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Microbiota-host interplay at the gut epithelial level, health and nutrition

Microbiota-host interplay at the gut epithelial level, health and nutrition Growing evidence suggests the implication of the gut microbiota in various facets of health and disease. In this review, the focus is put on microbiota-host molecular cross-talk at the gut epithelial level with special emphasis on two defense systems: intestinal alkaline phosphatase (IAP) and inducible heat shock proteins (iHSPs). Both IAP and iHSPs are induced by various microbial structural components (e.g. lipopolysaccharide, flagellin, CpG DNA motifs), metabolites (e.g. n-butyrate) or secreted signal molecules (e.g., toxins, various peptides, polyphosphate). IAP is produced in the small intestine and secreted into the lumen and in the interior milieu. It detoxifies microbial components by dephosphorylation and, therefore, down-regulates microbe-induced inflammation mainly by inhibiting NF-κB pro-inflammatory pathway in enterocytes. IAP gene expression and enzyme activity are influenced by the gut microbiota. Conversely, IAP controls gut microbiota composition both directly, and indirectly though the detoxification of pro-inflammatory free luminal adenosine triphosphate and inflammation inhibition. Inducible HSPs are expressed by gut epithelial cells in proportion to the microbial load along the gastro-intestinal tract. They are also induced by various microbial components, metabolites and secreted molecules. Whether iHSPs contribute to shape the gut microbiota is presently unknown. Both systems display strong anti-inflammatory and anti-oxidant properties that are protective to the gut and the host. Importantly, epithelial gene expressions and protein concentrations of IAP and iHSPs can be stimulated by probiotics, prebiotics and a large variety of dietary components, including macronutrients (protein and amino acids, especially L-glutamine, fat, fiber), and specific minerals (e.g. calcium) and vitamins (e.g. vitamins K1 and K2). Some food components (e.g. lectins, soybean proteins, various polyphenols) may inhibit or disturb these systems. The general cellular and molecular mechanisms involved in the microbiota-host epithelial crosstalk and subsequent gut protection through IAP and iHSPs are reviewed along with their nutritional modulation. Special emphasis is also given to the pig, an economically important species and valuable biomedical model. Keywords: Diet, Gut, Inducible heat shock protein, Inflammation, Intestinal alkaline phosphatase, Microbiota Background aiming at digestion and nutrient absorption and the The gastrointestinal tract (GIT) is, like the skin or the large intestine specialized in the fermentation of un- lung, a major interface organ between the environment digested materials. The gut epithelium is also the first and interior milieu. It is the site with the highest load of line of GIT (and body) defense and protection. Its action microorganisms (also referred to as “the microbiota”). is complementary to that of the associated mucosal im- This is especially true in the large intestine due to sub- mune system whose development and maintenance are stantial amounts of undigested dietary and endogenous induced by the microbiota [1]. Thus gut epithelial cells - (e.g. mucus, enzymes) components amenable to micro- enterocytes and colonocytes - are polarized key players bial fermentation. Gut epithelial cells are thus the first influenced by both the environment (e.g. food, patho- cells to be exposed to nutrients and the microbiota, with gens, toxicants) and body metabolism and functions. complementary functions between the small intestine The gut epithelium has developed over time various mechanisms for sensing not only nutrients but also mi- crobial structural components (e.g. lipopolysaccharide, Correspondence: jean-paul.lalles@inra.fr 1 LPS; peptidoglycan, flagellin, CpG DNA motifs), metab- Division of Human Nutrition Division, INRA Clermont-Ferrand, France Human Nutrition Research Center – West, Nantes, France olites (e.g. short chain fatty acids, SCFA) or secreted Full list of author information is available at the end of the article © The Author(s). 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Lallès Journal of Animal Science and Biotechnology (2016) 7:66 Page 2 of 8 molecules (e.g. toxins, polyphosphate chains, other com- an array of physiological properties that include: entero- pounds still unknown). These sensors include for ex- cyte apical surface pH maintenance through the control ample Toll-like receptors (TLRs) [2, 3] and receptors to of bicarbonate secretion, absorption of nutrients and SCFA. All these mechanisms make the molecular basis minerals (e.g. fatty acids, calcium), detoxification (by de- of the crosstalk between the host and the gut microbiota phosphorylation) of pro-inflammatory microbial compo- at the epithelial level. nents (e.g. LPS, flagellin, CpG DNA motifs, uridine Numerous experimental and clinical data have shown diphsophate (UDP)) and, ultimately control of gut (and that defects in gut barrier function may lead to chronic systemic) inflammation [20, 21]. IAP is an enzyme dy- inflammatory diseases and sometimes cancers [4–7]. namically produced by the enterocyte in the small intes- These diseases affect not only the GIT but also other or- tine and secreted both luminally and basolaterally. Part gans (e.g. liver, brain) and include diverse metabolic dis- of lumen IAP escapes digestion in the bowel, remains turbances (ranging from glucose intolerance and insulin active along the large intestine and can still be detected resistance, type-2 diabetes to metabolic syndrome and in small amounts in the feces. obesity), known risk factors for cardiovascular disorders. Previous data suggested IAP to participate indirectly Importantly, more recent investigations has highlighted to the control of intestinal barrier function [21], but a that many of these diseases may be modulated by the direct involvement was demonstrated in mice recently gut microbiota [8], though cause-and-effects relation- [22]. More precisely, IAP stimulates gene expression of ships are often poorly understood. For instance, chronic key tight junctions (Zonula occludens ZO-1 and ZO-2; metabolic diseases and obesity may be related to body occludin) and their correct cellular localization. entry of enteric microbial components (e.g. LPS) thus Many recent data now converge to indicate that IAP not triggering chronic low-grade, “metabolic” inflammation only detoxifies microbial components but also contributes [9, 10]. This in turn favors diet energy extraction, fat to shape the gut microbiota and to prevent microbial en- synthesis and adipose tissue development, and shifts en- teric translocation into the body [14]. Free exogenous (e.g. ergy metabolism towards fat deposition and adipose tis- from bovine intestine) IAP per se does not seem to influ- sue inflammation, thus leading to metabolic syndrome ence bacterial growth but enterocyte-bound IAP could and obesity. The diet is a major lever of gut microbiota delay that of Escherichia coli in vitro (with no effects on modulation and is now regarded as a serious approach other bacteria such as Clostridium difficile, S. typhimur- for maintaining high microbiota diversity (or gene rich- ium or Enterococcus faecalis)[23–25]. Mice deleted for ness) and preserving health as well as correcting dysbio- Iap gene (called Akp3 in this species) were reported to dis- sis often observed in many chronic diseases [11]. This is play fecal microbiota that were different from those of of utmost importance in the context of drastic reduction wild-type mice: marked decrease in the overall load of of food diversity over the last decades [12]. both aerobic and anaerobic bacteria, drastic reduction in The present review focuses on two specialized defense E. coli population and, conversely, increases in Clostri- and protection systems at the epithelial level, namely in- diales, Lactobacilli and Enterococci [24]. The