
B. animalis subsp. lactis CCDM 374 | Caco-2 cells, HT29-MTX cells | [61] |
B. breve 4 | Caco-2 cells, HT29-MTX cells | [62] |
B. breve 5 | ||
B. breve 25 | ||
B. longum 4 | ||
B. longum 16 | ||
B. longum 18 | ||
B. longum 22 | ||
B. bifidum 8 | ||
B. bifidum 7 | ||
B. infantis 1 | ||
B. animalis IATA-A2 | Caco-2 cells, HT29-MTX cells | [64] |
B. bifidum IATA-ES2 | ||
Bifidobacterium animalis subsp. lactis Bb12 | ||
B. bifidum DSM 20082 | Caco-2 cells, HT29-MTX cells; rat cecal mucus | [65] |
B. breve DSM 20213 | ||
B. longum DSM 20219 | ||
B. animalis DSM 20104 | ||
B. longum CSCC 5089 | Caco-2 cells | [63] |
B. bifidum DNG6 | Caco-2 cells | [66] |
B. lactis NCC362 | Caco-2 cells | [67] |
B. longum NCC 490 | ||
B. adolescentis NCC251 | ||
B. bifidum NCC 189 | ||
B. breve MB226 | ||
B. bifidum S16 | ||
B. bifidum S17 | ||
B. infantis E18 | ||
B. adolescentis ATCC 15706 | Caco-2 cells | [68] |
B. adolescentis TMC 2704 | ||
B. adolescentis TMC 2705 | ||
B. animalis TMC 5101 | ||
B. infantis TMC 2906 | ||
B. infantis TMC 2908 | ||
B. longum TMC 2607 | ||
B. longum TMC 2608 | ||
B. longum TMC 2609 | ||
B. bifidum TMC 3101 | ||
B. bifidum TMC 3108 | ||
B. bifidum TMC 3115 | ||
B. bifidum TMC 3116 | ||
B. bifidum TMC 3117 | ||
B. breve TMC 3207 | ||
B. breve TMC 3217 | ||
B. breve TMC 3218 | ||
B. breve TMC 3219 | ||
B. infantis ATCC 15697 | Glycan array | [86] |
Interestingly, Bifidobacterium animalis subsp. lactis and unclassified Bifidobacterium species were shown to adhere well to mucus isolated from the feces of newborns, 2-month-old infants, 6-month-old infants, and adults (25 to 52 years), but had substantially lower adhesion to mucus derived from the feces of elderly individuals (74 to 93 years)[41]. It was also found that B. animalis subsp. lactis had diminished adhesion to mucus isolated during episodes of diarrhea[50]. These findings point to the integrity of mucus for adhesion.
In addition to human stool and tissue derived mucus, B. dentium, B. bifidum, B. adolescentis, B. breve,
The binding of Bifidobacterium to intestinal mucus is regulated by diverse adhesins [Figure 1]. Bifidobacterium species employ pili, surface adhesion proteins, moonlighting proteins, and other surface-anchored proteins to adhere to intestinal mucus [Table 2][73-75]. For example, B. bifidum has several known mucin-binding partners. B. bifidum possesses two sortase-dependent pili that promote bacterial coaggregation and bind to mucus-producing Caco-2 cells[76]. Another study found that B. bifidum produces an extracellular sialidase that mediates adhesion to mucus via a conserved sialidase domain peptide that interacts with mucin carbohydrates[77]. Similar to B. bifidum, B. longum also expresses multiple mucus-binding proteins. B. bifidum and B. longum both have been shown to express extracellular transaldolases that function as an adhesin that is capable of binding mucin[78,79]. A recent study found that B. longum harbors 21 putative adhesion proteins[75]. Using an overexpression system in a heterologous host, it was found that FimM exhibited significant adhesion to mucus-producing LS174T goblet cells, and it was further found that mucin was one of the major adhesion receptors for the FimM protein[75]. Homologs of FimM were also identified in B. bifidum, B. gallinarum, and 23 other B. longum strains by sequence similarity analysis. Another study found that B. longum harbors a protein with high homology to type 2 glycoprotein-binding fimbriae that may mediate mucus adhesion[80]. B. longum additionally produces the moonlighting proteins EF-Tu and enolase, which indirectly promote adhesion to mucus-producing Caco-2 cells through interactions with host plasminogen[81]. Likewise, enolase plays the role of an adhesion factor in B. lactis Bl07[82], and GroEL is another moonlighting protein that has been indicated as an adhesion factor for
Figure 1. Schematic outlining examples of the various mechanisms by which Bifidobacterium adhere to mucus. (A) Extracellular vesicles released by Bifidobacterium can bind to mucus, and in turn, this binding can inhibit pathogen colonization; (B) Bifidobacterium possess a wide array of pili and fimbriae, including FimM and its homologs, type 2 fimbriae, and type IVb pili, which bind to mucus; (C) Other proteins such as F1SBPs (family-1 binding proteins), BL0155 (a type of ABC transport transmembrane protein), GroEL (a heat shock protein), and EF-Tu (Elongation Factor Tu) are involved in mucus binding; (D) Endo-α-N-acetylgalactosaminidase, transaldolase, sialidase, and enolase are enzymes that facilitate mucus adhesion.
Literature review of mucus and cell binding adhesins in Bifidobacterium species and strains
Bifidobacterium species | Adhesin | Ref. |
B. bifidum PRL2010 | Sortase-dependent pili | [76] |
B. bifidum ATCC 15696 | Extracellular sialidase | [77] |
B. bifidum A8 | Extracellular transaldolase | [79] |
B. longum NCC2705 | Extracellular transaldolase | [78] |
B. longum BBMN68 | Putative adhesion proteins | [75] |
B. longum BBMN68 | FimM | [75] |
B. bifidum 85B | FimM homologs | [75] |
B. gallinarum CACC 514 | FimM homologs | [75] |
B. longum NCC2705 | Type 2 glycoprotein-binding fimbriae homolog | [80] |
B. longum NCC2705 | EF-Tu | [81] |
B. longum NCC2705 | Enolase | [81] |
B. animalis subsp. lactis Bl07 | Enolase | [82] |
B. animalis subsp. lactis KLDS 2.0603 | GroEL | [83] |
B. longum VMKB44 | Blap-1 | [84] |
B. longum JCM1217 | Endo-α-N-acetylgalactosaminidase | [85] |
B. longum subsp. infantis ATCC 15697 | Family 1 of solute binding proteins (F1SBPs) | [86,87] |
B. breve UCC2003 | Type IVb pilus-type proteins | [82,83,88] |
B. longum NCC2705 | Extracellular vesicles | [89] |
As another example of the various adhesins employed by Bifidobacterium species, B. longum was found to possess a 26-amino-acid peptide called Blap-1 that mediates adhesion to HT-29 cells. Interestingly, genomic analysis revealed that Blap-1 was an identical match to a site in a large extracellular transmembrane protein encoded by the BL0155 open reading frame of B. longum NCC2705[84]. Additionally, B. longum possesses an endo-α-N-acetylgalactosaminidase that contains binding sites specific to the protein core of mucin glycoproteins[85]. Furthermore, the genome of B. longum subsp. infantis encodes several family 1 of solute binding proteins (F1SBPs), and these proteins were shown to bind and transport mucin oligosaccharides[86,87]. In addition to B. bifidum and B. longum, B. breve has type IVb pilus-type proteins that facilitate colonization in the host gut[82,83,88]. Interestingly, it has also been shown that B. longum produces extracellular vesicles that export mucin-binding cytoplasmic proteins, and these proteins promote the adhesion of B. longum to mucus[89]. It has also been recently shown that the polyamine Spermidine significantly increased the adhesion of B. bifidum Bb12 to mucus isolated from healthy infants[90], suggesting that secreted factors could also influence the adherence of Bifidobacterium to mucus. Together, these studies indicate that although multiple Bifidobacterium species can bind to mucus, the mechanisms of adhesion appear to be diverse, even among strains of the same species.
The structure of mucus likely dictates the consequences of mucus binding for Bifidobacterium species. In the small intestine, the mucus is loose and not attached to the epithelium. As a result, mucus adhesion likely does not promote persistent colonization of the small intestine. In contrast, in the colon, the mucus is highly organized and adhesion to colonic mucus most likely allows Bifidobacterium species to persist and colonize the colon. The adhesion of Bifidobacterium to colonic mucus is also thought to increase the transit time of the bacteria in the gut, thereby maximizing its beneficial properties[91,92]. It has also been shown that colonization of the mucus layer by Bifidobacterium species positively regulates goblet cells. These interactions are all viewed as beneficial for the host. As a result of these positive attributes, the ability to adhere to human intestinal mucus is a commonly employed criterion for the selection of probiotic organisms[75,93,94].
