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- Springer Journals
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- Copyright © The Author(s) 2023
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- 2049-1891
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- 10.1186/s40104-023-00838-z
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Abstract
Background Pectin is a heteropolysaccharide that acts as an intestinal immunomodulator, promoting intestinal development and regulating intestinal flora in the gut. However, the relevant mechanisms remain obscure. In this study, pigs were fed a corn-soybean meal-based diet supplemented with either 5% microcrystalline cellulose (MCC) or 5% pectin for 3 weeks, to investigate the metabolites and anti-inflammatory properties of the jejunum. Result The results showed that dietary pectin supplementation improved intestinal integrity (Claudin-1, Occludin) and inflammatory response [interleukin (IL)-10], and the expression of proinflammatory cytokines (IL-1β, IL-6, IL-8, TNF-α) was down-regulated in the jejunum. Moreover, pectin supplementation altered the jejunal microbiome and tryptophan-related metabolites in piglets. Pectin specifically increased the abundance of Lactococcus, Enterococcus, and the microbiota-derived metabolites (skatole (ST ), 3-indoleacetic acid (IAA), 3-indolepropionic acid (IPA), 5-hydrox- yindole-3-acetic acid (HIAA), and tryptamine ( Tpm)), which activated the aryl hydrocarbon receptor (AhR) pathway. AhR activation modulates IL-22 and its downstream pathways. Correlation analysis revealed the potential relationship between metabolites and intestinal morphology, intestinal gene expression, and cytokine levels. Conclusion In conclusion, these results indicated that pectin inhibits the inflammatory response by enhancing the AhR-IL22-signal transducer and activator of transcription 3 signaling pathway, which is activated through tryptophan metabolites. Keywords Dietary fiber, Gut microbiota, Immune pectin, Tryptophan metabolites † 3 Guoqi Dang and Xiaobin Wen contributed equally to this work. The Key Laboratory of Feed Biotechnology of Ministry of Agriculture, National Engineering Research Center of Biological Feed, Feed *Correspondence: Research Institute, Chinese Academy of Agricultural Sciences, No.12 Liang Chen Zhongguancun South Street, Haidian District, Beijing 100081, China chenliang01@caas.cn Hongfu Zhang zhanghongfu@caas.cn State Key Laboratory of Animal Nutrition, Institute of Animal Sciences, Chinese Academy of Agricultural Sciences, Beijing 100193, China Precision Livestock and Nutrition Unit, Gembloux Agro-Bio Tech, TERRA Teaching and Research Centre, Liège University, Passage des Déportés 2, Gembloux, Belgium © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Dang et al. Journal of Animal Science and Biotechnology (2023) 14:38 Page 2 of 15 gut health regulator. To bridge this knowledge, we exam- Introduction ined the changes in serum, gut microbiota, and trypto- Weaning is one of the most critical periods in both phan metabolite following pectin supplementation in al animal production and infant growth and develop- pig model. This study gave a novel perspective for pro - ment. The gastrointestinal tract of animals is not fully moting a new understanding of how pectin promotes gut developed at this stage [1]. It is susceptible to changes health. in feeding patterns and nutrition, leading to stress and diarrhea. Given the omnivorous and physiological simi- Materials and methods larities between weaned piglets and human infants, the Ethics statement piglet is regarded as the most suitable animal model for All animal experiments were approved by the Animal studying gut health [2]. Ethics Committees of Institute of Animal Sciences, Chi- Pectin, predominantly composed of α-1,4-linked nese Academy of Agricultural Sciences (Ethics Code Per- D-galacturonic acid (GalA) monomers, is abundant in mit IAS2019-37). citrus, apple, lemon peels and pulp. As a typical ferment- able dietary fiber, pectin can regulate the human and ani - Standards and chemicals mal intestinal microbiota [3–5]. It can also strengthen the Pectin extracted from citrus peel (Henan Yuzhong Bio- mucus layer to restrict the entry of hazardous substances technology Co., Ltd., Zhengzhou, China) mainly con- [6, 7]. Furthermore, it can enhance the integrity of the sisted of galacturonic acid (white powder, with purity of epithelial cell layer [8] and maintain intestinal integrity in > 81.4%, DM: 13.5%). Microcrystalline cellulose (MCC) piglets exposed to lipopolysaccharide or high-fat diet [9]. is a β-1,4-multi-bonded linear carbohydrate consist- The gastrointestinal tract is home to a diverse com - ing of glucose residues with 99.5% purity. (Beijing NCC munity of trillions of microorganisms collectively known Technology R&D Center, China). Reference standards as the gut microbiota [10], and this intricate commu- for tryptophan (Trp), tryptamine (Tpm), 3-indoleacetic nity is central to gut health and disease [11]. Moreover, acid (IAA) and kynurenine (Kyn) were purchased from the gut microbiota is associated with its ability to defend Sigma-Aldrich (St. Louis, MO, USA); 5-hydroxyindole- against enteropathogens, absorb nutrients, and maintain 3-acetic acid (HIAA) and skatole (ST) were obtained a healthy immune system [12–14]. However, pectin can from Cato Research Chemicals Inc. (Eugene, OR, USA); also have direct effects in the small-intestinal sites [7]. 