The potential role of adherence factors in probiotic function in the gastrointestinal tract of adults and pediatrics: a narrative review of experimental and human studies

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The term ”colonization” used in this review refers to temporary presence and replication of the administered bacteria.^Citation26 In addition, colonization is investigated tracing both (e.g. through stools) the administered bacteria and the strains (beneficial, pathogenic) whose abundance is affected by the administered bacteria. The presence or absence of probiotics in the stools is very strain-specific and it depends on the composition of the indigenous microbiota which can favor longer persistence for certain individuals in healthy and diseased GIT.^Citation27 This highlights the importance of proper dose selection and sample size when designing clinical trials evaluating probiotics. Probiotics can directly or indirectly affect colonization of other bacteria.^Citation28 All these direct and indirect mechanisms consequently facilitate survival and replication or bacteria that are associated with health. Direct influence by probiotic is provided by production of e.g. antimicrobial peptides, short chain fatty acids or/and nutrients. In addition direct binding to immune cells can trigger immune responses against specific bacteria. The later is less studied for specific probiotics. Indirectly probiotics can impact colonization by stimulating mucin production, hence adherence. Other consequente downstream effects, mentioned throughout the review, are also anti-inflammation mechanism, reinforcement of intestinal barrier function (e.g. tight junctions on IECs). Once probiotic bacteria are administered the extent to which they colonize has been shown to depend on:^Citation29 The age group of individuals under study: infants, children, adults, elderly. Frequency of administration: few single doses (e.g. in acute diarrhea) vs short term (few weeks) vs long term administration (several weeks). Dose: whether considered high or low dose is dependent on the individual studies for specific strains. Dose choice is for the most driven by the age of the individuals, condition of the GIT, and dose identification by in vitro screening of the probiotic. Colonization, in the sense of long-term persistence, can be considered a potential safety issue and however permanente colonization is rare.^Citation30

Figure 1. Examples of mode of action of probiotic adhesion factors. The figure shows binding and downstream effects on intestinal epithelial cells (IECs) and immune cells, reported for some probiotics with characterized adhesins. Probiotic pili-mediated adhesion favors a better colonization³⁴ (1a), direct interaction to the intestinal mucus glycoproteins³⁵ (1b), increased expression of tight junction-encoding genes³⁶ (1c) and direct interaction to antigen-presenting cells (dendritic cells)³⁷ (1d). SLPs-mediated adhesion through SLPs on bacteria or isolated SLPs occurs through interaction with TLR receptors on IECs (2a) and immune cells (macrophages)^23,38,39(2b) possibly this sustains production of fecal IgA⁴⁰(2c). Studies using bacterial mutants of either SLPs or SLPs co-localized molecules show that SLPs trigger antigen-presenting cells (dendritic cells) inducing pro-inflammatory (IL-12, TNF-α, IL-1β) and anti-inflammatory cytokines (IL-6, IL-10)(2d).^41–43 Probiotic EPSs-mediated adhesion directly on other bacteria and/or competition for common adhesion sites on the host promotes “competitive exclusion” of pathogens or interferes with probiotic adhesion (3a).^44,45 EPSs were shown to protect from innate immune mechanism via AMPs the probiotic LGG after adhesion to IECs⁴⁶ (3b). PSA on B. fragilis or isolated PSA has been shown to inhibit IL-1β induced inflammation through interaction with TLR2 and 4 on IECs^47,48 (4a) and can also directly bind to antigen-presenting cells (dendritic cells) triggering downstream immune responses^49,50(4b). Distinct adhesins in the bacteria cells, not belonging to any of the aforementioned class, could support the sustained effects of L. casei on IgA and calprotectin ^51–54(5). LGG probiotic triggers immediate adaptive immune response via B cells in humans.¹³ Although the responsible upstream adhesion factors are not known the immediate effect is most possibly due to adhesion factors (6). The illustrative figure is shown without subdivision of GIT location (i.e. small or large intestine) but regional differences in the GIT immune system are of utmost importance.⁵⁵ In addition, the figure does not represent all mechanisms investigated by the studies in this review or literature but is meant to illustrate examples. Abbreviations: IECs, intestinal epithelial cells; PSA, polysaccharide A; SLPs, surface layer proteins; EPS, exopolysaccharides; IL, interleukin; IgA, immunoglobulin A; LGG, Lacticaseibacillus rhamnosus GG; AMPs, antimicrobial peptides. Created with BioRender.com.