The binding of Bifidobacterium to intestinal mucus extends beyond a mere physical attachment; it serves as a gateway for host-microbe crosstalk. By positioning themselves within the mucus, Bifidobacterium strains gain proximity to host cells, enabling the effective delivery of health-promoting molecules, metabolites, and signaling compounds[18,95,96]. Furthermore, the presence of Bifidobacterium within the mucus layer influences the spatial organization and composition of the gut microbiota, thereby impacting the overall microbial ecosystem. In several studies, the ability to bind to the mucus layer allowed Bifidobacterium species to create a niche and exclude pathogens[54,56,57,62,64,92,97]. One study found that a probiotic containing Bifidobacterium could inhibit pathogenic colonization of Escherichia coli, and this protective effect was dependent on MUC2 expression by Caco-2 cells[98]. This data suggests that mucus adhesion is critical for excluding pathogens. In addition to excluding pathogens, Bifidobacterium species likely have synergistic interactions with other commensal microbes in the mucus layer. Bifidobacterium has been shown to cross-fed commensal Eubacterium rectale[99], E. hallii[100,101], and Faecalibacterium prausnitzii[102]. In each of these scenarios, Bifidobacterium-commensal co-cultures generated elevated levels of butyrate, a beneficial short-chain fatty acid, compared to the mono-cultures. The literature clearly indicates that Bifidobacterium species readily bind to mucus, and this mucus adhesion likely sets the stage for a range of beneficial effects on both the host and the gut microbial community.
MUCUS DEGRADATION BY BIFIDOBACTERIUM SPECIES
In addition to serving as a binding site for bacteria, mucus can act as a nutrient source. The mucin protein is heavily O-glycosylated and has multiple structures of repeating α- and β-linked N-acetyl-galactosamine (GalNAc), N-acetyl-glucosamine (GlcNAc), and galactose (Gal) residues, terminated with α-linked fucose (Fuc), and sialic acid (Neu5Ac) residues[103]. Mucus-degrading bacteria harbor specific glycosyl hydrolases (GHs) that enzymatically degrade mucin glycans[3,4,103-106]. After cleavage, the released glycan oligosaccharides can feed the bacteria or other microbes in the vicinity[3,107]. In order to degrade mucin glycans, intestinal bacteria must possess GH33 sialidases (also known as neuraminidases), which cleave terminal sialic acid residues. For efficient glycan cleavage, bacteria can also generate GH29 or GH95 to remove fucose residues. Once the terminal sugars are removed, the underlying GalNAc, GlcNAc, and galactose residues can be removed. Bacteria can have GH101 or GH129 to remove GalNAc, GH84, GH85, GH89, or GH20 to remove GlcNAc, or GH2, GH35, GH42, and GH98 to remove galactose residues. Some bacteria also encode for GH16, endo-acting O-glycanases that remove larger glycan structures. A recent genome analysis confirmed that B. bifidum harbored the largest repertoire of mucus-degrading GHs among the Bifidobacterium species[103]. All B. bifidum genomes had GH33, GH29, GH95, GH20, GH2, GH42, GH101, GH129, GH89, and GH84[103], suggesting that this species was capable of cleaving sialic acid, fucose, GalNAc, GlcNAc, and galactose from mucus glycans. B. breve, B. longum, and B. scardovii were also found to possess multiple mucus-associated GHs. This finding is consistent with other genome studies and in vitro studies, which report that B. bifidum, B. longum, and B. breve can degrade mucus[19,100,103,108-112]. In contrast, B. adolescentis,
Mucin degradation is considered to be a normal process of intestinal mucus turn-over[116] and begins within the first few months of life[117,118]. Infants are commonly colonized with mucin-degrading B. bifidum,
In addition to being found in infants, mucus-degrading Bifidobacterium species are present in adults and have been linked to the suppression of detrimental mucus degradation. One example of excessive mucus degradation that may be prevented by Bifidobacteria is in the context of a Westernized diet, a diet characterized by low fiber but high fat and sugar. It has been demonstrated in mice harboring defined microbial communities that consuming a Westernized diet leads to an expansion of mucin-degrading bacteria such as Akkermansia muciniphila and Bacteroides caccae, and this shift enables the bacterial community to target the mucus layer for digestion in lieu of dietary fibers[122]. In a model with complex native gut microbiota, mice fed a Westernized diet similarly exhibited an expansion of Akkermansia and a corresponding decrease in Bifidobacterium species[123] and increased susceptibility to pathogens and inflammation. In this setting, the addition of B. longum NCC 2705 or the prebiotic inulin resulted in elevated levels of endogenous Bifidobacterium species, reduced mucus degradation, and restored the mucus barrier. In a similar vein, B. bifidum G9-1 was shown to protect against mucus degradation by
MUCUS MODULATION BY BIFIDOBACTERIUM SPECIES
Modulation of mucus by Bifidobacteria in homeostasis
Although some bifidobacteria have mucolytic properties, they generally have an overall positive net effect in regulating intestinal mucus. Several studies have found that Bifidobacterium species elevate mucus levels in vitro and in vivo [Table 3 and Figure 2]. In vitro, B. infantis, B. breve, B. longum and a probiotic cocktail containing these microbes and others (VSL#3) was found to stimulate mucus secretion in human mucus-producing LS174T cells[126]. The probiotic cocktail was also found to increase MUC2 expression and secretion in rat colonic loops[126]. In another study, B. dentium was reported to increase MUC2 in human mucus-producing T84 cells[18]. Short-chain fatty acids (SCFA) have been demonstrated to increase MUC2 expression[127], and Bifidobacterium species are known to produce high levels of SCFA acetate. The application of acetate was likewise able to increase MUC2 gene and protein levels in T84 cells[18]. In vivo,
Figure 2. Representative diagram of Bifidobacterium-goblet cell interactions. (A) Bifidobacterium species can generate acetate, which can elevate MUC2 expression and protein; (B) Bifidobacterium species can also generate varying levels of GABA, which can activate autophagy-driven expulsion of mucus. Through these mechanisms, Bifidobacteria are speculated to positively regulate goblet cells. GABA: B. dentium-generated gamma-aminobutyric acid.
Literature review of the positive effects of Bifidobacteria on mucus expression, mucin levels and mucus expulsion
Bifidobacterium species | Finding | Experimental model | Ref. |
B. infantis | Increased mucus secretion | LS174T cells | [126] |
B. breve | Increased mucus secretion | LS174T cells | [126] |
B. longum | Increased mucus secretion | LS174T cells | [126] |
VSL#3 | Increased mucus secretion | LS174T cells | [126] |
VSL#3 | Increased MUC2 expression and secretion | Rat colonic loops | [126] |
B. dentium ATCC 27678 | Increased mucus expression and secretion | T84 cells | [18] |
B. dentium ATCC 27678 | Increased MUC2 expression and mucus levels | Adult gnotobiotic mice | [18] |
B. bifidum FPLC AA22 | Increased mucus levels | Adult gnotobiotic mice | [129] |
B. longum FPLC 117 | Increased mucus levels | Adult gnotobiotic mice | [128] |
B. breve UCC2003 | Increased MUC2 expression | Neonatal conventional mice | [35] |
B. breve (probiotic cocktail) | Increased goblet cells per crypt and increased mucus levels | Adult conventional mice | [130] |
Modulation of mucus by Bifidobacteria in inflammation and infectious diseases
There is a wide array of data that demonstrate the substantial benefits of Bifidobacterium in the context of disease. Colitis is one of the most frequently investigated intestinal diseases, and a variety of Bifidobacterium species have exhibited the ability to alleviate major complications of colitis. In general, Bifidobacterium species have been shown to (1) limit inflammation-associated goblet cell and mucus depletion and MUC2 and (2) reduce pro-inflammatory cytokines [Figure 3, Tables 4 and 5].
Figure 3. Diagram outlining the major beneficial effects, especially in improving goblet cell function and in reducing inflammation, per Bifidobacterium species in disease models. GABA: B. dentium-generated gamma-aminobutyric acid; NEC: necrotizing enterocolitis; SCFAs: short-chain fatty acids.