precise testinal alkaline phosphatase (IAP) and inducible heat mechanisms for these IAP-dependent changes in gut shock proteins (iHSPs). Both of them are modulated by microbiota composition are not fully understood yet but the microbiota and the diet and confer gut epithelial (and they may involve alterations in epithelial surface pH body) protection due to their potent anti-inflammatory and reduced gut inflammatory tone [26, 27]. Another and anti-oxidant capacities. Data available in the pig are pathway of microbial control involving IAP was re- also reviewed given the economic importance of this cently reported [28, 29]. Free luminal adenosine tri- species and its high potential as a biomedical model phosphate (ATP), a strong pro-inflammatory danger for studies on development, microbiology, physiology, signal, dose-dependently inhibited microbial growth, neurobiology and nutrition [13–16]. In particular, the targeting more specifically Gram-positive (but not weaning period is critical to pig rearing due to high Gram-negative) bacteria [29]. IAP was able to dephos- stress, GIT pathophysiology, growth check and in- phorylate and detoxify ATP, thus ultimately releasing creased risk of enteric diseases [17, 18]. Fortunately, free adenosine which is a strong anti-inflammatory selected dietary approaches may help circumvent molecule. Importantly, ATP was shown to drive cell dif- these disorders [19]. Therefore, dietary components ferentiation of Th17 T lymphocytes that produce IL-17 improving gut health through stimulating IAP and in- and IL-22 cytokines. The former is known to favor neu- ducible HSP proteins are briefly reviewed here too. trophil tissue infiltration while both cytokines stimulate antibacterial peptide production. IAP was already Intestinal alkaline phosphatase and the gut microbiota shown to inhibit gut tissue infiltration of neutrophils in Intestinal alkaline phosphatase (IAP), the specific intes- zebra fish [23], thus strengthening the anti-inflammatory tinal isoform of ubiquitous AP gene products, displays capabilities of IAP. Lallès Journal of Animal Science and Biotechnology (2016) 7:66 Page 3 of 8 Regarding bacterial translocation, earlier investigations shown to be strong inducers of gut epithelial iHSPs in reported an inhibitory effect of IAP [30]. However, later vitro and sometimes in vivo, though others (e.g. Entero- work suggested a rather indirect influence though IAP- bacter aerogenes and Proteus mirabilis for Gram-negative driven down-regulation of inflammation and subsequent species; Enterococcus faecalis for Gram-positive species) reinforcement of gut barrier function [31, 32]. had no effects on iHSPs. In the same line, many probio- Collectively these data indicate that IAP directly and tics, especially of Lactobacilli and Bifidobacteria strains, indirectly controls gut microbiota load and balance and but not all probiotics (e.g. E. coli Nissle 1917) were dem- that this directly connects to gut inflammatory tone. onstrated to induce gut epithelial HSPs and different cell sensors (e.g. TLRs or other molecules) and signaling path- Inducible heat shock proteins and the gut microbiota ways (often p 38 MAPK) have been disclosed (Table 1) Beside the general roles of HSPs as intracellular protein (see also Table 2 and Table of ref. [34]). Finally, some (e.g. chaperones, those induced specifically in gut epithelial metronidazole), but not all antibiotics (or mixtures) may cells, namely HSP25 (or HSP27, depending on the host decrease iHSP levels and increase gut susceptibility to species) and HSP70 are involved in many vital functions microbial toxins (e.g. C. difficile toxin A). (e.g. cell proliferation and apoptosis, immune responses) Collectively these data suggest that iHSP induction at and the control of inflammation and oxidation [33, 34]. the gut level might be one important mechanism of gut Importantly, iHSPs regulate gut barrier function, by spe- epithelial protection by commensal bacteria and probio- cifically controlling the expression of key tight junction tics and that any alterations in this protection may be proteins (e.g. occludin) and by down-regulating adverse detrimental to the host. effects of oxidative and inflammatory stress on cells [33]. In rodents, epithelial iHSPs are expressed at low and Dietary modulation of gut defense and protection high levels in the small and large intestines, respectively systems [34]. This actually reflects the loads of microbes present We have reviewed that many dietary compounds can along these compartments and that are a major factor of modulate both IAP and iHSP gene expressions and pro- iHSP induction. Indeed, intestinal and colonic epithelial tein concentrations or activities [20, 21, 34]. cells per se are equally responsive to iHSP-inducing stimuli and the gut proximal-distal iHSP gradient disap- pears in germfree animals [35, 36]. Intestinal alkaline phosphatase The microbiota-host epithelial crosstalk is first Food intake per se is a stimulator of IAP while starvation brought about by specific microbial compounds, includ- has opposing effects [30]. Dietary added calcium stimu- ing structural components (e.g. LPS, lipoteichoic acid, lates IAP in rat intestine [39]. Calcium is known to be flagellin), metabolites (especially n-butyrate but also pro- protective in colonic inflammation models but the impli- pionate), toxins (e.g. toxin A from Clostridium difficile, cation of IAP was not explored. Free phosphorus had enterotoxin B superantigen from Staphylococcus aureus) inhibitory effects on IAP while bound phosphate (e.g. to and other soluble substances (e.g. various peptides like starch in some potato varieties) is dose-dependently fMLP) [34]. All these substances are recognized by spe- stimulatory. Therefore, calcium-to-phosphorus ratio and cific receptors (e.g. TLRs) or are internalized in gut epi- their chemical forms in the diet are critical to IAP activity. thelial cells by specific transporters (e.g. the peptide Besides, vitamins K1 (philloquinone) and K2 (menaquin- transporter PepT1), and intracellular signaling pathways one-4) could also stimulate IAP in rodents. involve various kinases (especially p38 MAPK) [34]. Many HSP inducers are active at very low concentra- Table 1 Molecular sensors, microbial component and tions (ng order) and responses are often fast (within a intracellular signalling pathways involved in the induction of HSPs by intestinal epithelial cells (adapted from ref. [34]) few hours). Therefore, the physiological epithelial iHSP tone is under direct influence of the gut microbiota Molecular sensor/receptor Microbial component Signalling pathway on intestinal epithelial cell recognized involved composition and metabolic activities. Their stimuli are, TLR-2 Lipoteichoic acid ? in turn, essential for permanently triggering optimal levels of epithelial defense given the fact that iHSPs con- TLR-4 Lipopolysaccharide MAPK p38, ERK1/2 fer protection to gut epithelial cells exposed to oxidative TLR-5 Flagellin MAPK p38 stress and inflammation [34]. GPR-41 & GPR-43 Butyrate, propionate ? Anaerobic bacteria (e.g. Bacteroides fragilis)were re- (putatively) ported to have important roles in HSP induction [37, 38]. PepT1 fMLP peptide MAPK p38 A variety of Gram-negative bacteria (e.g. E. coli)and OCTN-2 ERGMT peptide MAPK p38 Gram-positive bacteria (Bifidobacterium breve, Lactobacil- Integrin-β Polyphosphate chains MAPK p38 lus paracasei, L. plantarum, L. Johnsonii) have been Lallès Journal of Animal Science and Biotechnology (2016) 7:66 Page 4 of 8 Fat intake stimulates IAP in rodents and this has been iHSPs in the ileum and the colon of rats. Conversely, interpreted as an adaptive response to fat-dependent in- pro-inflammatory, high sulfated saccharides like dextran creases in intestinal LPS uptake and translocation (via sulfate sodium and carrageenans are known to disturb the chylomicron pathway) into the interior milieu [40]. iHSP phosphorylation and functionalities, thus favoring The degree of saturation and length of fatty acids are gut inflammation. Therefore, the