3-indolylpropionic acid (IPA) and serotonin (5-HT) were It has been shown that the non-esterified GalA residues from Laboratory of the Government Chemist (Tedding- rich in pectin can bind to toll like receptor 2 (TLR2) via ton, UK) and Beijing Wokai Biotechnology Co., Ltd. ionic bonds [15]. The pectin suppresses the TLR2/1 sig - (China), respectively. Assay kits, including interleukin nal (TLR2 can form heterodimers with TLR1), and then IL-17, IL-22 were purchased from Nanjing Jiancheng IL-6 secretion is reduced, thereby reducing the inflam - Bioengineering Institute (Jiangsu, China). matory response and ameliorating the damage [16]. Recently, many studies have focused on the function Experimental design and animal care of microbial tryptophan catabolites in the gut and their A total of 16 crossbred barrows aged 21 d (6.77 ± 0.92 kg; contributions to host physiology [17]. For instance, aryl Duroc × Landrace × Yorkshire) were randomly assigned hydrocarbon receptor (AhR) ligands; 3-indole ethanol to one of two diets with eight piglets per treatment. No (IE), 3-indole pyruvate (IPA), and 3-indole aldehyde (IA) antibiotics were administered to the piglets throughout reduce gut permeability [18]. Serotonin (5-HT), another the 4-week experiment. Piglets were fed ad libitum and catabolite, plays an important role in gastrointestinal had free access to water. A corn-soybean basal diet was absorption, transit, and secretion. Besides, it also regu- formulated to meet nutritional requirements of National lates mood, behavior, pain modulation, and cognitive Research Council (NRC, 2012) [22]. After a 3-d of adap- function via the central nervous system [19]. Accord- tion, piglets were fed a diet containing either 5% micro- ing to a representative study, pectin supplementation crystalline cellulose (w/w) as the control (CON) group may not only alter the intestinal flora of mice, but also or 5% pectin (w/w) as the treatment (PEC) group for 3 increase the tryptophan metabolites of the flora by acti - weeks. All piglets were housed in separated pens with vating the AHR pathway [20]. Previous research from daily-cleaned plastic slatted floors. our laboratory has demonstrated the anti-inflammatory effects of pectin on gut immunity [21]. However, the pre - Sample collection cise mechanism by which pectin promotes gut health Blood samples were acquired from the jugular vein via remains unknown. a sterilized syringe before the pigs were sacrificed at the u Th s, the intriguing question was whether microbial end of the experiment. The serum was then separated by tryptophan catabolite is the link between pectin and the Dang et al. Journal of Animal Science and Biotechnology (2023) 14:38 Page 3 of 15 centrifugation for 10 min at 3000 × g at 4 °C and stored Table 1 Primer sequences used for real-time PCR in aliquots at −80 °C for cytokines analysis. The middle Gene Primer Nucleotide sequences (5′ to 3′) section (2 cm) of the jejunum was obtained and fixed in β-actin FGCG TAG CAT TTG CTG CAT GA 4% paraformaldehyde for histological examination. The RGCG TGT GTG TAA CTA GGG GT intestinal segment was washed with ice-cold phosphate ZO-1 FCTC CAG GCC CTT ACC TTT CG buffered saline (PBS), and the mucosa was scraped off RGGG GTA GGG GTC CTT CCT AT using a glass microscope slide. Mucosa samples were Occludin FCAG GTG CAC CCT CCA GAT TG immediately snap-frozen in liquid nitrogen and stored RTAT GTC GTT GCT GGG TGC AT at −80 °C to further investigate the bacterial community, Claudin-1 FTCG ACT CCT TGC TGA ATC TG genes, and protein expression. RTTA CCA TAC CTT GCT GTG GC IL-1β FGCC AGT CTT CAT TGT TCA GGTTT Intestinal morphology RCCA AGG TCC AGG TTT TGG GT The hematoxylin-eosin (HE) staining of the jejunum IL-6 FTCC AAT CTG GGT TCA ATC A was performed according to the methods as previ- RTCT TTC CCT TTT GCC TCA ously described [23]. Briefly, specimens of jejunum IL-8 FTAC GCA TTC CAC ACC TTT C were embedded in paraffin, sectioned (5 μm thickness), RGGC AGA CCT CTT TTC CAT T and stained with HE for histological evaluation [villus IL-10 FTCG GCC CAG TGA AGA GTT TC height (VH)]. Microphotographs were taken with a Leica RGGA GTT CAC GTG CTC CTT GA DM2000 light