Literature review of strain-specific effects of Bifidobacterium species on mucus modulation in the context of inflammation or infectious disease
Bifidobacterium species | Finding | Intestinal site | Experimental model | Ref. |
B. bifidum FL-276.1 | Increased MUC2, improved mucus, reduce colitis | Colon | DSS-colitis | [166] |
B. bifidum FL-228.1 | Increased MUC2, improved mucus, reduce colitis | Colon | DSS-colitis | [166] |
B. bifidum BGN4 | Improved mucus, reduce colitis | Colon | DSS-colitis | [168] |
B. longum subsp. longum YS108R | Increased MUC2, improved mucus, reduce colitis | Colon | DSS-colitis | [169] |
B. longum Bif10 | Increased MUC2, improved mucus, reduce colitis | Colon | DSS-colitis | [171] |
B. breve Bif11 | Increased MUC2, improved mucus, reduce colitis | Colon | DSS-colitis | [171] |
B. breve CBT BR3 | Improved mucus, reduce colitis | Colon | DSS-colitis | [170] |
B. animalis subsp. lactis A6 | Improved mucus, reduce colitis | Colon | DSS-colitis | [167] |
B. infantis GMCC0460.1 | Improved mucus, reduce colitis | Colon | DSS-colitis | [172] |
B. infantis 2017012 | Improved mucus, reduce colitis | Colon | DSS-colitis | [176] |
B. infantis unclassified strain | Improved mucus, reduce colitis | Colon | DSS-colitis | [176] |
B. breve H4-2 | Improved mucus, reduce colitis | Colon | DSS-colitis | [174] |
B. breve H9-3 | Improved mucus, reduce colitis | Colon | DSS-colitis | [174] |
B. lactis BL-99 | Improved mucus, reduce colitis | Colon | Zebrafish colitis model | [177] |
B. dentium ATCC 27678 | Increased MUC2, improved mucus, reduce colitis | Colon | TNBS-colitis | [96] |
B. infantis unclassified strain | Improved mucus, reduce colitis | Colon | TNBS-colitis | [178] |
B. longum Bar 33 | Improved mucus, reduce colitis | Colon | TNBS-colitis | [176] |
B. animalis subsp. lactis CNCM-I2494 | Improved mucus, reduce colitis | Colon | DNBS-colitis | [179] |
B. bifidum E3 | Increased MUC2, improved mucus | Small intestine | LPS-induced injury | [180] |
B. infantis E4 | Increased MUC2, improved mucus | Small intestine | LPS-induced injury | [180] |
B. lactis BB12 | Increased MUC2, improved mucus | Small intestine | LPS-induced injury | [180] |
B. bifidum OLB637 | Increased mucin expression | Small intestine | Rat model of NEC | [181] |
B. bifidum G9-1 | Increased MUC2, improved mucus | Small intestine | Rotavirus mouse model | [185] |
B. infantis PCM | Improved mucus | Small intestine | Cronobacter sakazakii mouse model | [186] |
Literature review of strain-specific effects of Bifidobacterium species on immune modulation in the context of inflammation
Bifidobacterium species | Finding | Body site | Experimental model | Ref. |
B. infantis | Reduced pro-inflammatory cytokines & increased IL-10 | Colon | TNBS colitis | [176] |
B. breve CBT BR3 | Reduced pro-inflammatory cytokines & increased IL-10 | Colon | TNBS colitis | [170] |
B. longum and B. animalis (probiotic cocktail) | Reduced pro-inflammatory cytokines & increased IL-10 | Colon | TNBS colitis | [178] |
B. dentium ATCC 27678 | Reduced pro-inflammatory cytokines & increased IL-10 | Serum and colon | TNBS colitis | [96] |
Bifidobacterium animalis subspecies lactis CNCM-I2494 | Reduced pro-inflammatory cytokines & increased IL-10 | Colon and T cells | DNBS colitis | [179] |
B. longum Bif10 | Reduced pro-inflammatory cytokines | Serum and colon | DSS colitis | [171] |
B. breve Bif11 | Reduced pro-inflammatory cytokines | Serum and colon | DSS colitis | [171] |
B. longum Bif16 | Reduced pro-inflammatory cytokines | Serum and colon | DSS colitis | [171] |
Colitis-inducing compounds are known to activate ER stress[131-134], and ER stress has been linked to intestinal inflammation in multiple animal models[135-139]. Goblet cells are particularly sensitive to ER stress since producing and folding MUC2 is a complex process[140,141]. It has been speculated that modulation of goblet cell ER stress by Bifidobacterium species may represent a key pathway by which bifidobacteria promote intestinal health. In mucus-producing Caco-2 cells, the application of live B. breve YIT 12272 and B. adolescentis YIT 4011T alleviated tunicamycin-induced ER stress[142]. In another study using mucus-producing T84 cells, it was shown that B. dentium ATCC 27678-secreted metabolites could also suppress tunicamycin- or thapsigarin-induced ER stress[96]. Analysis of the B. dentium metabolites revealed that this strain generated substantial levels of γ-glutamylcysteine, a compound that can be converted into the powerful antioxidant glutathione and suppress oxidative and ER stress[131,133,143-147]. B. dentium metabolites harboring γ-glutamylcysteine and application of commmerically available γ-glutamylcysteine both elevated glutathione, suppressed inflammatory NF-κB activation, reduced IL-8 secretion, and attenuated the induction of the unfolded protein response (UPR) genes GRP78, CHOP, and sXBP1 in T84 cells and TNBS-treated mice[96]. These data suggest that Bifidobacterium species can reduce goblet cell ER stress.
When goblet cells undergo ER stress, they are unable to adequately synthesize and secrete MUC2, leading to a reduction in goblet cell number and a thinning of the intestinal mucus layer. Several animal models have shown that goblet cell ER stress or loss of mucus leads to intestinal inflammation (Winnie, MUC2-/-,
Several studies have found that Bifidobacterium species can limit the reduction of goblet cells and improve the mucus barrier in the setting of chemically induced intestinal inflammation [Table 4]. For example,
Bifidobacterium species also have positive roles in modulating mucus in other inflammatory models. For example, B. bifidum, B. infantis, and B. lactis increased MUC2 in the small intestine during LPS-induced injury[180]. In a rat model of necrotizing enterocolitis (NEC), B. bifidum was shown to increase mucin and TFF3 expression and decrease the disease severity[181]. B. longum EVC001 and B. infantis BB-02 also decreased NEC occurrence in animals[182,183]. Even more promising is a double-blind, randomized, controlled study of very-low-birth-weight preterm infants, in which a combination of B. breve strain Yakult and
Rotavirus gastroenteritis is another disease where Bifidobacterium species have been shown to beneficially modulate the mucus layer. B. bifidum G9-1 was shown to increase MUC2, normalize mucin-positive goblet cells in the small intestine, and reduce the incidence, diarrheal scores, and intestinal damage in the supplemented group with rotavirus compared to the control group with rotavirus alone[185]. B. infantis PCM has also been shown to maintain goblet cells and reduce epithelial damage in the small intestine of mice infected with the pathogen Cronobacter sakazakii[186]. These data demonstrate that goblet cells and mucin production are also beneficially influenced by bifidobacteria in the small and large intestines in multiple inflammatory models.
Pro-inflammatory cytokines have been shown to negatively regulate goblet cells, while anti-inflammatory compounds such as IL-10 are known to alleviate ER stress and enhance goblet cell function. Another pathway by which Bifidobacterium species positively modulate goblet cells is through the modulation of intestinal cytokines [Table 5]. In TNBS-induced colitis mouse models, supplementation of B. infantis,
OVERALL EFFECTS OF BIFIDOBACTERIUM-MUCUS INTERACTIONS ON THE HOST
The literature suggests that the intestinal mucus layer plays a crucial role in the interaction of Bifidobacterium species with the host. It appears that the majority of Bifidobacterium species bind to intestinal mucus and establish a unique niche that affords them an advantageous position for their beneficial activities. Within the mucus layer, some Bifidobacterium species can degrade mucus, while others must rely on other nutrient sources. In the mucus layer, Bifidobacterium species likely perform the following functions: (1) exclude pathogens; (2) cross-fed commensal bacteria; (3) limit excessive mucus degradation; (4) secrete compounds such as acetate, which elevate MUC2 expression and increase mucus production; (5) reduce goblet cell ER stress; (6) limit inflammation- and infection-driven goblet cell loss; (7) suppress pro-inflammatory cytokines; and (8) increase anti-inflammatory pro-goblet cell IL-10.
The literature points to the capacity for Bifidobacterium species to beneficially modulate goblet cell number and function, thereby regulating the mucus layer and intestinal barrier function. This modulation of the goblet cells by Bifidobacterium is likely even more important during the setting of infection and inflammation. Through these interactions, Bifidobacterium species facilitate a dynamic interplay that contributes to gut homeostasis and overall host health.