type of dietary fiber is also important to consider [20, 21]. Saturated and important to consider when iHSP stimulation is needed. medium-chain fatty acids appear as stronger inducers of Surprisingly, various polyphenols were often shown to IAP compared to poly-unsaturated fatty acids (PUFA). be potent inhibitors of gut iHSPs (e.g. quercetin), though Saturated fats are known for shifting the gut microbiota they display anti-oxidant properties [34]. Finally, dietary towards more Gram-negative bacteria and, therefore, mycotoxins with high oxidant capacity (e.g. zearalenone, more pro-inflammatory microbial components and more fumonisins) induce iHSPs but this response is usually in- inflammation [41]. Importantly, intestinal tissue con- sufficient to counteract mycotoxin toxicity. centration of (n-3) PUFA was recently demonstrated Many probiotics, especially Lactobacillus and Bifido- to determine the level of gene expression and enzyme bacteria strains are inducers of gut epithelial iHSPs and activity of IAP which, in turn modified the gut micro- contribute to gut protection (see Tables 3 and 5 in ref. biota composition and enhances barrier function [42]. [34]). These probiotics can induce either or both (HSP25 In particular, the proteobacteria phylum (e.g. E. coli and HSP70) iHSPs, depending on the strain. Inhibition and other LPS-producing species) was reduced while of pro-inflammatory cytokine (e.g. IL-8) secretion and of anti-inflammatory bacteria (e.g. Bifidobacteria, Lactoba- some pathogens (e.g. S. typhimurium) has been docu- cilli; Akkermansia muciniphila) were enhanced in (n-6) mented too. The probiotic-dependent protection are me- PUFA-fed, genetically engineered (Fat-1) mice that are diated by various microbial triggers: cell wall components able to convert dietary (n-6) PUFA into (n-3) PUFA. This (lipoteichoic acids, LPS, flagellins), metabolites (butyrate, contributes to explain, especially at the gut level the anti- propionate) or secreted molecules (e.g. peptides; poly- inflammatory properties of (n-3) PUFA. phosphate) (Table 1). A number of epithelial cell mem- brane sensors have been identified (TLRs, peptide Inducible gut epithelial HSPs transporters, etc.) while others remain to be discovered. Many dietary components are modulators of gut epithe- Intracellular signaling often involves kinases, and espe- lial iHSPs [43]. This includes notably various amino cially p38 MAPK. Interestingly, Japanese groups have se- acids and proteins, fiber, zinc, n-butyrate and many pro- lected Lactobacillus (L. paracasei and L. brevi)probiotic biotics. The stronger inducer of iHSPs is without contest strains that produce high amounts of long-chain polypho- L-glutamine whose action is fast and of high magnitude. sphates (up to 700 phosphate units) that are responsible Its mode of action involves polyamines that increase the for improving epithelial barrier function in vitro and in binding between transcription factor HSF-1 and heat- mice [43–46]. Polyphosphate is endocytosed by the cell shock element on Hsp genes. Putrescine and spermidine, through caveolin-1 and integrin-β1 mechanisms and and their precursor ornithine stimulate the induction of p38-MAPK-dependent gene expression and protein both HSP25 and HSP70 in various gut epithelial cell production of HSP27. Endocytosis is the key step for lines in vitro. Spermine seems to induce HSP25 only. polyphosphate protective action [44, 45]. As a result, Molecular mechanisms of L-glutamine action involve synthetic long-chain polyphosphates added to the diet the up-regulation of Hsf1 gene expression and promoter may be serious candidates for mimicking the protect- activation resulting in iHSP production and subsequent ive action of those probiotics in vivo. down-regulation of the pro-inflammatory NF-κB path- Collectively these data support the diet (including way (by inhibiting protein p65 nuclear translocation and probiotics) as a major lever for stimulating gut defense cell apoptosis). Other iHSP-stimulatory L-amino acids, systems and controlling inflammation and oxidative though less effective than glutamine include glutamate, stress. arginine, threonine and metabolic intermediates like cit- rulline [34]. Regarding dietary proteins, plant lectins (from kidney bean or wheat germ) inhibit iHSP expres- Gut IAP and iHSP defense systems and their nutritional sion while wheat gluten (involved e.g. in celiac disease) modulation in the pig disturbs iHSP cellular localization in vitro, thus increas- The pig is a major source of meat worldwide and it is ing cell sensitivity to oxidation and inflammation. increasingly used as a biomedical model in various Mineral and organic forms of zinc as well as SCFA like domains [13–16]. Most of the mechanisms of gut epithe- butyrate (n- and iso- forms) and propionate are strong lial protection by IAP or iHSPs and their modulation by inducers of gut epithelial iHSPs in vitro. Pectin, a soluble dietary components have been described, at least partly and fermentable fiber (but not cellulose) stimulates both in the swine species too (e.g. for IAP: [47]). Lallès Journal of Animal Science and Biotechnology (2016) 7:66 Page 5 of 8 Intestinal alkaline phosphatase reflected dietary fatty acid profiles, suggesting a link with Pigs display three alkaline phosphatase gene copies in IAP levels [43, 57]. Furthermore, wheat arabinoxylan the intestine, thus being intermediate between domestic alone or associated with cellulose was recently shown to carnivorous (single copy) and ruminants (seven copies) increase ileal total AP activity [58]. This was interpreted [48]. IAP is strongly inhibited after early weaning in pigs as positive as it is essentially the IAP isoform that is and this is considered as a major factor in post-weaning present in the small intestine [20, 21]. The Authors also disorders and enhanced piglet sensitivity to enteric infec- reported increased AP activity in the mid-colon in re- tions [49]. The hormone glucagon-like peptide 2 (GLP-2), sponse to arabinoxylan supplementation [58]. This obser- known for its intestine-trophic properties has been re- vation should be interpreted with caution because it was cently shown to stimulate duodenal and jejunal IAP in total AP (and not specifically IAP isoform) activity that weaned pigs injected with exogenous (human) GLP-2 was measured and this could reflect a sign of colonic in- [50]. This was associated with the maturation of intestinal flammation, e.g. resulting from increased tissue infiltration epithelial cells. Finally, piglets born to sows treated with by neutrophils [21]. Thus, effects of dietary components antibiotics (amoxicillin) around parturition transiently dis- on GIT AP activity should be interpreted carefully accord- played lower Iap gene expression and IAP enzyme activity ing to GIT segment and efforts to differentiate between than piglets born to untreated sows [51]. true IAP isoform and nonspecific AP activities using appropriate AP inhibitors [20] should be considered. Inducible gut epithelial HSPs Interestingly, IAP was shown to be higher in pigs selected Pigs display substantial and fairly similar iHSP concen- for low, compared to high residual feed intake and this trations in the small and large intestine [52–54], con- was associated with lower inflammation and circulating trary to laboratory rodents that are virtually devoid of levels of LPS [59]. These data collectively suggest that IAP iHSPs in the small intestine (except in its distal part: the is influenced by the type/source of dietary fat and fiber ileum) [34]. Growing pigs even displayed higher iHSP and also reduces LPS intestinal translocation and inflam- concentrations in the ileum than in the colon [55]. mation in pigs. Also, intestinal IAP could be one key to Intra-uterine growth retarded piglets were shown to dis- residual feed intake and feed efficiency. play higher duodenal and jejunal HSP70, as hallmarks of fetal stress in utero [55]. iHSPs have been evidenced to iHSPs Feed intake modulates iHSPs along pig GIT [52]. be modulated by