microscope (Leica, Wetzlar, Germany) at a IL-17 FCTC TCG TGA AGG CGG GAA TC magnification of 40. VH was performed using Image Pro RGTA ATC TGA GGG CCG TCT GG software [24]. TNF-α FCGT CGC CCA CGT TGT AGC CAAT RGCC CAT CTG TCG GCA CCA CC Serum inflammatory cytokines AhR FCAT GCT TTG GTC TTT TAT GC The ELISA kit was employed to detect serum cytokines RTTC CCT TTC TTT TTC TGT CC as previous describe [25]. Quantitative analysis of pro- CYP1A1 FCCT TCA CCA TCC CTC ACA GT inflammatory cytokine (IL-17), and anti-inflammatory RATC ACC TTT TCA CCC AGT GC cytokine (IL-22) in serum were measured by ELISA kits CYP1B1 FAAT AAC GGG GGA AAT TCC TG (Nanjing Jiancheng Bioengineering Institute, Nanjing, RCAC CGA AAC ACA ATG CAA TC China) according to the detection kit instructions. RegIIIγ FAAC CTG GAT GGG TGC AGA CGTG RTTG GTT CCA AGC CCT CGG TG Quantitative real‑time (qRT) PCR analysis IL-22 FCTA CAT CAC CAA CCG CAC CT Total RNA was extracted from the jejunum mucosa, RTCA GAG TTG GGG AAC AGC AC using the RNeasy Mini Kit (GeneBetter, Beijing, China). The concentration of each RNA sample was quanti - ZO-1 Zonula occludens-1, IL-1 Interleukin 1, IL-6 Interleukin 6, IL-8 Interleukin 8, IL-10 Interleukin 10, IL-17 Interleukin17, TNF-α Tumor necrosis factor-alpha, fied using the NanoDrop 2000 (Nanodrop Technolo - CYP1A1 Cytochrome P450, family 1, subfamily A, polypeptide 1, CYP1B1 gies, Wilmington, DE, USA). The cDNA was transcribed Cytochrome P450, family 1, subfamily B, polypeptide 1, IL-22 Interleukin 22 at 37 °C for 15 min and 85 °C for 5 s using the Prime- ScriptTM RT reagent kit with gDNA Eraser (Takara Bio- medical Technology in Beijing, China). qRT-PCR with 40 Waltham, MA, USA). It was quantified with the BCA amplification cycles was conducted with a commercial protein assay kit (Cat# 23225, Thermo, Waltham, MA, kit (PerfectStart Green qPCR SuperMix, TransGen Bio- USA). Total proteins in the amount of 30 μg were loaded tech, Beijing, China). In detail, a total of 10 μL reaction for separation onto 10% SDS-PAGE. The proteins mixture contain 1 μL of cDNA, 0.4 μL forward primer, were then transferred onto a polyvinylidene difluoride 0.4 μL reverse primer, 0.2 μL of ROX, and 3 μL of PCR- (PVDF) membrane at 90 V for 1.5 h using the wet trans- grade water. The gene of β-actin was used as an internal fer method. The membranes were then incubated in 5% control. Primers used were listed in Table 1. The relative skimmed milk for 2 h at room temperature for block- gene expression level between the control group and the ing. After incubation with a primary antibody Occludin -ΔΔCt treatment group was calculated by the 2 method, (Thermo Fisher Scientific Inc., #40-4700, 1:5000), Clau - and the value was normalized to the internal control. din-1 (Thermo Fisher Scientific Inc., #51-9000, 1:5000), IL-22 (Abcam, #ab193813, 1:2000), STAT3 (Bioword- Western blotting assay technology; #AP0365, 1:1000), P-STAT3 (Biowordtech- Total protein was extracted from jejunum tissue nology; #AP0248, 1:1000), and β-actin (CST, #4970 T, using RIPA lysis buffer (Thermo Fisher Scientific Inc., Dang et al. Journal of Animal Science and Biotechnology (2023) 14:38 Page 4 of 15 1:4000) overnight at 4 °C, the membranes were incubated 9–11 min (100% B), and the flow rate was 0.3 mL/min, with HRP-labeled goat anti-mouse or goat anti-rabbit and the column temperature was 40 °C. The amount of secondary antibodies (1:5000). Protein blots were visu- each metabolite was calculated according to standard alized using a gel imaging system (Tanon 2500R; Tanon curves with known metabolite levels. Science & Technology Co., Ltd., Shanghai, China). The band density was quantified using Image J 10.0 software Statistical analysis and normalized to β-actin. Data conforming to normal distribution were compared using Student t-test, while those with non-normally dis- 16S ribosomal RNA (rRNA) amplicon sequencing tributed were tested using Kruskal-Wallis test (CYP1A1, Genomic DNA was extracted from the jejunum mucosa serum IL-17, TNF-α). These analyses were performed TM using the EZNA Soil DNA Kit (D5625-02, Omega using the JMP software (JMP R version 10.0.0, SAS Insti- Bio-Tek Inc., Norcross, GA, USA), as directed by the tute, Cary, NC, USA) for Windows. manufacturer. The hypervariable region V3-V4 of the Raw data obtained from gut microbiota were processed bacterial 16S rRNA gene was amplified by a two-step using the free online platform of Majorbio I-Sanger PCR using specific primers (338F, 5′-ACT CCT ACG Cloud Platform (www.i- sanger. com). For β-diversity, GGA GGC AGC AG-3′ and 806R, 5′-GGA CTA CH principal-coordinate analysis (PCoA) plots were pro- VGGG TWT CTAAT-3′) with unique 8-bp barcodes to duced using Bray-Curtis distances, and community sig- facilitate multiplexing. The amplicons were sequenced nificance was confirmed