LIMITATIONS AND GAPS IN THE FIELD
While these findings are compelling, there are still several gaps in knowledge. First, it is unclear which Bifidobacterium strains are the most effective at positively regulating goblet cell function. Very few studies have performed head-to-head comparisons of different Bifidobacterium strains and studies vary in terms of mouse strain (C57B6/J, BALBc, Swiss Webster, etc.), colonization status (mono-association, gnobotioic with defined communities, conventional, etc.), and challenge (TNBS, DSS, DNBS, LPS, infection etc.). These variables make it difficult to tease out the nuances between strains and effects. Second, the metabolites that drive goblet cell-specific attributes of Bifidobacterium are not well characterized. It is well documented that Bifidobacterium species can generate acetate and this SCFA can elevate MUC2 levels, but it is likely that other metabolites also stimulate MUC2. In addition to modulating MUC2 levels, Bifidobacterium species can influence goblet cells in other ways, such as suppressing ER stress, promoting autophagy, and stimulating mucus expulsion. Likewise, it is not clear how bifidobacteria members regulate IL-10 production, which could indirectly affect goblet cell homeostasis. These pathways need to be explored with multiple Bifidobacterium strains.
The advent of intestinal organoids is a promising new technology to address Bifidobacterium-goblet cell interactions. This model maintains segment specificity, is not immortalized, and is not cancer-derived. Importantly, intestinal organoids harbor MUC2-positive goblet cells and have been previously used to examine bacterial-host interactions, including Bifidobacterium[95,187-189]. We anticipate that many future studies will employ this model to define the mechanisms by which Bifidobacterium species regulate goblet cells and interact with intestinal mucus.
Although there are still large gaps in the field, the wealth of literature allows us to make some key observations on conserved bifidobacteria functions, such as mucus binding, suppression of inflammation-driven goblet cell depletion, and elevation of MUC2. Understanding the interaction between Bifidobacterium and the intestinal mucus layer is imperative for unraveling the mechanisms underlying their beneficial effects. With this knowledge, there is immense potential for developing targeted therapeutic interventions.
DECLARATIONS
Authors’ contributions
Drafted manuscript: Gutierrez A, Puckett B
Edited and revised manuscript: Gutierrez A, Puckett B, Engevik MA
Provided funding: Engevik MA
Availability of data and materials
Not applicable.
Financial support and sponsorship
This study was supported by the NIH K01DK123195 (MAE).
Conflicts of interest
All authors declared that there are no conflicts of interest.
Ethical approval and consent to participate
All work was carried out in accordance with the WHO Code of Ethics (Helsinki Declaration) on experiments with humans.
Consent for publication
Not applicable.
Copyright
© The Author(s) 2023.
REFERENCES
1. Song C, Chai Z, Chen S, Zhang H, Zhang X, Zhou Y. Intestinal mucus components and secretion mechanisms: what we do and do not know. Exp Mol Med 2023;55:681-91.
2. Corfield AP, Wagner SA, Clamp JR, Kriaris MS, Hoskins LC. Mucin degradation in the human colon: production of sialidase, sialate O-acetylesterase, N-acetylneuraminate lyase, arylesterase, and glycosulfatase activities by strains of fecal bacteria. Infect Immun 1992;60:3971-8.
3. Bell A, Juge N. Mucosal glycan degradation of the host by the gut microbiota. Glycobiology 2021;31:691-6.
4. Tailford LE, Crost EH, Kavanaugh D, Juge N. Mucin glycan foraging in the human gut microbiome. Front Genet 2015;6:81.
5. McGuckin MA, Lindén SK, Sutton P, Florin TH. Mucin dynamics and enteric pathogens. Nat Rev Microbiol 2011;9:265-78.
6. McDole JR, Wheeler LW, McDonald KG, et al. Goblet cells deliver luminal antigen to CD103+ dendritic cells in the small intestine. Nature 2012;483:345-9.
7. Aihara E, Engevik KA, Montrose MH. Trefoil factor peptides and gastrointestinal function. Annu Rev Physiol 2017;79:357-80.
8. Croucher SC, Houston AP, Bayliss CE, Turner RJ. Bacterial populations associated with different regions of the human colon wall. Appl Environ Microbiol 1983;45:1025-33.
9. Vasapolli R, Schütte K, Schulz C, et al. Analysis of transcriptionally active bacteria throughout the gastrointestinal tract of healthy individuals. Gastroenterology 2019;157:1081-92.e3.
10. Turroni F, Marchesi JR, Foroni E, et al. Microbiomic analysis of the bifidobacterial population in the human distal gut. ISME J 2009;3:745-51.
11. Collado MC, Donat E, Ribes-Koninckx C, Calabuig M, Sanz Y. Imbalances in faecal and duodenal Bifidobacterium species composition in active and non-active coeliac disease. BMC Microbiol 2008;8:232.
12. von Wright A, Vilpponen-salmela T, Llopis MP, et al. The survival and colonic adhesion of Bifidobacterium infantis in patients with ulcerative colitis. Int Dairy J 2002;12:197-200.
13. Ahmed S, Macfarlane GT, Fite A, McBain AJ, Gilbert P, Macfarlane S. Mucosa-associated bacterial diversity in relation to human terminal ileum and colonic biopsy samples. Appl Environ Microbiol 2007;73:7435-42.
14. Chassaing B, Gewirtz AT. Identification of inner mucus-associated bacteria by laser capture microdissection. Cell Mol Gastroenterol Hepatol 2019;7:157-60.
15. O’Callaghan A, van Sinderen D. Bifidobacteria and their role as members of the human gut microbiota. Front Microbiol 2016;7:925.
16. O’Neill I, Schofield Z, Hall LJ. Exploring the role of the microbiota member Bifidobacterium in modulating immune-linked diseases. Emerg Top Life Sci 2017;1:333-49.
17. Grimm V, Westermann C, Riedel CU. Bifidobacteria-host interactions - an update on colonisation factors. Biomed Res Int 2014;2014:960826.
18. Engevik MA, Luk B, Chang-Graham AL, et al. Bifidobacterium dentium fortifies the intestinal mucus layer via autophagy and calcium signaling pathways. mBio 2019;10:e01087-19.
19. Ruas-Madiedo P, Gueimonde M, Fernández-García M, de los Reyes-Gavilán CG, Margolles A. Mucin degradation by Bifidobacterium strains isolated from the human intestinal microbiota. Appl Environ Microbiol 2008;74:1936-40.
20. Png CW, Lindén SK, Gilshenan KS, et al. Mucolytic bacteria with increased prevalence in IBD mucosa augment in vitro utilization of mucin by other bacteria. Am J Gastroenterol 2010;105:2420-8.
21. Lugli GA, Milani C, Turroni F, et al. Comparative genomic and phylogenomic analyses of the bifidobacteriaceae family. BMC Genomics 2017;18:568.
22. Lugli GA, Milani C, Turroni F, et al. Investigation of the evolutionary development of the genus Bifidobacterium by comparative genomics. Appl Environ Microbiol 2014;80:6383-94.
23. Milani C, Turroni F, Duranti S, et al. Genomics of the genus Bifidobacterium reveals species-specific adaptation to the glycan-rich gut environment. Appl Environ Microbiol 2016;82:980-91.
24. Nuriel-Ohayon M, Neuman H, Koren O. Microbial changes during pregnancy, birth, and infancy. Front Microbiol 2016;7:1031.
25. Makino H, Martin R, Ishikawa E, et al. Multilocus sequence typing of bifidobacterial strains from infant’s faeces and human milk: are bifidobacteria being sustainably shared during breastfeeding? Benef Microbes 2015;6:563-72.
27. Arboleya S, Salazar N, Solís G, et al. Assessment of intestinal microbiota modulation ability of Bifidobacterium strains in in vitro fecal batch cultures from preterm neonates. Anaerobe 2013;19:9-16.
28. Bäckhed F, Roswall J, Peng Y, et al. Dynamics and stabilization of the human gut microbiome during the first year of life. Cell Host Microbe 2015;17:690-703.
29. Lim ES, Zhou Y, Zhao G, et al. Early life dynamics of the human gut virome and bacterial microbiome in infants. Nat Med 2015;21:1228-34.
30. Makino H, Kushiro A, Ishikawa E, et al. Mother-to-infant transmission of intestinal bifidobacterial strains has an impact on the early development of vaginally delivered infant’s microbiota. PLoS One 2013;8:e78331.
31. Turroni F, Peano C, Pass DA, et al. Diversity of bifidobacteria within the infant gut microbiota. PLoS One 2012;7:e36957.
32. Khonsari S, Suganthy M, Burczynska B, Dang V, Choudhury M, Pachenari A. A comparative study of bifidobacteria in human babies and adults. Biosci Microb Food H 2016;35:97-103.
33. Luk B, Veeraragavan S, Engevik M, et al. Postnatal colonization with human “infant-type” Bifidobacterium species alters behavior of adult gnotobiotic mice. PLoS One 2018;13:e0196510.
