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. 2026 Jan 17;16:15. doi: 10.1186/s13568-025-02003-3

Lactiplantibacillus plantarum P16 mitigated murine colitis through modulation of immune response and gut microbiota

Zhixian Chen 1,2,3, Qian Cheng 1,2,3, Xiaoli Zhang 1,2,3, Zhouhuang Sheng 1,2,3, Lei Shi 1,2,3, Yan Zhang 1,2,3,✉
PMCID: PMC12894483  PMID: 41546766

Abstract

Probiotics show potential for preventing and mitigating inflammatory bowel disease (IBD), though their efficacy and mechanisms are strain-specific. This study aimed to elucidate the protective mechanism of Lactiplantibacillus (L.) plantarum P16 against dextran sulfate sodium (DSS)-induced ulcerative colitis (UC). The strain exhibited high gastrointestinal tolerance, with survival rates of approximately 86% in artificial gastric fluid (pH 3.0) and 94% in 0.3% bile salt after 3 h of incubation. Moreover, L. plantarum P16 showed stronger adhesion to Caco-2 cells, indicating a high potential for intestinal colonization. In a DSS-induced colitis model, L. plantarum P16 administration alleviated colitis by reducing the disease activity index (DAI), suppressing pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), and mitigating colonic tissue damage while preserving epithelial barrier integrity. Additionally, L. plantarum P16 treatment increased short-chain fatty acid (SCFA) levels. 16 S rRNA amplicon sequencing of cecal content revealed that L. plantarum P16 supplementation restored gut microbial homeostasis by elevating the abundances of Firmicutes and Verrucomicrobiota, particularly Akkermansia, while reducing the proportions of Bacteroides and Helicobacter. These findings demonstrated that L. plantarum P16 could alleviate colitis by ameliorating intestinal inflammation and restoring gut microbiota dysbiosis, proposing a novel perspective of L. plantarum P16 for UC management.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13568-025-02003-3.

Keywords: Lactiplantibacillus plantarum P16, Colitis, Intestinal barrier, Short-chain fatty acids, Cytokines, Gut microbiota

Introduction

Inflammatory bowel disease (IBD) is a chronic gastrointestinal inflammatory disorder characterized by a steadily increasing incidence in recent years, rendering it a globally concerning health issue (Khan et al. 2019). IBD principally comprises two distinct clinical entities: Crohn’s disease (CD) and ulcerative colitis (UC) (Seyedian et al. 2019). UC exclusively occurs in the colon and persists, while CD is intermittent and can involve any part of the digestive tract (Liu et al. 2023). Diarrhea, abdominal pain, and bloody stools were the commonly clinical symptoms of UC patients (Chen et al. 2021). More seriously, UC can increase the risk of developing colorectal cancer (Neumann et al. 2011). At present, the pathogenesis of UC remains incompletely understood, but it is widely attributed to a combination of genetic, environmental, immunological, and intestinal barrier factors (Wu et al. 2022). Current clinical management of UC has expanded from 5-aminosalicylic acid to a variety of options including immunosuppressants, biologics (e.g., anti-TNF-α monoclonal antibodies), and small-molecule targeted drugs (e.g., JAK inhibitors) (Wangchuk et al. 2024). However, these therapies face challenges such as variable efficacy and safety concerns (Wangchuk et al. 2024). Concurrently, traditional agents such as glucocorticoids and non-steroidal anti-inflammatory drugs are associated with well-documented risks of gastrointestinal injury upon prolonged administration (Fan et al. 2024). Therefore, exploring novel strategies focusing on intestinal barrier repair and microbiota modulation is crucial.

Probiotics contribute to host health through multiple mechanisms, such as modulating gut microbiota, inhibiting pathogen colonization, and regulating immune responses (Abraham and Quigley 2017). Lactic acid bacteria represent one of the safest and most widely used probiotics in commercial applications. Lactobacillus species are known for their diverse probiotic functions, which include immune enhancement, antioxidant activity, and anti-obesity effects (Hu et al. 2020; Kerry et al. 2018). Notably, the potential of L. plantarum in preventing and treating colitis has been extensively studied, revealing its multi-faceted protective effects (Hasannejad-Bibalan et al. 2020). Research demonstrates that L. plantarum exerts benefits through several key pathways. On one hand, it directly mitigates inflammation—exemplified by strain JS19 reducing lipid peroxidation and other strains modulating immune cell activity and cytokine secretion (Khan et al. 2022; Ren et al. 2023; Tanaka et al. 2020; Wu et al. 2022). On the other hand, it strengthens the intestinal barrier function through upregulating intestinal mucin (MUC2) expression and increasing short-chain fatty acids (SCFAs) production (Khan et al. 2022; Sun et al. 2020). Furthermore, L. plantarum aids in restoring gut microbiota homeostasis in murine colitis models by promoting beneficial bacteria and suppressing pathogenic species (Xia et al. 2020; Yu et al. 2020). These multifaceted findings underscore the promise of L. plantarum as an effective and safe therapeutic option for ulcerative colitis, although its efficacy and mechanism may vary among different strains.