weaning along the GIT of piglets [52]. Many feed ingredients, including amino acids and pro- Small intestine iHSPs were not influenced in piglets teins, carbohydrates (including fiber) and fat are known born to sows given antibiotics (amoxicillin) around par- to modulate gut function in pigs [18]. However, only turition but colonic HSP70 was transiently decreased some studies specifically investigated iHSPs. [53]. Important links between iHSPs and the gut micro- L-glutamine as repeatedly been shown to improve biota were demonstrated in pigs (fed chicory inulin, see growth performance and intestinal anatomy and function below) [55]. These included: negative correlations be- in weaned piglets [18], and these effects were partly medi- tween HSP27 and lumenal bacteria (L. reuteri and ated by intestinal epithelial HSP70 [60]. L-glutamine also Enterobacteriacae), positive correlations between iHSPs improved intestinal maturation in intra-uterine growth and lactic acid-producing bacteria or L. Johnsonii. Ileal retarded pig neonates through HSP70-mediated mecha- HSP27 and colonic HSP70 correlated negatively with nisms [61]. Protective iHSP-mediated effects on the gut the diversity of mucosa-associated bacteria and Rose- were also brought about with diets supplemented with buria faecis (a butyrate producer). Colonic HSP70 cor- L-arginine, α-ketoglutarate and N-carbamyl-glutamate related negatively with Prevotella brevis but positively [62, 63]. Besides, soybean proteins are considered as with the anti-inflammatory bacterium Faecalibacterium toxic for the gut of piglets [64]. The storage protein prausnitzii [56]. Although such individual correlations β-conglycinin was recently shown to inhibit gut HSP70 are difficult to interpret in terms of cause-and effect re- in pigs, probably contributing to the adverse effects of lationships, they suggest intimate interactions between soybean proteins [65]. Conversely, a weaning diet supple- iHSPsand thegut microbiotainpigs. mented with a melon pulp rich in the anti-oxidant enzyme superoxide dismutase decreased iHSP protein concentra- Dietary modulation of gut IAP and iHSPs in pigs tions along the GIT of already weaned piglets, but this IAP Few data are available on the effects of dietary probably reflected reduced oxidative stress [66]. Finally, factors on IAP in pigs [20, 21]. First, feed intake is an zinc oxide up-regulated Hsp70 gene in porcine IPEC-J2 important IAP modulator in pig gut [53]. Regarding epithelial cell line but could not be shown to do so at high fat, Dudley et al. [57] reported higher IAP in pigs fed zinc level (2,200 ppm) in vivo [67–69]. Regarding dietary high fat diets with saturated (tallow), compared to un- fiber, chicory pectin was recently shown to stimulate ileal saturated (corn oil) fat sources. Intestinal cell membranes and colonic HSP27 in growing pigs [56]. Interestingly, Lallès Journal of Animal Science and Biotechnology (2016) 7:66 Page 6 of 8 Fig. 1 Various food components (nutrients, minerals, vitamins) modulate inducible heat shock proteins (iHSPs) and intestinal alkaline phosphatase (IAP) in the epithelium of the small intestine. It is mostly microbial compounds, fermentation products (short-chain fatty acids, SCFA) and other unknown secreted molecules of microbial origin that induce iHSP in the large intestine (nb: IAP expression and activity are very low there). Luminal IAP contributes to control the gut microbiota (present in low numbers) in the small intestine. Luminal IAP also partially escapes digestion in the small intestine and is active to shape the gut microbiota in the large intestine. iHSPs and IAP display potent anti-oxidant and anti-inflammatory properties that dynamically stimulate gut epithelial resistance to oxidative stress and inflammation. IAP is also anti-inflammatory systemically ileal iHSP27 was positively correlated with fiber intake highlighting better the importance of dietary compo- and various correlations between iHSPs and the gut nents for stimulating IAP- and (or) iHSP-dependent microbiota were set up for both the ileum and the mechanisms of gut epithelial protection. colon (see above) [56]. Also, two probiotic strains (L. Abbreviations johnsonii strain P47-HY and L. reuteri strain P43- ATP: Adenosine triphosphate; CpG DNA: Cytosine-phosphate-guanidine HUV) were demonstrated to stimulate iHSPs in deoxyribonucleic acid; ERGMT: Glutamyl-arginyl-glycyl-methionyl-threonine; IPEC-J2 porcine intestinal cell line in vitro [70]. By ERK1/2: Extracellular signal-regulated kinase; fMLP: N-Formylmethionyl- leucyl-phenylalanine; GIT: Gastrointestinal tract; GPR: G-protein coupled contrast, another probiotic (Enterococcus faecium receptor; HSF: Heat shock factor; HSP: Heat shock protein (iHSP, inducible strain NCIMB) did not do so in this porcine cell line, HSP); IAP: Intestinal alkaline phosphatase; LPS: Lipopolysaccharide; MAPK despite its stimulation on HSP70 in human Caco2 p38: p38 Mitogen-activated protein kinase; NF-κB: Nuclear factor-kappa B; OCTN-2: Organic cation transporter; PepT1: Peptide transporter 1; cells [71]. This highlights the host species-dependent PUFA: Polyunsaturated fatty acid; SCFA: Short-chain fatty acid; TLR: Toll-like specificity of probiotic effects on gut epithelial cells. receptor; UDP: Uridine diphosphate; ZO: Zonula occludens Finally, we showed that the mycotoxin fumonisin-B1 Funding slightly stimulated iHSP70 (but not iHSP27) in the je- This review was prepared as a normal activity of the Author within INRA. junum, without effects on iHSPs in the colon of There was no special funding from INRA for preparing the review and INRA already weaned pigs [72]. had no role in the preparation of the manuscript. Authors’ contributions Conclusions JPL gathered and read all the literature and wrote the entire paper. The present review summarizes the published infor- mation on gut protection and defense systems, Competing interest namely IAP and inducible HSPs, in rodent species The author declares that he has no competing interests. and in pigs (Fig. 1). It also highlights the stimulation Consent for publication of these protection systems by a variety of dietary Not applicable. components that could, therefore be used to promote gut health. Importantly, many probiotic strains dis- Ethics approval and consent to participate play protective properties that involve IAP and (or) Not applicable. iHSP stimulation. Data in pigs are more limited than Data sharing and repository in laboratory rodents but they also support roles for Not applicable. IAP and iHSPs in microbiota - host interactions and in controlling gut function and inflammation. Author details Division of Human Nutrition Division, INRA Clermont-Ferrand, France. Additional work is needed (especially in pigs) for 2 3 Human Nutrition Research Center – West, Nantes, France. Present Address: setting up unequivocal cause-and effect relationships INRA – SDAR, Domaine de la Motte, B.P. 35327, F-35653 Le Rheu Cedex, in the microbiota-host interaction for gut health and France. 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Soybean-derived beta- � We provide round the clock customer support conglycinin affects proteome expression in pig intestinal cells in vivo and in � Convenient online submission vitro. J Anim Sci. 2011;89:743–53. 66. Lallès JP, Lacan D, David JC. A melon pulp concentrate rich in superoxide � Thorough peer review dismutase reduces stress proteins along the gastrointestinal tract of pigs. � Inclusion in PubMed and all major indexing services Nutrition. 2011;27:358–63. � Maximum visibility for your research 67. Sargeant HR, Miller HM, Shaw MA. Inflammatory response of porcine epithelial IPEC J2 cells to enterotoxigenic E. coli infection is modulated by Submit your manuscript at zinc supplementation. Mol Immunol. 2011;48:2113–21. www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Animal Science and Biotechnology Springer Journals

Microbiota-host interplay at the gut epithelial level, health and nutrition

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2016 The Author(s).