34. Luck B, Engevik MA, Ganesh BP, et al. Bifidobacteria shape host neural circuits during postnatal development by promoting synapse formation and microglial function. Sci Rep 2020;10:7737.
35. Kiu R, Treveil A, Harnisch LC, et al. Bifidobacterium breve UCC2003 induces a distinct global transcriptomic program in neonatal murine intestinal epithelial cells. iScience 2020;23:101336.
36. Sudo N, Chida Y, Aiba Y, et al. Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J Physiol 2004;558:263-75.
37. Turroni F, Milani C, Ventura M, van Sinderen D. The human gut microbiota during the initial stages of life: insights from bifidobacteria. Curr Opin Biotechnol 2022;73:81-7.
38. Taft DH, Liu J, Maldonado-Gomez MX, et al. Bifidobacterial dominance of the gut in early life and acquisition of antimicrobial resistance. mSphere 2018;3:e00441-18.
39. Lin C, Lin Y, Zhang H, et al. Intestinal ‘infant-type’ Bifidobacteria mediate immune system development in the first 1000 days of life. Nutrients 2022;14:1498.
41. Ouwehand AC, Isolauri E, Kirjavainen PV, Salminen SJ. Adhesion of four Bifidobacterium strains to human intestinal mucus from subjects in different age groups. FEMS Microbiol Lett 1999;172:61-4.
42. Arboleya S, Watkins C, Stanton C, Ross RP. Gut Bifidobacteria populations in human health and aging. Front Microbiol 2016;7:1204.
43. Sovran B, Hugenholtz F, Elderman M, et al. Age-associated impairment of the mucus barrier function is associated with profound changes in microbiota and immunity. Sci Rep 2019;9:1437.
44. Elderman M, Sovran B, Hugenholtz F, et al. The effect of age on the intestinal mucus thickness, microbiota composition and immunity in relation to sex in mice. PLoS One 2017;12:e0184274.
45. Saffrey MJ. Aging of the mammalian gastrointestinal tract: a complex organ system. Age 2014;36:9603.
46. He F, Ouwehan AC, Hashimoto H, Isolauri E, Benno Y, Salminen S. Adhesion of Bifidobacterium spp. to human intestinal mucus. Microbiol Immunol 2001;45:259-62.
47. Kirjavainen PV, Ouwehand AC, Isolauri E, Salminen SJ. The ability of probiotic bacteria to bind to human intestinal mucus. FEMS Microbiol Lett 1998;167:185-9.
48. Harata G, Yoda K, Wang R, et al. Species- and age/generation-dependent adherence of Bifidobacterium bifidum to human intestinal mucus in vitro. Microorganisms 2021;9:542.
49. Mantziari A, Tölkkö S, Ouwehand AC, et al. The effect of donor human milk fortification on the adhesion of probiotics in vitro. Nutrients 2020;12:182.
50. Juntunen M, Kirjavainen PV, Ouwehand AC, Salminen SJ, Isolauri E. Adherence of probiotic bacteria to human intestinal mucus in healthy infants and during rotavirus infection. Clin Diagn Lab Immunol 2001;8:293-6.
51. Ouwehand AC, Niemi P, Salminen SJ. The normal faecal microflora does not affect the adhesion of probiotic bacteria in vitro. FEMS Microbiol Lett 1999;177:35-8.
52. Collado MC, Gueimonde M, Sanz Y, Salminen S. Adhesion properties and competitive pathogen exclusion ability of bifidobacteria with acquired acid resistance. J Food Prot 2006;69:1675-9.
53. Kainulainen V, Reunanen J, Hiippala K, et al. BopA does not have a major role in the adhesion of Bifidobacterium bifidum to intestinal epithelial cells, extracellular matrix proteins, and mucus. Appl Environ Microbiol 2013;79:6989-97.
54. Collado MC, Jalonen L, Meriluoto J, Salminen S. Protection mechanism of probiotic combination against human pathogens: in vitro adhesion to human intestinal mucus. Asia Pac J Clin Nutr 2006;15:570-5.
55. Collado MC, Meriluoto J, Salminen S. Development of new probiotics by strain combinations: is it possible to improve the adhesion to intestinal mucus? J Dairy Sci 2007;90:2710-6.
56. Gueimonde M, Margolles A, de los Reyes-Gavilán CG, Salminen S. Competitive exclusion of enteropathogens from human intestinal mucus by Bifidobacterium strains with acquired resistance to bile - a preliminary study. Int J Food Microbiol 2007;113:228-32.
57. Collado MC, Gueimonde M, Hernández M, Sanz Y, Salminen S. Adhesion of selected Bifidobacterium strains to human intestinal mucus and the role of adhesion in enteropathogen exclusion. J Food Prot 2005;68:2672-8.
58. Gueimonde M, Noriega L, Margolles A, de los Reyes-Gavilan CG, Salminen S. Ability of Bifidobacterium strains with acquired resistance to bile to adhere to human intestinal mucus. Int J Food Microbiol 2005;101:341-6.
59. Engevik MA, Danhof HA, Hall A, et al. The metabolic profile of Bifidobacterium dentium reflects its status as a human gut commensal. BMC Microbiol 2021;21:154.
60. los Reyes-Gavilán CG, Suárez A, Fernández-García M, Margolles A, Gueimonde M, Ruas-Madiedo P. Adhesion of bile-adapted Bifidobacterium strains to the HT29-MTX cell line is modified after sequential gastrointestinal challenge simulated in vitro using human gastric and duodenal juices. Res Microbiol 2011;162:514-9.
61. Kadlec R, Jakubec M. The effect of prebiotics on adherence of probiotics. J Dairy Sci 2014;97:1983-90.
62. Bernet MF, Brassart D, Neeser JR, Servin AL. Adhesion of human bifidobacterial strains to cultured human intestinal epithelial cells and inhibition of enteropathogen-cell interactions. Appl Environ Microbiol 1993;59:4121-8.
63. Gandhi A, Shah NP. Effect of salt stress on morphology and membrane composition of Lactobacillus acidophilus, Lactobacillus casei, and Bifidobacterium bifidum, and their adhesion to human intestinal epithelial-like Caco-2 cells. J Dairy Sci 2016;99:2594-605.
64. Laparra JM, Sanz Y. Comparison of in vitro models to study bacterial adhesion to the intestinal epithelium. Lett Appl Microbiol 2009;49:695-701.
65. Aissi EA, Lecocq M, Brassart C, Bouquelet S. Adhesion of some Bifidobacterial strains to human enterocyte-like cells and binding to mucosal glycoproteins. Microb Ecol Health Dis 2001;13:32-9.
66. Zhang G, Zhao J, Wen R, Zhu X, Liu L, Li C. 2'-Fucosyllactose promotes Bifidobacterium bifidum DNG6 adhesion to Caco-2 cells. J Dairy Sci 2020;103:9825-34.
67. Riedel CU, Foata F, Goldstein DR, Blum S, Eikmanns BJ. Interaction of bifidobacteria with Caco-2 cells-adhesion and impact on expression profiles. Int J Food Microbiol 2006;110:62-8.
68. Morita H, He F, Fuse T, et al. Adhesion of lactic acid bacteria to caco-2 cells and their effect on cytokine secretion. Microbiol Immunol 2002;46:293-7.
69. Serafini F, Strati F, Ruas-Madiedo P, et al. Evaluation of adhesion properties and antibacterial activities of the infant gut commensal Bifidobacterium bifidum PRL2010. Anaerobe 2013;21:9-17.
70. Izquierdo E, Medina M, Ennahar S, Marchioni E, Sanz Y. Resistance to simulated gastrointestinal conditions and adhesion to mucus as probiotic criteria for Bifidobacterium longum strains. Curr Microbiol 2008;56:613-8.
71. Collado MC, Grześkowiak Ł, Salminen S. Probiotic strains and their combination inhibit in vitro adhesion of pathogens to pig intestinal mucosa. Curr Microbiol 2007;55:260-5.
72. Macfarlane S, Woodmansey EJ, Macfarlane GT. Colonization of mucin by human intestinal bacteria and establishment of biofilm communities in a two-stage continuous culture system. Appl Environ Microbiol 2005;71:7483-92.
73. Klijn A, Mercenier A, Arigoni F. Lessons from the genomes of bifidobacteria. FEMS Microbiol Rev 2005;29:491-509.
74. Westermann C, Gleinser M, Corr SC, Riedel CU. A critical evaluation of bifidobacterial adhesion to the host tissue. Front Microbiol 2016;7:1220.
75. Xiong Y, Zhai Z, Lei Y, Xiao B, Hao Y. A novel major pilin subunit protein fimm is involved in adhesion of Bifidobacterium longum BBMN68 to intestinal epithelial cells. Front Microbiol 2020;11:590435.