with a Wilcoxon Rank-Sum using the Illumina HiSeq sequencing platform, as pre- test. All data were presented as mean ± standard error of viously described. The Majorbio Cloud Platform (www. the mean (SEM). Acceptable significance levels were at ∗ ∗∗ major bio. com) was used to analyze the raw data. The P < 0.05 and P ≤ 0.01. raw reads were deposited to the Sequence Read Archive Spearman’s or Mantel’s correlation was used to analyze (SRA) database (Accession Number: PRJNA876628) the correlation between the mucosal tryptophan metabo- of NCBI. A more detailed methodology was described lites, gene expression (inflammatory cytokines, STAT3/ previously [21]. IL-22 pathway), and tryptophan and its derivatives in the jejunum. Trp and its metabolites analysis by liquid chromatograph‑mass spectrometer (LC‑MS) Results Methanol was used to extract Trp and its metabolites Dietary pectin supplementation improved the integrity (ST, IAA, IPA, HIAA, Tpm, 5-HT, Kyn) from the jeju- of jejunum num mucosa. The methanol extraction solutions were To determine the effects of pectin supplementation on pre-cooled for 30 min at −20 °C. After being vortexed for intestinal integrity, HE staining, qPCR, and western 1 min, the samples were grinded 3 times (30 s for each blotting methods were used to examine the jejunum time and 10 s intervals) with high throughput Tissue- morphology and tight junctions. Histopathology stain- lyser instrument (Scientz-48, Jingxin, Shanghai, China). ing results showed that the villus height was increased The supernatant was collected after centrifugation at significantly (P < 0.05) in the PEC group than in control 10,000 × g for 5 min and filtered through 0.22 μm filter (Fig. 1A–B). Additionally, the mRNA expression levels of membranes (Jin Teng, Tianjin, China). tight junction proteins Claudin-1 (P = 0.005), Occludin LC-MS analysis was performed on Agilent 1290 (P = 0.016), and zonula occludens-1 (ZO-1, P = 0.108) UHPLC electrospray ionization-time-of-flight mass were increased (Fig. 1C–E). Western blotting results spectrometer (ESI-TOF-MS) coupled with Agilent 1260 showed that the protein level of Claudin-1 increased SFC-Ultivo equipped with an Agilent ZORBAX Eclipse greatly (P < 0.05), however, the level of Occludin did not XDB-C18 column (3.0 mm × 150 mm, 1.8 μm). A linear change significantly (Fig. 1F). It was indicated that pec- gradient was obtained by mixing eluent A (water + 0.1% tin supplementation improved intestinal barrier and gut formic acid) and eluent B (100% methanol). The elu - integrity. tion gradient for 5-HT and ST was as follows: 0–0.5 min (20% B), 0.5–1 min (20%–40% B), 1–3 min (65%–75% B), Pectin supplementation altered the expression levels 3–4 min (75%–90% B), 4–7 min (90%–100% B) at the flow of inflammatory cytokines in the jejunal mucosa rate of 0.5 mL/min. For the remaining metabolites (Trp, and serum IAA, IPA, HIAA, Tpm, Kyn), the elution gradient was set The inflammatory cytokines were also detected in the as follows: 0–0.5 min (20% B), 0.5–1 min (20%–40% B), jejunal mucosa and serum. In the jejunal mucosa, pectin 1–2 min (40%–50% B), 2–3 min (50%–80% B), 3–4 min supplementation downregulated the expression of pro- (80% B), 4–7 min (80%–85% B), 7–9 min (85%–100% B), inflammatory cytokines, IL-1β (Fig. 2A; P < 0.05), IL-6 Dang et al. Journal of Animal Science and Biotechnology (2023) 14:38 Page 5 of 15 Fig. 1 Eec ff ts of pectin on jejunal morphology in piglets. A Representative images of hematoxylin-eosin staining in the jejunum; B Jejunal villus height; C Jejunal mRNA expression levels of Claudin-1; D Jejunal mRNA expression levels of Occludin; E Jejunal mRNA expression levels of ZO-1 (n = 6). F Jejunal protein expression levels of tight junction proteins (Occludin, Claudin-1) (n = 4). Data were expressed as mean ± SEM. P < 0.05, ** *** P < 0.01, P < 0.001 (Fig. 2B; P < 0.05), IL-8 (Fig. 2C; P < 0.05), IL-17 (Fig. 2D; compared to the control group. Additionally, after pectin P = 0.066), and TNF-α (Fig. 2E; P < 0.05). On the other supplementation, a diminished expression level of IL-17 hand, the expression of the anti-inflammatory cytokine (Fig. 2G; P < 0.05) and an enhanced expression level of IL-10 (Fig. 2F; P = 0.088) was increased in the PEC group IL-22 (Fig. 2H; P < 0.008) was observed in the serum. Dang et al. Journal of Animal Science and Biotechnology (2023) 14:38 Page 6 of 15 Fig. 2 Pectin supplement altered the expression levels of inflammatory cytokines in the jejunum and serum. A IL-1β; B IL-6; C IL-8; D IL-17; E TNF-α; * ** *** F IL-10; A–F were detected levels in Jejunum; G IL-17; and H IL-22 were detected in serum, n = 6. P < 0.05; P < 0.01; P < 0.001; data are presented as the mean ± SEM (n = 6) u Th s, pectin supplementation in the diet regulated the (Fig. 3C). The composition of the gut microbial com - jejunum inflammatory responses in piglets. munity was then analyzed at the genus level. Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria consti- Pectin supplementation altered the bacterial community tuted the majority of the microbiota at the phylum level in jejunum mucosa (Fig. 3D). Pectin boosted the abundance of Proteobacte- Following size filtering, quality control, and chimera ria, whereas decreased the abundance of Actinobacteria checking, 16S rRNA amplicon sequencing results (Fig. 3E). Noticeable alterations in their microbial com- revealed a total of 859,243 reads ranging from 35,227 to position were detected at the genus level (Fig. 3F). Pectin 74,138 reads per sample, to examine the effect of pec - significantly reduced the relative abundance of Strepto - tin on microbial population in the jejunum. Sequencing coccus, Prevotella_9, Megamonas, Eubacterium, Megas- counts were normalized to acquire normalized reads for phaera, Prevotella_2, and Actidaminococcus, whereas it each sample into operational taxonomic units (OTUs) increased the relative abundance of Enterococcus, Lacto- based on 97% identity. coccus, and Morganella (Fig. 3G, P < 0.05). As indicated in Fig. 3, a Venn diagram was utilized to reveal the common and unique OTUs in the control and/ Pectin altered the levels of microbiota‑derived tryptophan or pectin supplementation groups. Pigs in the CON and metabolites in jejunum pectin groups had 367 and 1025 distinct OTUs, respec- Trp is an important metabolite related to gut microbiota. tively, and 769 common OTUs (Fig. 3A). Addition- Various diets and bacterial populations influenced the ally, alpha diversity (Sobs indexes) revealed that the gut concentration of Trp and its derivatives. The Trp-derived microbial flora diversity of pectin-treated piglets was sig - metabolites in the jejunal mucosa were determined to nificantly different from that of the control piglets, at the evaluate whether a change in the intestinal microbiota OTU level in the jejunal mucosa (Fig. 3B). This was fur - affects the production of Trp and its related metabolites ther supported by the beta diversity presented in PCoA after pectin supplementation. The concentration of Trp Dang et al. Journal of Animal Science and Biotechnology (2023) 14:38 Page 7 of 15 Fig. 3 Eec ff ts of pectin on the jejunum microbial diversity. A Venn diagram; B The alpha diversity indices (Sobs); C The beta diversity presented by the PCoA plot based on the OTU level; D The abundance of the intestinal microbiota composition at the phylum level; E Differences in microbial community composition between two groups at phylum level; F The abundance of the intestinal microbiota composition at the genus level; G Differences in microbial community composition between two groups at phylum level. Data were expressed as mean ± SEM, n = 8. P < 0.05; ** *** P < 0.01; P < 0.001 Dang et al. Journal of Animal Science and Biotechnology (2023) 14:38 Page 8 of 15 Fig. 4 Eec ff t of pectin on the jejunum microbial tryptophan metabolism concentration. A Trp (tryptophan); B ST (Skatole); C IAA (3-Indole acetic acid); D IPA (3-indolepropionic). E 5-Hydroxyindole-3-acetic acid; F Tpm ( Tryptamine); G 5-HT (5-hydroxytryptamine); H Kyn (Kynurenine). Data are * ** *** presented as the mean ± SE, (n = 8). P < 0.05; P < 0.01; P < 0.001 was significantly lower in the pectin group compared to protein levels of IL-22 and P-STAT/STAT3 were increased, the CON group (Fig. 4A). As for indole derivatives, the however, not to a significant level (Fig. 5G–H, P > 0.05). concentrations of ST (Fig. 4B), IAA (Fig. 4C), 3- IPA These results mentioned above suggested that pectin can (Fig. 4D), HIAA (Fig. 4E), and Tpm (Fig. 4F) were signifi - activate the AhR-IL-22-STAT3 signaling pathways. cantly higher in the pectin-fed piglets than in the CON group (P < 0.05). Particularly, the content of IPA reached AhR activation in mucosa is potentially correlated extremely significant levels (Fig. 4D; P < 0.001). Addi- with mucosal tryptophan metabolites tionally, two other pathway metabolites, 5-HT and Kyn Spearman rank correlations coefficient and significance were not significantly different between these two groups tests revealed a correlation between the various bacteria (Fig. 4G–H). Accordingly, adding pectin facilitated tryp- and the tryptophan metabolites (Fig. 6A). The concen - tophan metabolism towards the indoles as AhR ligands in tration of Trp was significantly and negatively correlated the piglet intestine. with the abundance of Lactococcus, whereas it was sig- nificantly and positively linked to the abundance of The changed Trp metabolism by pectin supplementation Prevotella_9. The concentration of IAA was positively activated the AhR/IL‑22/STAT3 signaling pathway in jejunal correlated with the abundance of Enterococcus, Lacto- mucosa