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10.1186/s40104-016-0123-7
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Abstract

Growing evidence suggests the implication of the gut microbiota in various facets of health and disease. In this review, the focus is put on microbiota-host molecular cross-talk at the gut epithelial level with special emphasis on two defense systems: intestinal alkaline phosphatase (IAP) and inducible heat shock proteins (iHSPs). Both IAP and iHSPs are induced by various microbial structural components (e.g. lipopolysaccharide, flagellin, CpG DNA motifs), metabolites (e.g. n-butyrate) or secreted signal molecules (e.g., toxins, various peptides, polyphosphate). IAP is produced in the small intestine and secreted into the lumen and in the interior milieu. It detoxifies microbial components by dephosphorylation and, therefore, down-regulates microbe-induced inflammation mainly by inhibiting NF-κB pro-inflammatory pathway in enterocytes. IAP gene expression and enzyme activity are influenced by the gut microbiota. Conversely, IAP controls gut microbiota composition both directly, and indirectly though the detoxification of pro-inflammatory free luminal adenosine triphosphate and inflammation inhibition. Inducible HSPs are expressed by gut epithelial cells in proportion to the microbial load along the gastro-intestinal tract. They are also induced by various microbial components, metabolites and secreted molecules. Whether iHSPs contribute to shape the gut microbiota is presently unknown. Both systems display strong anti-inflammatory and anti-oxidant properties that are protective to the gut and the host. Importantly, epithelial gene expressions and protein concentrations of IAP and iHSPs can be stimulated by probiotics, prebiotics and a large variety of dietary components, including macronutrients (protein and amino acids, especially L-glutamine, fat, fiber), and specific minerals (e.g. calcium) and vitamins (e.g. vitamins K1 and K2). Some food components (e.g. lectins, soybean proteins, various polyphenols) may inhibit or disturb these systems. The general cellular and molecular mechanisms involved in the microbiota-host epithelial crosstalk and subsequent gut protection through IAP and iHSPs are reviewed along with their nutritional modulation. Special emphasis is also given to the pig, an economically important species and valuable biomedical model. Keywords: Diet, Gut, Inducible heat shock protein, Inflammation, Intestinal alkaline phosphatase, Microbiota Background aiming at digestion and nutrient absorption and the The gastrointestinal tract (GIT) is, like the skin or the large intestine specialized in the fermentation of un- lung, a major interface organ between the environment digested materials. The gut epithelium is also the first and interior milieu. It is the site with the highest load of line of GIT (and body) defense and protection. Its action microorganisms (also referred to as “the microbiota”). is complementary to that of the associated mucosal im- This is especially true in the large intestine due to sub- mune system whose development and maintenance are stantial amounts of undigested dietary and endogenous induced by the microbiota [1]. Thus gut epithelial cells - (e.g. mucus, enzymes) components amenable to micro- enterocytes and colonocytes - are polarized key players bial fermentation. Gut epithelial cells are thus the first influenced by both the environment (e.g. food, patho- cells to be exposed to nutrients and the microbiota, with gens, toxicants) and body metabolism and functions. complementary functions between the small intestine The gut epithelium has developed over time various mechanisms for sensing not only nutrients but also mi- crobial structural components (e.g. lipopolysaccharide, Correspondence: jean-paul.lalles@inra.fr 1 LPS; peptidoglycan, flagellin, CpG DNA motifs), metab- Division of Human Nutrition Division, INRA Clermont-Ferrand, France Human Nutrition Research Center – West, Nantes, France olites (e.g. short chain fatty acids, SCFA) or secreted Full list of author information is available at the end of the article © The Author(s). 2016 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Lallès Journal of Animal Science and Biotechnology (2016) 7:66 Page 2 of 8 molecules (e.g. toxins, polyphosphate chains, other com- an array of physiological properties that include: entero- pounds still unknown). These sensors include for ex- cyte apical surface pH maintenance through the control ample Toll-like receptors (TLRs) [2, 3] and receptors to of bicarbonate secretion, absorption of nutrients and SCFA. All these mechanisms make the molecular basis minerals (e.g. fatty acids, calcium), detoxification (by de- of the crosstalk between the host and the gut microbiota phosphorylation) of pro-inflammatory microbial compo- at the epithelial level. nents (e.g. LPS, flagellin, CpG DNA motifs, uridine Numerous experimental and clinical data have shown diphsophate (UDP)) and, ultimately control of gut (and that defects in gut barrier function may lead to chronic systemic) inflammation [20, 21]. IAP is an enzyme dy- inflammatory diseases and sometimes cancers [4–7]. namically produced by the enterocyte in the small intes- These diseases affect not only the GIT but also other or- tine and secreted both luminally and basolaterally. Part gans (e.g. liver, brain) and include diverse metabolic dis- of lumen IAP escapes digestion in the bowel, remains turbances (ranging from glucose intolerance and insulin active along the large intestine and can still be detected resistance, type-2 diabetes to metabolic syndrome and in small amounts in the feces. obesity), known risk factors for cardiovascular disorders. Previous data suggested IAP to participate indirectly Importantly, more recent investigations has highlighted to the control of intestinal barrier function [21], but a that many of these diseases may be modulated by the direct involvement was demonstrated in mice recently gut microbiota [8], though cause-and-effects relation- [22]. More precisely, IAP stimulates gene expression of ships are often poorly understood. For instance, chronic key tight junctions (Zonula occludens ZO-1 and ZO-2; metabolic diseases and obesity may be related to body occludin) and their correct cellular localization. entry of enteric microbial components (e.g. LPS) thus Many recent data now converge to indicate that IAP not triggering chronic low-grade, “metabolic” inflammation only detoxifies microbial components but also contributes [9, 10]. This in turn favors diet energy extraction, fat to shape the gut microbiota and to prevent microbial en- synthesis and adipose tissue development, and shifts en- teric translocation into the body [14]. Free exogenous (e.g. ergy metabolism towards fat deposition and adipose tis- from bovine intestine) IAP per se does not seem to influ- sue inflammation, thus leading to metabolic syndrome ence bacterial growth but enterocyte-bound IAP could and obesity. The diet is a major lever of gut microbiota delay that of Escherichia coli in vitro (with no effects on modulation and is now regarded as a serious approach other bacteria such as Clostridium difficile, S. typhimur- for maintaining high microbiota diversity (or gene rich- ium or Enterococcus faecalis)[23–25]. Mice deleted for ness) and preserving health as well as correcting dysbio- Iap gene (called Akp3 in this species) were reported to dis- sis often observed in many chronic diseases [11]. This is play fecal microbiota that were different from those of of utmost importance in the context of drastic reduction wild-type mice: marked decrease in the overall load of of food diversity over the last decades [12]. both aerobic and anaerobic bacteria, drastic reduction in The present