76. Turroni F, Serafini F, Foroni E, et al. Role of sortase-dependent pili of Bifidobacterium bifidum PRL2010 in modulating bacterium-host interactions. Proc Natl Acad Sci U S A 2013;110:11151-6.
77. Nishiyama K, Yamamoto Y, Sugiyama M, et al. Bifidobacterium bifidum extracellular sialidase enhances adhesion to the mucosal surface and supports carbohydrate assimilation. mBio 2017;8:e00928-17.
78. González-Rodríguez I, Sánchez B, Ruiz L, et al. Role of extracellular transaldolase from Bifidobacterium bifidum in mucin adhesion and aggregation. Appl Environ Microbiol 2012;78:3992-8.
79. Yuan J, Wang B, Sun Z, et al. Analysis of host-inducing proteome changes in Bifidobacterium longum NCC2705 grown in vivo. J Proteome Res 2008;7:375-85.
80. Schell MA, Karmirantzou M, Snel B, et al. The genome sequence of Bifidobacterium longum reflects its adaptation to the human gastrointestinal tract. Proc Natl Acad Sci U S A 2002;99:14422-7.
81. Wei X, Yan X, Chen X, et al. Proteomic analysis of the interaction of Bifidobacterium longum NCC2705 with the intestine cells Caco-2 and identification of plasminogen receptors. J Proteomics 2014;108:89-98.
82. Candela M, Biagi E, Centanni M, et al. Bifidobacterial enolase, a cell surface receptor for human plasminogen involved in the interaction with the host. Microbiology 2009;155:3294-303.
83. Sun Y, Zhu DQ, Zhang QX, et al. The expression of GroEL protein amplified from Bifidobacterium animalis subsp. lactis KLDS 2.0603 and its role in competitive adhesion to Caco-2. Food Biotechnol 2016;30:292-305.
84. Shkoporov AN, Khokhlova EV, Kafarskaia LI, et al. Search for protein adhesin gene in Bifidobacterium longum genome using surface phage display technology. Bull Exp Biol Med 2008;146:782-5.
85. Suzuki R, Katayama T, Kitaoka M, et al. Crystallographic and mutational analyses of substrate recognition of endo-alpha-N-acetylgalactosaminidase from Bifidobacterium longum. J Biochem 2009;146:389-98.
86. Garrido D, Kim JH, German JB, Raybould HE, Mills DA. Oligosaccharide binding proteins from Bifidobacterium longum subsp. infantis reveal a preference for host glycans. PLoS One 2011;6:e17315.
87. Tam R, Saier MH Jr. Structural, functional, and evolutionary relationships among extracellular solute-binding receptors of bacteria. Microbiol Rev 1993;57:320-46.
88. O’Connell Motherway M, Zomer A, Leahy SC, et al. Functional genome analysis of Bifidobacterium breve UCC2003 reveals type IVb tight adherence (Tad) pili as an essential and conserved host-colonization factor. Proc Natl Acad Sci U S A 2011;108:11217-22.
89. Nishiyama K, Takaki T, Sugiyama M, et al. Extracellular vesicles produced by Bifidobacterium longum export mucin-binding proteins. Appl Environ Microbiol 2020;86:e01464-20.
90. Mantziari A, Mannila E, Collado MC, Salminen S, Gómez-Gallego C. Exogenous polyamines influence in vitro microbial adhesion to human mucus according to the age of mucus donor. Microorganisms 2021;9:1239.
91. Tuo Y, Song X, Song Y, et al. Screening probiotics from Lactobacillus strains according to their abilities to inhibit pathogen adhesion and induction of pro-inflammatory cytokine IL-8. J Dairy Sci 2018;101:4822-9.
92. Monteagudo-Mera A, Rastall RA, Gibson GR, Charalampopoulos D, Chatzifragkou A. Adhesion mechanisms mediated by probiotics and prebiotics and their potential impact on human health. Appl Microbiol Biotechnol 2019;103:6463-72.
93. Klaenhammer TR, Kullen MJ. Selection and design of probiotics. Int J Food Microbiol 1999;50:45-57.
94. Tuomola E, Crittenden R, Playne M, Isolauri E, Salminen S. Quality assurance criteria for probiotic bacteria. Am J Clin Nutr 2001;73:393S-8S.
95. Engevik MA, Luck B, Visuthranukul C, et al. Human-derived Bifidobacterium dentium modulates the mammalian serotonergic system and gut-brain axis. Cell Mol Gastroenterol Hepatol 2021;11:221-48.
96. Engevik MA, Herrmann B, Ruan W, et al. Bifidobacterium dentium-derived y-glutamylcysteine suppresses ER-mediated goblet cell stress and reduces TNBS-driven colonic inflammation. Gut Microbes 2021;13:1-21.
97. Fukuda S, Toh H, Hase K, et al. Bifidobacteria can protect from enteropathogenic infection through production of acetate. Nature 2011;469:543-7.
98. Yu JY, He XL, Puthiyakunnon S, et al. Mucin2 is required for probiotic agents-mediated blocking effects on meningitic e. coli-induced pathogenicities. J Microbiol Biotechnol 2015;25:1751-60.
99. Rivière A, Gagnon M, Weckx S, Roy D, De Vuyst L. Mutual cross-feeding interactions between Bifidobacterium longum subsp. longum NCC2705 and eubacterium rectale ATCC 33656 explain the bifidogenic and butyrogenic effects of arabinoxylan oligosaccharides. Appl Environ Microbiol 2015;81:7767-81.
100. Bunesova V, Lacroix C, Schwab C. Mucin cross-feeding of infant bifidobacteria and eubacterium hallii. Microb Ecol 2018;75:228-38.
101. Schwab C, Ruscheweyh HJ, Bunesova V, Pham VT, Beerenwinkel N, Lacroix C. Trophic interactions of infant Bifidobacteria and eubacterium hallii during L-Fucose and fucosyllactose degradation. Front Microbiol 2017;8:95.
102. Rios-Covian D, Gueimonde M, Duncan SH, Flint HJ, de los Reyes-Gavilan CG. Enhanced butyrate formation by cross-feeding between Faecalibacterium prausnitzii and Bifidobacterium adolescentis. FEMS Microbiol Lett 2015;362:fnv176.
103. Glover JS, Ticer TD, Engevik MA. Characterizing the mucin-degrading capacity of the human gut microbiota. Sci Rep 2022;12:8456.
104. Fang J, Wang H, Zhou Y, Zhang H, Zhou H, Zhang X. Slimy partners: the mucus barrier and gut microbiome in ulcerative colitis. Exp Mol Med 2021;53:772-87.
105. Crouch LI, Liberato MV, Urbanowicz PA, et al. Prominent members of the human gut microbiota express endo-acting O-glycanases to initiate mucin breakdown. Nat Commun 2020;11:4017.
106. Raba G, Luis AS. Mucin utilization by gut microbiota: recent advances on characterization of key enzymes. Essays Biochem 2023;67:345-53.
107. Marcobal A, Southwick AM, Earle KA, Sonnenburg JL. A refined palate: bacterial consumption of host glycans in the gut. Glycobiology 2013;23:1038-46.
108. Turroni F, Bottacini F, Foroni E, et al. Genome analysis of Bifidobacterium bifidum PRL2010 reveals metabolic pathways for host-derived glycan foraging. Proc Natl Acad Sci U S A 2010;107:19514-9.
109. Ruiz L, Gueimonde M, Couté Y, et al. Evaluation of the ability of Bifidobacterium longum to metabolize human intestinal mucus. FEMS Microbiol Lett 2011;314:125-30.
110. Katayama T, Sakuma A, Kimura T, et al. Molecular cloning and characterization of Bifidobacterium bifidum 1,2-alpha-L-fucosidase (AfcA), a novel inverting glycosidase (glycoside hydrolase family 95). J Bacteriol 2004;186:4885-93.
111. Egan M, Motherway MO, Kilcoyne M, et al. Cross-feeding by Bifidobacterium breve UCC2003 during co-cultivation with Bifidobacterium bifidum PRL2010 in a mucin-based medium. BMC Microbiol 2014;14:282.
112. Takada H, Katoh T, Sakanaka M, Odamaki T, Katayama T. GH20 and GH84 β-N-acetylglucosaminidases with different linkage specificities underpin mucin O-glycan breakdown capability of Bifidobacterium bifidum. J Biol Chem 2023;299:104781.
113. Gibson GR, Beatty ER, Wang X, Cummings JH. Selective stimulation of bifidobacteria in the human colon by oligofructose and inulin. Gastroenterology 1995;108:975-82.