Table 1. Modifications of adhesion structures affects the probiotic function. Specific modification of surface structures on probiotics, hypothesised to be potential adhesins, affected GIT rewiring with respect to direct interaction, immune stimulation through inflammatory cytokines production and pathogens inhibition.

Probiotic bacteria	Adhesion factor	Method	Function affected and mechanisms	Ref
Ligilactobacillus salivarius REN	SLP CbpA	Deletion mutant	Reduced ability to colonise the human gut as an effect of a deletion mutation in SLP CbpA.	^Citation119
Lacticaseibacillus rhamnosus GG	SpaCBA pili	Purification of the SpaCBA pili	Direct interaction of SpaCBA pili glycans with immune cells (DCs) via the C-type lectin receptor DC-SIGN, a key functional PRR modulating cytokine responses.	^Citation37
Lacticaseibacillus rhamnosus GG	SpaCBA pili	SpaCBA pilus knockout mutant	Mutant increased IL-8 expression, possibly through lipoteichoic acid on bacteria that binds to TLR2 on IECs	^Citation108
Lacticaseibacillus rhamnosus GG	SpaC pili	Isogenic mutant that lacks SpaC pili protein	Decreased IECs adhesion, cell proliferation and protection against intestinal injury by radiation by isogenic mutant.	^Citation89
Lacticaseibacillus rhamnosus GG	SpaCBA pili	Pilus-deficient LGG strain	Increased immune cell (NK cell) activity and no change in fecal microbial genus Parabacteroides.	^Citation109
Bacteroides fragilis NCTC 9343	Polysaccharide A (PSA)	Mutant lacking PSA, Purified PSA	Mutant: Failure to prevent disease and pro-inflammatory cytokine production in colon. PSA In vivo: Is needed to suppress pro-inflammatory IL-17 production by intestinal immune cells. PSA In vitro: Inhibits IL-1β induced inflammation on IECs.	^Citation47–49
Bacteroides fragilis (non-toxigenic)	Component of type VI secretion system (T6SS)	Deletion mutant	Mutant confers colonization resistance to enterotoxigenic Bacteroides fragilis that is associated with IBD, childhood diarrhea and colon cancer.	^Citation150,Citation151
Enterococcus Faecium WEFA23	SLP	Removal of SLP by treatment with 5 mol/L LiCl, isolated SLP	Removal of SLP reduced adhesion capacity on pathogen Listeria monocytogenes CMCC54007. Isolated SLP decreases apoptosis of IECs induced by the pathogen.	^Citation152
Lacticaseibacillus paracasei (Lbp (LAP))	Surface-associated LAP from LbpLAP	LAP-expressing recombinant	Reduced ability of pathogen Listeria monocytogenes to adhere and invade as an effect of LAP-recombinant probiotic via receptor Hsp60 interaction to mammalian cells.	^Citation153
Limosilactobacillus fermentum MCC 2760 (former^Citation16 Lactobacillus fermentum MCC 2760)	Cell wall extract and crude bacteria culture filtrate	Extracts and conditioned media	Cell wall extraction induced the expression of IL-6, and crude culture filtrate enhanced the expression of IL-10 (anti-inflammatory cytokine).	^Citation154
Lactobacillus rhamnosus KL 53A and Lactobacillus casei Fyos	EPS	Enzymatic deglycosylation	Changes in the exopolysaccharide structure decreased adhesion efficiency of probiotic on IECs.	^Citation155
Lactobacillus acidophilus NCFM	SLP homolog PrtX	PrtX-deficient strain (gene deletion)	Prt-X deficient strain had increased adhesion to mucin and fibronectin. On antigen presenting cells (DCs) it increased induction of IL-6, IL-12 (pro-inflammatory) and IL-10 (anti-inflammatory), but IL-10/IL-12 ratio, (measure of the balance between pro-inflammatory and anti-inflammatory states) was higher.	^Citation42
Lactobacillus acidophilus NCFM	SLP A	Knockout mutant lacking SLP, purified SLP protein	Wild type bacteria adhered to DCs and consequently anti-inflammatory IL-10 production was higher with higher doses. Knockout bacteria for SLP A protein reduced binding to DCs (antigen presenting cells).	^Citation41
L. Helveticus MIMLh5 and NS8	SLP	Removal of SLP by treatment with 5 mol/L LiCl, isolated SLP	Both probiotic and isolated SLP showed similar mechanism of action via TLR2. Dampening of production of IL-10 was observed with probiotic stimulation but not isolated SLP.	^Citation23,^Citation39
B. bifidum ATCC 15696	Sialidase	Mutant of Siabb2 sialidase	Mutant decreased adhesion to IECs and mucin relative to the wild-type strain. SiaBb2 engages HMOs and mucin sialic acid for metabolic purposes and may facilitate Bifidobacterial adhesion.	^Citation156