review focuses on two specialized defense E. coli population and, conversely, increases in Clostri- and protection systems at the epithelial level, namely in- diales, Lactobacilli and Enterococci [24]. The precise testinal alkaline phosphatase (IAP) and inducible heat mechanisms for these IAP-dependent changes in gut shock proteins (iHSPs). Both of them are modulated by microbiota composition are not fully understood yet but the microbiota and the diet and confer gut epithelial (and they may involve alterations in epithelial surface pH body) protection due to their potent anti-inflammatory and reduced gut inflammatory tone [26, 27]. Another and anti-oxidant capacities. Data available in the pig are pathway of microbial control involving IAP was re- also reviewed given the economic importance of this cently reported [28, 29]. Free luminal adenosine tri- species and its high potential as a biomedical model phosphate (ATP), a strong pro-inflammatory danger for studies on development, microbiology, physiology, signal, dose-dependently inhibited microbial growth, neurobiology and nutrition [13–16]. In particular, the targeting more specifically Gram-positive (but not weaning period is critical to pig rearing due to high Gram-negative) bacteria [29]. IAP was able to dephos- stress, GIT pathophysiology, growth check and in- phorylate and detoxify ATP, thus ultimately releasing creased risk of enteric diseases [17, 18]. Fortunately, free adenosine which is a strong anti-inflammatory selected dietary approaches may help circumvent molecule. Importantly, ATP was shown to drive cell dif- these disorders [19]. Therefore, dietary components ferentiation of Th17 T lymphocytes that produce IL-17 improving gut health through stimulating IAP and in- and IL-22 cytokines. The former is known to favor neu- ducible HSP proteins are briefly reviewed here too. trophil tissue infiltration while both cytokines stimulate antibacterial peptide production. IAP was already Intestinal alkaline phosphatase and the gut microbiota shown to inhibit gut tissue infiltration of neutrophils in Intestinal alkaline phosphatase (IAP), the specific intes- zebra fish [23], thus strengthening the anti-inflammatory tinal isoform of ubiquitous AP gene products, displays capabilities of IAP. Lallès Journal of Animal Science and Biotechnology (2016) 7:66 Page 3 of 8 Regarding bacterial translocation, earlier investigations shown to be strong inducers of gut epithelial iHSPs in reported an inhibitory effect of IAP [30]. However, later vitro and sometimes in vivo, though others (e.g. Entero- work suggested a rather indirect influence though IAP- bacter aerogenes and Proteus mirabilis for Gram-negative driven down-regulation of inflammation and subsequent species; Enterococcus faecalis for Gram-positive species) reinforcement of gut barrier function [31, 32]. had no effects on iHSPs. In the same line, many probio- Collectively these data indicate that IAP directly and tics, especially of Lactobacilli and Bifidobacteria strains, indirectly controls gut microbiota load and balance and but not all probiotics (e.g. E. coli Nissle 1917) were dem- that this directly connects to gut inflammatory tone. onstrated to induce gut epithelial HSPs and different cell sensors (e.g. TLRs or other molecules) and signaling path- Inducible heat shock proteins and the gut microbiota ways (often p 38 MAPK) have been disclosed (Table 1) Beside the general roles of HSPs as intracellular protein (see also Table 2 and Table of ref. [34]). Finally, some (e.g. chaperones, those induced specifically in gut epithelial metronidazole), but not all antibiotics (or mixtures) may cells, namely HSP25 (or HSP27, depending on the host decrease iHSP levels and increase gut susceptibility to species) and HSP70 are involved in many vital functions microbial toxins (e.g. C. difficile toxin A). (e.g. cell proliferation and apoptosis, immune responses) Collectively these data suggest that iHSP induction at and the control of inflammation and oxidation [33, 34]. the gut level might be one important mechanism of gut Importantly, iHSPs regulate gut barrier function, by spe- epithelial protection by commensal bacteria and probio- cifically controlling the expression of key tight junction tics and that any alterations in this protection may be proteins (e.g. occludin) and by down-regulating adverse detrimental to the host. effects of oxidative and inflammatory stress on cells [33]. In rodents, epithelial iHSPs are expressed at low and Dietary modulation of gut defense and protection high levels in the small and large intestines, respectively systems [34]. This actually reflects the loads of microbes present We have reviewed that many dietary compounds can along these compartments and that are a major factor of modulate both IAP and iHSP gene expressions and pro- iHSP induction. Indeed, intestinal and colonic epithelial tein concentrations or activities [20, 21, 34]. cells per se are equally responsive to iHSP-inducing stimuli and the gut proximal-distal iHSP gradient disap- pears in germfree animals [35, 36]. Intestinal alkaline phosphatase The microbiota-host epithelial crosstalk is first Food intake per se is a stimulator of IAP while starvation brought about by specific microbial compounds, includ- has opposing effects [30]. Dietary added calcium stimu- ing structural components (e.g. LPS, lipoteichoic acid, lates IAP in rat intestine [39]. Calcium is known to be flagellin), metabolites (especially n-butyrate but also pro- protective in colonic inflammation models but the impli- pionate), toxins (e.g. toxin A from Clostridium difficile, cation of IAP was not explored. Free phosphorus had enterotoxin B superantigen from Staphylococcus aureus) inhibitory effects on IAP while bound phosphate (e.g. to and other soluble substances (e.g. various peptides like starch in some potato varieties) is dose-dependently fMLP) [34]. All these substances are recognized by spe- stimulatory. Therefore, calcium-to-phosphorus ratio and cific receptors (e.g. TLRs) or are internalized in gut epi- their chemical forms in the diet are critical to IAP activity. thelial cells by specific transporters (e.g. the peptide Besides, vitamins K1 (philloquinone) and K2 (menaquin- transporter PepT1), and intracellular signaling pathways one-4) could also stimulate IAP in rodents. involve various kinases (especially p38 MAPK) [34]. Many HSP inducers are active at very low concentra- Table 1 Molecular sensors, microbial component and tions (ng order) and responses are often fast (within a intracellular signalling pathways involved in the induction of HSPs by intestinal epithelial cells (adapted from ref. [34]) few hours). Therefore, the physiological epithelial iHSP tone is under direct influence of the gut microbiota Molecular sensor/receptor Microbial component Signalling pathway on intestinal epithelial cell recognized involved composition and metabolic activities. Their stimuli are, TLR-2 Lipoteichoic acid ? in turn, essential for permanently triggering optimal levels of epithelial defense given the fact that iHSPs con- TLR-4 Lipopolysaccharide MAPK p38, ERK1/2 fer protection to gut epithelial cells exposed to oxidative TLR-5 Flagellin MAPK p38 stress and inflammation [34]. GPR-41 & GPR-43 Butyrate, propionate ? Anaerobic bacteria (e.g. Bacteroides fragilis)were re- (putatively) ported to have important roles in HSP induction [37, 38]. PepT1 fMLP peptide MAPK p38 A variety of Gram-negative bacteria (e.g. E. coli)and OCTN-2 ERGMT peptide MAPK p38 Gram-positive bacteria (Bifidobacterium breve, Lactobacil- Integrin-β Polyphosphate chains MAPK p38 lus paracasei, L. plantarum, L. Johnsonii) have been Lallès Journal of Animal Science and Biotechnology (2016) 7:66 Page 4 of 8 Fat intake stimulates IAP in rodents and this has