of piglets coccus, and Rothia, but inversely correlated with Prevo- Microbial derived tryptophan catabolites (indole com- tella_9 and Megamonas. IPA was positively correlated pounds) are ligands for the AhR and act on the AhR in with the abundance of Lactococcus and Rothia, while it lymphoid cells. Therefore, we investigated the effect of was negatively correlated with Prevotella_9 and Megas- pectin on the AhR signaling pathway. We analyzed the phaera. Tpm had a significantly positive relationship with expression of AhR activation in the jejunum. All changes Enterococcus and Rothia, whereas it had a significantly in expression [AhR (Fig. 5A), IL-22 (Fig. 5B), cytochrome negative relationship with Megasphaera. P450 1A1 (CYP1A1, Fig. 5C), cytochrome P450 1B1 Moreover, the Mantel test demonstrated a significant (CYP1B1, Fig. 5D), recombinant regenerating islet derived correlation between Trp and the gene expression levels of protein 3 gamma (RegIIIγ, Fig. 5E)] were significantly Claudin-1, IL-17, CYP1A1, and RegIIIγ (Mantel’s r > 0.25, increased (P < 0.05). Similar results were obtained using P < 0.05, Fig. 6B). Beyond that, five genes (Occludin, IL-6, WB analysis of the IL-22-STAT3 pathway (Fig. 5F). The IL-10, IL-22, AhR) showed a significant correlation with Dang et al. Journal of Animal Science and Biotechnology (2023) 14:38 Page 9 of 15 Fig. 5 Dietary pectin supplementation influenced AhR activation and relative downstream genes expression in the jejunum of weaned piglets. A AhR; B IL-22; C CYP1A1. D CYP1B1. E RegIIIγ. F Protein abundances of IL-22, STAT3 and p-STAT3; G Protein abundances of IL-22; H The protein rate of * ** *** p-STAT3/STAT3. Data are presented as the mean ± SE, (n = 6). P < 0.05; P < 0.01; P < 0.001 ST (Mantel’s r > 0.25, P < 0.05). IAA significantly corre - was also associated with eight genes (Occludin, ZO-1, lated with Occludin, ZO-1, IL-22, CYP1A1, and CYP1B1. IL-10, IL-22, AhR, CYP1A1, CYP1B1, and RegIIIγ). There Additionally, we found that Claudin-1, CYP1B1, and was a significant relationship between Tpm and ZO-1, RegIIIγ showed a significant association with IPA. HIAA IL-6, TNF-α, IL-22, AhR, and RegIIIγ. Dang et al. Journal of Animal Science and Biotechnology (2023) 14:38 Page 10 of 15 Fig. 6 Heat maps of the Spearman rank correlation coefficient and significant tests between the differential bacteria and tryptophan metabolites (A). Pairwise comparisons if metabolites are demonstrated with a color gradient denoting Spearman’s correlation coefficient. Trp, ST, IAA, IPA, HIAA, and Tpm are related to inflammatory cytokines, jejunum morphology indices by partial spearman tests. Edge width corresponds to the Partial Spearman’s r statistic for the corresponding distance correlations and edge color denotes the statistical significance (B). Data are presented as the * ** *** mean ± SE, (n = 6). P < 0.05; P < 0.01; P < 0.001 Dang et al. Journal of Animal Science and Biotechnology (2023) 14:38 Page 11 of 15 Discussion pro-inflammatory cytokine (TNF-α , IL-6), and promoted During the weaning transition period, piglets are suscep- the release of IL-10 [37]. IL-17 is also a proinflammatory tible to infection by various pathogens and non-patho- cytokine mainly produced by Th17 cells and is associated gens, associated with a disrupted state of microbiota and with the pathogenesis of many autoimmune inflamma - an immature immune system [26]. Emerging evidence tory diseases [38]. IL-10, which is primarily secreted by demonstrated that pectin could enhance anti-inflamma - Tregs, reduces Th17 development and function, as well as tory properties, regulate the host microbiome [27], boost inhibits the secretion of proinflammatory cytokines and markers of mucus barrier function, modulate immuno- chemokines [39]. Research showed that the decreased logical activity [21, 28], and promote gut integrity [29]. In expression of IL-10 and the increased expression of IL-17 this study, we demonstrated that supplementing piglets might aggravate intestinal inflammation [40]. Interest - with pectin can boost their anti-inflammatory activity, ingly, the pectin treatment decreased the mRNA expres- which may be associated with changes in microbial tryp- sion level of IL-17 while increasing the mRNA expression tophan metabolites induced by pectin supplementation. level of IL-22, which was consistent with the data men- In this study, pectin was found to increase the villus tioned above from the previous studies. Moreover, the height, suggesting that it enhances intestinal health sta- levels of serum cytokines IL-17 and IL-22 were consistent tus and promotes nutrient absorption. Previous research with those of the jejunal mucosa. u Th s, we proposed that has also shown that dietary fiber treatment can improve pectin may modulate mucosal immunity by increasing the