114. Zhou JS, Gopal PK, Gill HS. Potential probiotic lactic acid bacteria Lactobacillus rhamnosus (HN001), Lactobacillus acidophilus (HN017) and Bifidobacterium lactis (HN019) do not degrade gastric mucin in vitro. Int J Food Microbiol 2001;63:81-90.
115. Subramani DB, Johansson ME, Dahlén G, Hansson GC. Lactobacillus and Bifidobacterium species do not secrete protease that cleaves the MUC2 mucin which organises the colon mucus. Benef Microbes 2010;1:343-50.
116. Derrien M, van Passel MW, van de Bovenkamp JH, Schipper RG, de Vos WM, Dekker J. Mucin-bacterial interactions in the human oral cavity and digestive tract. Gut Microbes 2010;1:254-68.
117. Norin KE, Gustafsson BE, Lindblad BS, Midtvedt T. The establishment of some microflora associated biochemical characteristics in feces from children during the first years of life. Acta Paediatr Scand 1985;74:207-12.
118. Midtvedt AC, Carlstedt-Duke B, Midtvedt T. Establishment of a mucin-degrading intestinal microflora during the first two years of human life. J Pediatr Gastroenterol Nutr 1994;18:321-6.
119. Karav S, Casaburi G, Frese SA. Reduced colonic mucin degradation in breastfed infants colonized by Bifidobacterium longum subsp. infantis EVC001. FEBS Open Bio 2018;8:1649-57.
120. Klaassens ES, Boesten RJ, Haarman M, et al. Mixed-species genomic microarray analysis of fecal samples reveals differential transcriptional responses of bifidobacteria in breast- and formula-fed infants. Appl Environ Microbiol 2009;75:2668-76.
121. Belzer C. Nutritional strategies for mucosal health: the interplay between microbes and mucin glycans. Trends Microbiol 2022;30:13-21.
122. Desai MS, Seekatz AM, Koropatkin NM, et al. A dietary fiber-deprived gut microbiota degrades the colonic mucus barrier and enhances pathogen susceptibility. Cell 2016;167:1339-53.e21.
123. Schroeder BO, Birchenough GMH, Ståhlman M, et al. Bifidobacteria or fiber protects against diet-induced microbiota-mediated colonic mucus deterioration. Cell Host Microbe 2018;23:27-40.e7.
124. Yoshihara T, Oikawa Y, Kato T, et al. The protective effect of Bifidobacterium bifidum G9-1 against mucus degradation by Akkermansia muciniphila following small intestine injury caused by a proton pump inhibitor and aspirin. Gut Microbes 2020;11:1385-404.
125. Mangin I, Dossou-Yovo F, Lévêque C, et al. Oral administration of viable Bifidobacterium pseudolongum strain patronus modified colonic microbiota and increased mucus layer thickness in rat. FEMS Microbiol Ecol 2018;94:fiy177.
126. Caballero-Franco C, Keller K, De Simone C, Chadee K. The VSL#3 probiotic formula induces mucin gene expression and secretion in colonic epithelial cells. Am J Physiol Gastrointest Liver Physiol 2007;292:G315-22.
127. Burger-van Paassen N, Vincent A, Puiman PJ, et al. The regulation of intestinal mucin MUC2 expression by short-chain fatty acids: implications for epithelial protection. Biochem J 2009;420:211-9.
128. Romond MB, Bezirtzoglou E, Romond C. Colonization of the Murine Gut by Bifidobacterium bifidum and Clostridium perfringens during ageing. Microb Ecol Health Dis 1998;10:91-4.
129. Romond MB, Haddou Z, Mielcareck C, Romond C. Bifidobacteria and human health: regulatory effect of indigenous bifidobacteria on Escherichia coli intestinal colonization. Anaerobe 1997;3:131-6.
130. Toumi R, Abdelouhab K, Rafa H, et al. Beneficial role of the probiotic mixture ultrabiotique on maintaining the integrity of intestinal mucosal barrier in DSS-induced experimental colitis. Immunopharmacol Immunotoxicol 2013;35:403-9.
131. Crespo I, San-Miguel B, Prause C, et al. Glutamine treatment attenuates endoplasmic reticulum stress and apoptosis in TNBS-induced colitis. PLoS One 2012;7:e50407.
132. Takagi T, Homma T, Fujii J, et al. Elevated ER stress exacerbates dextran sulfate sodium-induced colitis in PRDX4-knockout mice. Free Radic Biol Med 2019;134:153-64.
133. Ardite E, Sans M, Panés J, Romero FJ, Piqué JM, Fernández-Checa JC. Replenishment of glutathione levels improves mucosal function in experimental acute colitis. Lab Invest 2000;80:735-44.
134. Grisham MB, Volkmer C, Tso P, Yamada T. Metabolism of trinitrobenzene sulfonic acid by the rat colon produces reactive oxygen species. Gastroenterology 1991;101:540-7.
135. Brandl K, Rutschmann S, Li X, et al. Enhanced sensitivity to DSS colitis caused by a hypomorphic Mbtps1 mutation disrupting the ATF6-driven unfolded protein response. Proc Natl Acad Sci U S A 2009;106:3300-5.
136. Kaser A, Lee AH, Franke A, et al. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell 2008;134:743-56.
137. Heazlewood CK, Cook MC, Eri R, et al. Aberrant mucin assembly in mice causes endoplasmic reticulum stress and spontaneous inflammation resembling ulcerative colitis. PLoS Med 2008;5:e54.
138. Zhao F, Edwards R, Dizon D, et al. Disruption of Paneth and goblet cell homeostasis and increased endoplasmic reticulum stress in Agr2-/- mice. Dev Biol 2010;338:270-9.
139. Bertolotti A, Wang XZ, Novoa I, et al. Increased sensitivity to dextran sodium sulfate colitis in IRE1β-deficient mice. J Clin Invest 2001;107:585-93.
140. Cao SS. Epithelial ER stress in Crohn’s disease and ulcerative colitis. Inflamm Bowel Dis 2016;22:984-93.
141. Cao SS, Zimmermann EM, Chuang BM, et al. The unfolded protein response and chemical chaperones reduce protein misfolding and colitis in mice. Gastroenterology 2013;144:989-1000.e6.
142. Akiyama T, Oishi K, Wullaert A. Bifidobacteria prevent tunicamycin-induced endoplasmic reticulum stress and subsequent barrier disruption in human intestinal epithelial Caco-2 monolayers. PLoS One 2016;11:e0162448.
143. Allen J, Bradley RD. Effects of oral glutathione supplementation on systemic oxidative stress biomarkers in human volunteers. J Altern Complement Med 2011;17:827-33.
144. Chakravarthi S, Jessop CE, Bulleid NJ. The role of glutathione in disulphide bond formation and endoplasmic-reticulum-generated oxidative stress. EMBO Rep 2006;7:271-5.
145. Holmes EW, Yong SL, Eiznhamer D, Keshavarzian A. Glutathione content of colonic mucosa: evidence for oxidative damage in active ulcerative colitis. Dig Dis Sci 1998;43:1088-95.
146. Hwang C, Sinskey AJ, Lodish HF. Oxidized redox state of glutathione in the endoplasmic reticulum. Science 1992;257:1496-502.
147. Quintana-Cabrera R, Fernandez-Fernandez S, Bobo-Jimenez V, et al. γ-Glutamylcysteine detoxifies reactive oxygen species by acting as glutathione peroxidase-1 cofactor. Nat Commun 2012;3:718.
148. Hasnain SZ, Tauro S, Das I, et al. IL-10 promotes production of intestinal mucus by suppressing protein misfolding and endoplasmic reticulum stress in goblet cells. Gastroenterology 2013;144:357-68.e9.
149. Van der Sluis M, De Koning BA, De Bruijn AC, et al. Muc2-deficient mice spontaneously develop colitis, indicating that MUC2 is critical for colonic protection. Gastroenterology 2006;131:117-29.
150. Tadesse S, Corner G, Dhima E, et al. MUC2 mucin deficiency alters inflammatory and metabolic pathways in the mouse intestinal mucosa. Oncotarget 2017;8:71456-70.
151. Bergstrom K, Fu J, Johansson MEV, et al. Core 1- and 3-derived O-glycans collectively maintain the colonic mucus barrier and protect against spontaneous colitis in mice. Mucosal Immunol 2017;10:91-103.
152. Maurel M, Obacz J, Avril T, et al. Control of anterior GRadient 2 (AGR2) dimerization links endoplasmic reticulum proteostasis to inflammation. EMBO Mol Med 2019;11:e10120.