been iHSPs in the ileum and the colon of rats. Conversely, interpreted as an adaptive response to fat-dependent in- pro-inflammatory, high sulfated saccharides like dextran creases in intestinal LPS uptake and translocation (via sulfate sodium and carrageenans are known to disturb the chylomicron pathway) into the interior milieu [40]. iHSP phosphorylation and functionalities, thus favoring The degree of saturation and length of fatty acids are gut inflammation. Therefore, the type of dietary fiber is also important to consider [20, 21]. Saturated and important to consider when iHSP stimulation is needed. medium-chain fatty acids appear as stronger inducers of Surprisingly, various polyphenols were often shown to IAP compared to poly-unsaturated fatty acids (PUFA). be potent inhibitors of gut iHSPs (e.g. quercetin), though Saturated fats are known for shifting the gut microbiota they display anti-oxidant properties [34]. Finally, dietary towards more Gram-negative bacteria and, therefore, mycotoxins with high oxidant capacity (e.g. zearalenone, more pro-inflammatory microbial components and more fumonisins) induce iHSPs but this response is usually in- inflammation [41]. Importantly, intestinal tissue con- sufficient to counteract mycotoxin toxicity. centration of (n-3) PUFA was recently demonstrated Many probiotics, especially Lactobacillus and Bifido- to determine the level of gene expression and enzyme bacteria strains are inducers of gut epithelial iHSPs and activity of IAP which, in turn modified the gut micro- contribute to gut protection (see Tables 3 and 5 in ref. biota composition and enhances barrier function [42]. [34]). These probiotics can induce either or both (HSP25 In particular, the proteobacteria phylum (e.g. E. coli and HSP70) iHSPs, depending on the strain. Inhibition and other LPS-producing species) was reduced while of pro-inflammatory cytokine (e.g. IL-8) secretion and of anti-inflammatory bacteria (e.g. Bifidobacteria, Lactoba- some pathogens (e.g. S. typhimurium) has been docu- cilli; Akkermansia muciniphila) were enhanced in (n-6) mented too. The probiotic-dependent protection are me- PUFA-fed, genetically engineered (Fat-1) mice that are diated by various microbial triggers: cell wall components able to convert dietary (n-6) PUFA into (n-3) PUFA. This (lipoteichoic acids, LPS, flagellins), metabolites (butyrate, contributes to explain, especially at the gut level the anti- propionate) or secreted molecules (e.g. peptides; poly- inflammatory properties of (n-3) PUFA. phosphate) (Table 1). A number of epithelial cell mem- brane sensors have been identified (TLRs, peptide Inducible gut epithelial HSPs transporters, etc.) while others remain to be discovered. Many dietary components are modulators of gut epithe- Intracellular signaling often involves kinases, and espe- lial iHSPs [43]. This includes notably various amino cially p38 MAPK. Interestingly, Japanese groups have se- acids and proteins, fiber, zinc, n-butyrate and many pro- lected Lactobacillus (L. paracasei and L. brevi)probiotic biotics. The stronger inducer of iHSPs is without contest strains that produce high amounts of long-chain polypho- L-glutamine whose action is fast and of high magnitude. sphates (up to 700 phosphate units) that are responsible Its mode of action involves polyamines that increase the for improving epithelial barrier function in vitro and in binding between transcription factor HSF-1 and heat- mice [43–46]. Polyphosphate is endocytosed by the cell shock element on Hsp genes. Putrescine and spermidine, through caveolin-1 and integrin-β1 mechanisms and and their precursor ornithine stimulate the induction of p38-MAPK-dependent gene expression and protein both HSP25 and HSP70 in various gut epithelial cell production of HSP27. Endocytosis is the key step for lines in vitro. Spermine seems to induce HSP25 only. polyphosphate protective action [44, 45]. As a result, Molecular mechanisms of L-glutamine action involve synthetic long-chain polyphosphates added to the diet the up-regulation of Hsf1 gene expression and promoter may be serious candidates for mimicking the protect- activation resulting in iHSP production and subsequent ive action of those probiotics in vivo. down-regulation of the pro-inflammatory NF-κB path- Collectively these data support the diet (including way (by inhibiting protein p65 nuclear translocation and probiotics) as a major lever for stimulating gut defense cell apoptosis). Other iHSP-stimulatory L-amino acids, systems and controlling inflammation and oxidative though less effective than glutamine include glutamate, stress. arginine, threonine and metabolic intermediates like cit- rulline [34]. Regarding dietary proteins, plant lectins (from kidney bean or wheat germ) inhibit iHSP expres- Gut IAP and iHSP defense systems and their nutritional sion while wheat gluten (involved e.g. in celiac disease) modulation in the pig disturbs iHSP cellular localization in vitro, thus increas- The pig is a major source of meat worldwide and it is ing cell sensitivity to oxidation and inflammation. increasingly used as a biomedical model in various Mineral and organic forms of zinc as well as SCFA like domains [13–16]. Most of the mechanisms of gut epithe- butyrate (n- and iso- forms) and propionate are strong lial protection by IAP or iHSPs and their modulation by inducers of gut epithelial iHSPs in vitro. Pectin, a soluble dietary components have been described, at least partly and fermentable fiber (but not cellulose) stimulates both in the swine species too (e.g. for IAP: [47]). Lallès Journal of Animal Science and Biotechnology (2016) 7:66 Page 5 of 8 Intestinal alkaline phosphatase reflected dietary fatty acid profiles, suggesting a link with Pigs display three alkaline phosphatase gene copies in IAP levels [43, 57]. Furthermore, wheat arabinoxylan the intestine, thus being intermediate between domestic alone or associated with cellulose was recently shown to carnivorous (single copy) and ruminants (seven copies) increase ileal total AP activity [58]. This was interpreted [48]. IAP is strongly inhibited after early weaning in pigs as positive as it is essentially the IAP isoform that is and this is considered as a major factor in post-weaning present in the small intestine [20, 21]. The Authors also disorders and enhanced piglet sensitivity to enteric infec- reported increased AP activity in the mid-colon in re- tions [49]. The hormone glucagon-like peptide 2 (GLP-2), sponse to arabinoxylan supplementation [58]. This obser- known for its intestine-trophic properties has been re- vation should be interpreted with caution because it was cently shown to stimulate duodenal and jejunal IAP in total AP (and not specifically IAP isoform) activity that weaned pigs injected with exogenous (human) GLP-2 was measured and this could reflect a sign of colonic in- [50]. This was associated with the maturation of intestinal flammation, e.g. resulting from increased tissue infiltration epithelial cells. Finally, piglets born to sows treated with by neutrophils [21]. Thus, effects of dietary components antibiotics (amoxicillin) around parturition transiently dis- on GIT AP activity should be interpreted carefully accord- played lower Iap gene expression and IAP enzyme activity ing to GIT segment and efforts to differentiate between than piglets born to untreated sows [51]. true IAP isoform and nonspecific AP activities using appropriate AP inhibitors [20] should be considered. Inducible gut epithelial HSPs Interestingly, IAP was shown to be higher in pigs selected Pigs display substantial and fairly similar iHSP concen- for low, compared to high residual feed intake and this trations in the small and large intestine [52–54], con- was associated with lower inflammation and circulating trary to