morphological structure of the jejunum of piglets, as anti-inflammatory cytokines and decreasing pro-inflam - evidenced by an increase in VH and a decrease in crypts matory cytokines. depth (CD), resulting in decreased intestinal mucosal Due to its fermentation properties on microorgan- permeability [24, 30] and increased the intestinal barrier isms, most previous studies on dietary fiber focused on protection [31, 32]. the hindgut [41, 42]. In contrast, pectin was found to As an essential protein in the intestine, tight junction modulate the microbial composition of the foregut in proteins play a crucial role in gut barrier function, par- this study, although the foregut is not the primary site of ticularly in maintaining the integrity of the intestinal microbial fermentation. Wu et al. [21] reported that the barrier and preventing the spread of harmful substances supplementation of pectin in the piglet diet decreased the [33]. Recent research showed that feeding piglets inulin diversity and abundance of microorganisms in the small or pectin increases the gene expression of Claudin-1, intestine. Similar results were obtained in other stud- Occludin, and ZO-1 [21, 34]. As expected, the results of ies [43]. In contrast, other studies observed an increased our study were consistent with the previous work. Thus, abundance and diversity of ileal microbial in piglets [44, pectin supplementation during the weaning transition 45]. We also hypothesized that pectin supplementation period improved the intestinal barrier function of piglets. could affect gut health by altering the microbial com - Subsequently, we also investigated whether pectin may position or in other ways. As predicted by the preced- have an additional beneficial effect on the intestinal tract. ing analysis, our data revealed that pectin significantly As is well-known, TNF-α, IL-1β, and IL-6 are essential changed the composition and structure of the gut micro- proinflammatory response indicators. Additionally, mac - biota and increased the OTU number and alpha diversity. rophages produce IL-8, a small inflammatory cytokine. A healthy gut microbiota typically consists of four main This indicates that variations in these proinflammatory phyla: Firmicutes, Bacteroidetes, Actinobacteria, and cytokine levels may reflect the inflammatory response Proteobacteria [46]. In the present study, we observed status. A previous study revealed that low-methoxyl that pectin reduced the abundance of Actinobacteria in pectin might downregulate the mRNA levels of TNF-α, the jejunal mucosa. It has been reported that the abun- IL-1β, and IL-6 in ileum colonic tissues [35]. Further- dance of Actinobacteria was highly expressed in the gut more, pectin extract from apples might decrease the gene of goats with diarrhea [47]. Proteobacteria, an intestinal expression of IL-6 in mouse ileum tissue [9]. Similarly, commensal bacteria, was also significantly increased by pectin derived from oranges and lemons can improve pectin in the present study. However, pectin significantly intestinal inflammation by inhibiting the initiation of IL-6 decreased the abundance of Streptococcus, a known secretion [15]. In this study, we observed that adminis- facultative-anaerobe bacterium and an opportunistic tration of pectin reduced the mRNA expression of IL-1β, pathogen. Specifically, Streptococcus infection may cause IL-6, IL-8, and TNF-α in jejunal mucosa of piglets. More- mucosal damage [48] and is associated with an increased over, there are several trials suggested that a low degree of risk of colorectal cancer [49]. Our study also found that methyl-esterification-(DM) pectin could suppress TLR2- the indole-derivatives-producing bacteria (Lactobacillus TLR1 by directly blocking of TLR2 receptor [36], then and Enterococcus) in the gut showed a notable increase in slow down capsule implantation induced increasing in pectin group. Additionally, pectin significantly reduced Dang et al. Journal of Animal Science and Biotechnology (2023) 14:38 Page 12 of 15 the abundance of Prevotella_9, Megamonas, Eubacte- p-Stat3 downstream of AhR, which plays as an essential rium, Megasphaera, Prevotella_2, and Acidaminococcus. role in promoting the production of antimicrobial mol- Prevotella_9 and Megasphaera are generally regarded as ecules (CYP1A1, CYP1B1, and RegIIIγ). Consequently, opportunistic pathogens [50, 51]. Moreover, Megamonas, these antimicrobial molecules exerted the protective Eubacterium, and Acidaminococcus are commonly function of the intestinal barrier. This indicated that believed to be associated with fatty acid metabolism the altered in the microbiota structure and metabolite [52–55], which significantly decreased in pectin group. concentration in jejunal mucosa observed following Morganella, the Gram-negative bacillus, belongs to the pectin