153. Park SW, Zhen G, Verhaeghe C, et al. The protein disulfide isomerase AGR2 is essential for production of intestinal mucus. Proc Natl Acad Sci U S A 2009;106:6950-5.
154. Trabucchi E, Mukenge S, Baratti C, Colombo R, Fregoni F, Montorsi W. Differential diagnosis of Crohn’s disease of the colon from ulcerative colitis: ultrastructure study with the scanning electron microscope. Int J Tissue React 1986;8:79-84.
155. Hanski C, Born M, Foss HD, et al. Defective post-transcriptional processing of MUC2 mucin in ulcerative colitis and in Crohn’s disease increases detectability of the MUC2 protein core. J Pathol 1999;188:304-11.
156. Wenzel UA, Magnusson MK, Rydström A, et al. Spontaneous colitis in Muc2-deficient mice reflects clinical and cellular features of active ulcerative colitis. PLoS One 2014;9:e100217.
157. Tytgat KM, van der Wal JW, Einerhand AW, Büller HA, Dekker J. Quantitative analysis of MUC2 synthesis in ulcerative colitis. Biochem Biophys Res Commun 1996;224:397-405.
158. Pullan RD, Thomas GA, Rhodes M, et al. Thickness of adherent mucus gel on colonic mucosa in humans and its relevance to colitis. Gut 1994;35:353-9.
159. Raouf AH, Tsai HH, Parker N, Hoffman J, Walker RJ, Rhodes JM. Sulphation of colonic and rectal mucin in inflammatory bowel disease: reduced sulphation of rectal mucus in ulcerative colitis. Clin Sci 1992;83:623-6.
160. Larsson JM, Karlsson H, Crespo JG, et al. Altered O-glycosylation profile of MUC2 mucin occurs in active ulcerative colitis and is associated with increased inflammation. Inflamm Bowel Dis 2011;17:2299-307.
161. Antoni L, Nuding S, Wehkamp J, Stange EF. Intestinal barrier in inflammatory bowel disease. World J Gastroenterol 2014;20:1165-79.
162. Johansson ME, Gustafsson JK, Holmén-Larsson J, et al. Bacteria penetrate the normally impenetrable inner colon mucus layer in both murine colitis models and patients with ulcerative colitis. Gut 2014;63:281-91.
163. Zhang K, Kaufman RJ. From endoplasmic-reticulum stress to the inflammatory response. Nature 2008;454:455-62.
164. Shkoda A, Ruiz PA, Daniel H, et al. Interleukin-10 blocked endoplasmic reticulum stress in intestinal epithelial cells: impact on chronic inflammation. Gastroenterology 2007;132:190-207.
165. Eri RD, Adams RJ, Tran TV, et al. An intestinal epithelial defect conferring ER stress results in inflammation involving both innate and adaptive immunity. Mucosal Immunol 2011;4:354-64.
166. Cui QY, Tian XY, Liang X, et al. Bifidobacterium bifidum relieved DSS-induced colitis in mice potentially by activating the aryl hydrocarbon receptor. Food Funct 2022;13:5115-23.
167. Wang H, Fan C, Zhao Z, Zhai Z, Hao Y. Anti-inflammatory effect of Bifidobacterium animalis subsp. lactis A6 on DSS-induced colitis in mice. J Appl Microbiol 2022;133:2063-73.
168. Lee SY, Lee BH, Park JH, Park MS, Ji GE, Sung MK. Bifidobacterium bifidum BGN4 paraprobiotic supplementation alleviates experimental colitis by maintaining gut barrier and suppressing nuclear factor kappa B activation signaling molecules. J Med Food 2022;25:146-57.
169. Yan S, Yang B, Ross RP, et al. Bifidobacterium longum subsp. longum YS108R fermented milk alleviates DSS induced colitis via anti-inflammation, mucosal barrier maintenance and gut microbiota modulation. J Funct Foods 2020;73:104153.
170. Park IS, Kim JH, Yu J, et al. Bifidobacterium breve CBT BR3 is effective at relieving intestinal inflammation by augmenting goblet cell regeneration. J Gastroenterol Hepatol 2023;38:1346-54.
171. Singh S, Bhatia R, Khare P, et al. Anti-inflammatory Bifidobacterium strains prevent dextran sodium sulfate induced colitis and associated gut microbial dysbiosis in mice. Sci Rep 2020;10:18597.
172. Chen Y, Jin Y, Stanton C, et al. Alleviation effects of Bifidobacterium breve on DSS-induced colitis depends on intestinal tract barrier maintenance and gut microbiota modulation. Eur J Nutr 2021;60:369-87.
173. Chen Y, Zhang L, Hong G, et al. Probiotic mixtures with aerobic constituent promoted the recovery of multi-barriers in DSS-induced chronic colitis. Life Sci 2020;240:117089.
174. Niu MM, Guo HX, Cai JW, Meng XC. Bifidobacterium breve alleviates DSS-induced colitis in mice by maintaining the mucosal and epithelial barriers and modulating gut microbes. Nutrients 2022;14:3671.
175. Zhou L, Liu D, Xie Y, Yao X, Li Y. Bifidobacterium infantis induces protective colonic PD-L1 and foxp3 regulatory T cells in an acute murine experimental model of inflammatory bowel disease. Gut Liver 2019;13:430-9.
176. Zuo L, Yuan KT, Yu L, Meng QH, Chung PC, Yang DH. Bifidobacterium infantis attenuates colitis by regulating T cell subset responses. World J Gastroenterol 2014;20:18316-29.
177. Chen M, Liu C, Dai M, Wang Q, Li C, Hung W. Bifidobacterium lactis BL-99 modulates intestinal inflammation and functions in zebrafish models. PLoS One 2022;17:e0262942.
178. Roselli M, Finamore A, Nuccitelli S, et al. Prevention of TNBS-induced colitis by different Lactobacillus and Bifidobacterium strains is associated with an expansion of gammadeltaT and regulatory T cells of intestinal intraepithelial lymphocytes. Inflamm Bowel Dis 2009;15:1526-36.
179. Martín R, Laval L, Chain F, et al. Bifidobacterium animalis ssp. lactis CNCM-I2494 restores gut barrier permeability in chronically low-grade inflamed mice. Front Microbiol 2016;7:608.
180. Yue Y, Wang Y, Xie Q, et al. Bifidobacterium bifidum E3 combined with Bifidobacterium longum subsp. infantis E4 improves LPS-induced intestinal injury by inhibiting the TLR4/NF-κB and MAPK signaling pathways in vivo. J Agric Food Chem 2023;71:8915-30.
181. Khailova L, Dvorak K, Arganbright KM, et al. Bifidobacterium bifidum improves intestinal integrity in a rat model of necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol 2009;297:G940-9.
182. Lueschow SR, Boly TJ, Frese SA, et al. Bifidobacterium longum subspecies infantis strain EVC001 decreases neonatal murine necrotizing enterocolitis. Nutrients 2022;14:495.
183. Bergmann KR, Liu SX, Tian R, et al. Bifidobacteria stabilize claudins at tight junctions and prevent intestinal barrier dysfunction in mouse necrotizing enterocolitis. Am J Pathol 2013;182:1595-606.
184. Braga TD, da Silva GAP, de Lira PIC, de Carvalho Lima M. Efficacy of Bifidobacterium breve and Lactobacillus casei oral supplementation on necrotizing enterocolitis in very-low-birth-weight preterm infants: a double-blind, randomized, controlled trial. Am J Clin Nutr 2011;93:81-6.
185. Kawahara T, Makizaki Y, Oikawa Y, et al. Oral administration of Bifidobacterium bifidum G9-1 alleviates rotavirus gastroenteritis through regulation of intestinal homeostasis by inducing mucosal protective factors. PLoS One 2017;12:e0173979.
186. Weng M, Ganguli K, Zhu W, Shi HN, Walker WA. Conditioned medium from Bifidobacteria infantis protects against Cronobacter sakazakii-induced intestinal inflammation in newborn mice. Am J Physiol Gastrointest Liver Physiol 2014;306:G779-87.
187. Engevik KA, Matthis AL, Montrose MH, Aihara E. Organoids as a model to study infectious disease. In: Medina C, López-baena FJ, editors. Host-Pathogen Interactions. New York: Springer; 2018. p. 71-81.
188. Engevik MA, Banks LD, Engevik KA, et al. Rotavirus infection induces glycan availability to promote ileum-specific changes in the microbiome aiding rotavirus virulence. Gut Microbes 2020;11:1324-47.
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Gutierrez, A.; Puckett, B.; Engevik, M. A. Bifidobacterium and the intestinal mucus layer. Microbiome. Res. Rep. 2023, 2, 36. http://dx.doi.org/10.20517/mrr.2023.37
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