laboratory rodents that are virtually devoid of levels of LPS [59]. These data collectively suggest that IAP iHSPs in the small intestine (except in its distal part: the is influenced by the type/source of dietary fat and fiber ileum) [34]. Growing pigs even displayed higher iHSP and also reduces LPS intestinal translocation and inflam- concentrations in the ileum than in the colon [55]. mation in pigs. Also, intestinal IAP could be one key to Intra-uterine growth retarded piglets were shown to dis- residual feed intake and feed efficiency. play higher duodenal and jejunal HSP70, as hallmarks of fetal stress in utero [55]. iHSPs have been evidenced to iHSPs Feed intake modulates iHSPs along pig GIT [52]. be modulated by weaning along the GIT of piglets [52]. Many feed ingredients, including amino acids and pro- Small intestine iHSPs were not influenced in piglets teins, carbohydrates (including fiber) and fat are known born to sows given antibiotics (amoxicillin) around par- to modulate gut function in pigs [18]. However, only turition but colonic HSP70 was transiently decreased some studies specifically investigated iHSPs. [53]. Important links between iHSPs and the gut micro- L-glutamine as repeatedly been shown to improve biota were demonstrated in pigs (fed chicory inulin, see growth performance and intestinal anatomy and function below) [55]. These included: negative correlations be- in weaned piglets [18], and these effects were partly medi- tween HSP27 and lumenal bacteria (L. reuteri and ated by intestinal epithelial HSP70 [60]. L-glutamine also Enterobacteriacae), positive correlations between iHSPs improved intestinal maturation in intra-uterine growth and lactic acid-producing bacteria or L. Johnsonii. Ileal retarded pig neonates through HSP70-mediated mecha- HSP27 and colonic HSP70 correlated negatively with nisms [61]. Protective iHSP-mediated effects on the gut the diversity of mucosa-associated bacteria and Rose- were also brought about with diets supplemented with buria faecis (a butyrate producer). Colonic HSP70 cor- L-arginine, α-ketoglutarate and N-carbamyl-glutamate related negatively with Prevotella brevis but positively [62, 63]. Besides, soybean proteins are considered as with the anti-inflammatory bacterium Faecalibacterium toxic for the gut of piglets [64]. The storage protein prausnitzii [56]. Although such individual correlations β-conglycinin was recently shown to inhibit gut HSP70 are difficult to interpret in terms of cause-and effect re- in pigs, probably contributing to the adverse effects of lationships, they suggest intimate interactions between soybean proteins [65]. Conversely, a weaning diet supple- iHSPsand thegut microbiotainpigs. mented with a melon pulp rich in the anti-oxidant enzyme superoxide dismutase decreased iHSP protein concentra- Dietary modulation of gut IAP and iHSPs in pigs tions along the GIT of already weaned piglets, but this IAP Few data are available on the effects of dietary probably reflected reduced oxidative stress [66]. Finally, factors on IAP in pigs [20, 21]. First, feed intake is an zinc oxide up-regulated Hsp70 gene in porcine IPEC-J2 important IAP modulator in pig gut [53]. Regarding epithelial cell line but could not be shown to do so at high fat, Dudley et al. [57] reported higher IAP in pigs fed zinc level (2,200 ppm) in vivo [67–69]. Regarding dietary high fat diets with saturated (tallow), compared to un- fiber, chicory pectin was recently shown to stimulate ileal saturated (corn oil) fat sources. Intestinal cell membranes and colonic HSP27 in growing pigs [56]. Interestingly, Lallès Journal of Animal Science and Biotechnology (2016) 7:66 Page 6 of 8 Fig. 1 Various food components (nutrients, minerals, vitamins) modulate inducible heat shock proteins (iHSPs) and intestinal alkaline phosphatase (IAP) in the epithelium of the small intestine. It is mostly microbial compounds, fermentation products (short-chain fatty acids, SCFA) and other unknown secreted molecules of microbial origin that induce iHSP in the large intestine (nb: IAP expression and activity are very low there). Luminal IAP contributes to control the gut microbiota (present in low numbers) in the small intestine. Luminal IAP also partially escapes digestion in the small intestine and is active to shape the gut microbiota in the large intestine. iHSPs and IAP display potent anti-oxidant and anti-inflammatory properties that dynamically stimulate gut epithelial resistance to oxidative stress and inflammation. IAP is also anti-inflammatory systemically ileal iHSP27 was positively correlated with fiber intake highlighting better the importance of dietary compo- and various correlations between iHSPs and the gut nents for stimulating IAP- and (or) iHSP-dependent microbiota were set up for both the ileum and the mechanisms of gut epithelial protection. colon (see above) [56]. Also, two probiotic strains (L. Abbreviations johnsonii strain P47-HY and L. reuteri strain P43- ATP: Adenosine triphosphate; CpG DNA: Cytosine-phosphate-guanidine HUV) were demonstrated to stimulate iHSPs in deoxyribonucleic acid; ERGMT: Glutamyl-arginyl-glycyl-methionyl-threonine; IPEC-J2 porcine intestinal cell line in vitro [70]. By ERK1/2: Extracellular signal-regulated kinase; fMLP: N-Formylmethionyl- leucyl-phenylalanine; GIT: Gastrointestinal tract; GPR: G-protein coupled contrast, another probiotic (Enterococcus faecium receptor; HSF: Heat shock factor; HSP: Heat shock protein (iHSP, inducible strain NCIMB) did not do so in this porcine cell line, HSP); IAP: Intestinal alkaline phosphatase; LPS: Lipopolysaccharide; MAPK despite its stimulation on HSP70 in human Caco2 p38: p38 Mitogen-activated protein kinase; NF-κB: Nuclear factor-kappa B; OCTN-2: Organic cation transporter; PepT1: Peptide transporter 1; cells [71]. This highlights the host species-dependent PUFA: Polyunsaturated fatty acid; SCFA: Short-chain fatty acid; TLR: Toll-like specificity of probiotic effects on gut epithelial cells. receptor; UDP: Uridine diphosphate; ZO: Zonula occludens Finally, we showed that the mycotoxin fumonisin-B1 Funding slightly stimulated iHSP70 (but not iHSP27) in the je- This review was prepared as a normal activity of the Author within INRA. junum, without effects on iHSPs in the colon of There was no special funding from INRA for preparing the review and INRA already weaned pigs [72]. had no role in the preparation of the manuscript. Authors’ contributions Conclusions JPL gathered and read all the literature and wrote the entire paper. The present review summarizes the published infor- mation on gut protection and defense systems, Competing interest namely IAP and inducible HSPs, in rodent species The author declares that he has no competing interests. and in pigs (Fig. 1). It also highlights the stimulation Consent for publication of these protection systems by a variety of dietary Not applicable. components that could, therefore be used to promote gut health. Importantly, many probiotic strains dis- Ethics approval and consent to participate play protective properties that involve IAP and (or) Not applicable. iHSP stimulation. Data in pigs are more limited than Data sharing and repository in laboratory rodents but they also support roles for Not applicable. IAP and iHSPs in microbiota - host interactions and in controlling gut function and inflammation. Author details Division of Human Nutrition Division, INRA Clermont-Ferrand, France. Additional work is needed (especially in pigs) for 2 3 Human Nutrition Research Center – West, Nantes, France. Present Address: setting up unequivocal cause-and effect relationships INRA – SDAR, Domaine de la Motte, B.P. 35327, F-35653 Le Rheu Cedex, in the microbiota-host interaction for gut health and France. 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