Abbreviations: IL, Interleukin; SLP, Surface layer protein; EPS, Exopolysaccharide; PRR, Pattern recognition receptor; TLR, Toll like receptor; DCs, Dendritic cells; NK cell, Natural killer cell; IECs, Intestinal epithelial cells (e.g. Caco-2 cell line); IBD, Inflammatory Bowel Disease; LPS, Lipopolysaccharide; LiCl, Lithium Chloride; HMOs, Human milk oligosaccharides.

Figure 2. Age and probiotics adhesion. The figure shows a schematic view of probiotic and GIT characteristics changing with age. (a) Conventionally probiotics are given in increasing doses with age.¹⁸⁴ (b) IECs, which are among the main cells interacting with probiotics in the GIT and form the intestinal barrier function, are less established early in life but with age they are progressively shaped into a fully functioning GIT barrier.^10,188 Probiotic adhesion is strain- and age-dependent. In (c) are shown a few examples of probiotic strains, B. bifidum,¹⁸⁹ LGG,^10,189 B. lactis Bb12¹⁸⁹, in which age-dependency has been investigated within a single study. Created with BioRender.com

Figure 3. Key adhesion factors as potential proxy for a global probiotic function. Representation chart of some adhesion factors and potential application for global mechanisms with respective reference studies. First column: EPSs on LGG,^44–46 B. animalis⁶³ and B. breve.⁶⁷ Second column: PSA on B. fragilis.^47–50 Third column: Pili on B. bifidum^36,93 and LGG.^{37,106,108,109} Fourth column: SLPs and SLAPs on L. acidophilus.^41–43,115 Fifth column: distinct adhesins on L. plantarum^123,141 and L. reuteri.¹³¹ Abbreviations: EPS, exopolysaccharides; LGG, L. rhamnosus GG; PSA, polysaccharide A; SLPs, surface layer proteins; SLAPs, surface layer associated proteins; Cbp, collagen binding protein; Mub, mucus-binding protein. Created with BioRender.com

Figure 4. Ideal step-by-step workflow for studies of adhesion factors role in probiotic function. Given the mixed type of approaches found in literature the figure summarizes an ideal workflow for screening, experimental testing, and classification of probiotics considering adhesion factors. Bacteria from dairy, fermentation of fecal matter, etc, are isolated as potential probiotics (Step 1). Based on the bacteria type a hypothetical adhesion factor should be identified (Step 2). Then follows the purification of the adhesion factor (e.g. proteinic, polysaccharidic component), generation of mutants lacking, overexpressing the adhesion factor or enzymatic treatment of the bacteria (Step 3). In vitro studies, using most often IECs (e.g. Caco-2 cells) are the first experimental model used to investigate bacteria and adhesion factors for probiotic properties. Cell studies at this stage should ideally investigate the host receptors involved in the adhesion mechanism (Step 4). Once a probiotic and its adhesion mechanism have been identified, animal studies must aim to propose a dose range and mechanism of action in vivo (Step 5). Although adhesion factors are most often inert proteinic or complex carbohydrate by nature, hence considered safe, they could potentially be considered as drug-like when studying the metabolism in vivo to understand their half-life in the body. Once a preliminary hypothesis of the adhesin and healthy host is formulated, the next step should involve studies to decide which disease could benefit (Step 6). For instance, if it was hypothesized that an adhesion factor could benefit inflammatory conditions, established inflammatory models should be used to test this. Such models are for instance inflammation induced in IECs Caco-2 cell with inflammatory cytokines (e.g. IL-1β, TNF-α)⁴⁷ or/and animal models such as dextran sulfate sodium (DSS)-induced colitis in animals.¹¹ Next step comprises human trial conduction (Step 7). Although conduction of human trials in a stepwise manner takes longer, when possible, they should be performed in the following order: starting from pilot testing in healthy to study mainly safety, pilot trial in disease to mainly select a dose, and finally RCTs, Cross-Over or Parallel design trials with specific health outcomes. The 4 symbols represent samples used during human trials, intestinal biopsies, fecal samples, blood samples and symptoms questionnaires that can be used depending on the endpoint investigated and feasibility. Finally, considering both the probiotic and the host an adhesion factor-driven classification can be assigned to the probiotic (Step 8).

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Data availability statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.