treatment was the basis of immunomodulation, Enterobacteriaceae family. This study observed that pec - with the activated AhR/IL-22/Stat3 signaling pathway tin supplementation significantly increased the abun - providing a plausible mechanism. dance of Morganella. Therefore, our study showed that adding pectin significantly reduced the abundance of Conclusions harmful bacteria (Streptococcus) and increased the abun- In conclusion, our study found that adding pectin to the dance of beneficial bacteria (Enterococcus and Lacto - model could improve the intestinal integrity and gut bacillus) in the intestinal mucosa, to promote intestinal immunity by promoting tryptophan metabolism. This health. indicated that dietary pectin supplementation altered Lactobacillus and Enterococcus are related to trypto- jejunal microbial composition, thus promoting microbial phan metabolism. Specifically, tryptophan is an impor - tryptophan metabolism. Increased metabolites can act tant amino acid that mammals must obtain from their as ligands or signaling molecules to modulate the intes- diet, and it can be transformed into indole and indole tinal immune response through the AhR/IL-22/State3 derivatives by the gut microbiota [56, 57]. Then, it can pathway, ultimately reducing proinflammatory factors alter the immune-related signaling pathways that regu- and enhancing intestinal barrier function. These results late inflammation in the gut [58]. Only a few commensal provided a reliable theoretical foundation and guidance species, including Enterococcus [59, 60] and Lactobacillus for using pectin in mammals as a prospective intestinal [61], are known to produce indole derivatives, and many health defender. more are likely to be discovered. In this study, pectin sup- plementation decreased the concentration of Trp while Abbreviations increasing the amount of indole derivatives (ST, IAA, AhR Aryl hydrocarbon receptor IPA, HIAA, Tpm). Previous studies suggested that die- CYP1A1 C ytochrome P450 1A1 CYP1B1 Cytochrome P450 1B1 tary fiber supplementation increased the levels of indole GalA D-galacturonic acid derivates, including IPA [62]. Other studies also showed HE Ematoxylin-eosin that pectin can alleviate alcoholic hepatitis by promoting HIAA 5-Hydroxyindole-3-acetic acid IA Indoleacrylic acid the elevation of microbial metabolites, IAA, and Indole- IAA 3-indoleacetic acid 3-lactic acid [20]. This accorded with our research that IAALD 3-indole acetaldehyde pectin promotes the metabolism of tryptophan, shift-IALD 3-indole aldehyde IE 3-indole ethanol ing the metabolic direction toward the metabolism of IL Interleukin indoles. As a whole, pectin increased the content of IPA 3-indolepropionic acid indole derivatives in the gut, which had a beneficial effect Kyn Kynurenine MCC Microcrystalline cellulose on intestinal immunity. PVDF Polyvinylidene difluoride Group 3 innate lymphoid cells (ILC3) are greatly SRA Sequence Read Archive enriched in the lamina propria of the jejunum, the ST Skatole TPm Tryptamine highly expressed AhR in ILC3 can be activated by Trp Tryptophan tryptophan metabolites (indole derivates) as ligands, VH Villus height thereby promoting the production of IL-22 by ILC3 ZO-1 Zonula Occludens-1 5-HT Serotonin cells [63–66], and activates downstream pathways by inducing phosphorylation of Stat3, further promoting Acknowledgements the production of antimicrobial peptides and mucins We thank the China Scholarship Council for the student support (to Guoqi Dang). [67, 68]. Representative research showed that pectin supplementation altered the intestinal flora of mice, Authors’ contributions increased the tryptophan metabolites of the flora, and ZH, CL, and WW designed the research. DG wrote the manuscript. DG and WX carried out the animal experiments and conducted the experimental assay. reduced alcohol-induced liver damage by activating DG and ZR analyzed the data. ZH and MS supervised the work, and ZR, LC, CL, the AhR pathway [20, 29]. In this study, we found that MS, TS, and YB revised the final version of the manuscript. The authors read pectin treatment enhanced the levels of AhR, IL-22 and and approved the final manuscript. Dang et al. Journal of Animal Science and Biotechnology (2023) 14:38 Page 13 of 15 Funding from Jerusalem artichokes on gut microbiota in mice. Microorganisms. This work was supported by National Natural Science Foundation of China 2020;8(6):954. https:// doi. org/ 10. 3390/ micro organ isms8 060954. (NSFC) (31802072), China Scholarship Council (CSC NO. 202103250006), 11. Zhang Q, Hu J, Feng JW, Hu XT, Wang T, Gong WX, et al. 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Journal
Journal of Animal Science and Biotechnology – Springer Journals
Published: Mar 8, 2023
Keywords: Dietary fiber; Gut microbiota; Immune pectin; Tryptophan metabolites