Dextran sulfate sodium (DSS) is a highly water-soluble compound and exhibits toxicity towards colonic epithelial cells, leading to disruption of the epithelial barrier and increased permeability, ultimately inducing colitis (Chassaing et al. 2014). A concentration of 3%~5% DSS effectively induces colitis models with symptoms resembling those observed in human UC patients (Eichele and Kharbanda 2017; Zhou et al. 2019). Therefore, this study aimed to investigate the protective effects and underlying mechanisms of L. plantarum P16 in UC by a murine colitis model. We specifically evaluated its impact on inflammation, intestinal barrier integrity, and gut microbiota composition. This study provides new experimental evidence supporting the development of L. plantarum P16 as a potential probiotic intervention for UC via multi-target modulation.

Materials and methods

The experimental strain

The L. plantarum strains were isolated from pickles and identified by 16 S rDNA sequencing. The strains of L. plantarum P01, P02, P03, P04, and P05 were stored at -80 ℃ in our laboratory. The L. plantarum P16 was stored at the China Center for Typical Culture Collection (CCTCC, Wuhan, China; CCTCC No: M 2023767). The Lacticaseibacillus rhamnosus GG (LGG) was obtained from the Guangdong Microbial Culture Collection Center (GDMCC, Guangzhou, China; GDMCC 1.2223).

Testing for tolerance to the gastrointestinal tract

The simulated gastroenteric fluid was prepared according to previous studies (Chen et al. 2021; Sun et al. 2020). The artificial gastric juice consisted of a phosphate buffer solution (PBS) containing 0.3% pepsin, with the pH adjusted to 3.0. The simulated intestinal fluid was prepared by adding 0.2% (w/v) sodium thioglycolate to MRS (Hope Bio-technology Co., Ltd., Qingdao, China) medium, supplemented with 0.3% bile salt. After complete dissolution, the solutions were filter-sterilized (0.22 μm) for subsequent for subsequent experiments. The strains were activated through two generations of growth in MRS medium. The cells were then collected by centrifugation (10,000 rpm, 1 min) and adjusted to a density of 10⁸ CFU/mL. The 1 mL bacterial suspension was washed twice with PBS, centrifuged, and re-suspended with an equal volume of artificial gastric juice or simulated intestinal fluid, shaken well (0 h), and incubated at 37 ℃ for 3 h. The plate counting method was used to measure the viable bacterial count at 0 h and 3 h. The survival rate was calculated as the following formula:

graphic file with name d33e378.gif

Where N0 and Nt represent the number of viable bacteria at 0 h and 3 h, respectively.

Determination of adhesion ability of strains to Caco-2 cells

The human colon adenocarcinoma cell line Caco-2 (GDC0153) was obtained from the China Center for Type Culture Collection (CCTCC). The adhesion capacity was measured following the previous method with a slight modification (Fonseca et al. 2021). The Caco-2 cells were inoculated into a 12-well tissue culture plate of DMEM medium containing 10% (v/v) fetal bovine serum, and cultured at 37 ℃ in an atmosphere of 5% CO2 until 80% of the cells attached to the wall and grew into monolayers. The activated strain was inoculated into MRS medium and cultured at 37 ℃ overnight. Then 1mL bacterial solution was taken, washed, and re-suspended in DMED medium. The cultured Caco-2 cells were washed twice with phosphate buffer saline (PBS), 1 mL bacterial suspension (108 CFU/mL) was added to each well and cultured for 2 h at 37 ℃ in a 5% CO2 atmosphere. After that, the cells were washed three times with PBS to remove non-adherent bacteria, and the viable bacteria number in the bacterial solution was detected by plate counting method. The adhesion capacity was calculated as follows:

graphic file with name d33e396.gif

Animals and experimental protocols

Animals

The experiment was conducted in accordance with the Guidelines for Experimental Animal Welfare, and the procedures were approved by the Animal Care and Use Committee (Anping Center (Fu) No.202210220) of the Hubei Provincial Center for Disease Control and Prevention. Male specific pathogen-free BALB/c mice weighing 18–20 g were obtained from SPF (Beijing) Biotechnology Co., Ltd. (Beijing, China, Certificate number: SCXK (Jing) 2019-0010). The mice were acclimated to the experimental conditions for one week prior to the test. Animals were housed in plastic cages under standard management conditions and provided with basic diets and sterilized water. The temperature of the feeding room was controlled at 20–24 ℃, relative humidity at 45–55%, and a light cycle of 12 h.

Establishment of colitis model

The establishment process of the experimental colitis model was illustrated in Fig. 2A. After the adaptive feeding stage, the mice were randomly divided into three groups: the normal control group (NC), the DSS-induced colitis group (DSS), and the L. plantarum P16 intervention group (P16). During the experiment, the mice in the NC group were fed normally and received 0.2 mL of sterile normal saline daily, the mice in the DSS and the P16 group were administrated 0.2 mL sterile normal saline and L. plantarum P16 suspension (5 × 109 CFU/mL) by oral gavage every day, respectively. On the 8th to 14th day of the experiment, with the exception of the NC group, all other mice drank 3% DSS (3 600 − 50 000 Da, MP Biomedicals, USA) solution for 7 consecutive days. During the experiment, all mice were weighed and orally gavaged at a fixed time daily, and fresh DSS solution was replaced every other day. Upon completion of the experimental period, the mice were euthanized via cervical dislocation. All personnel involved in animal care, experimental procedures, and data collection remained blinded to group assignments.

Fig. 2.

Fig. 2

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L. plantarum P16 alleviated DSS-induced experimental colitis. A: Experimental design; B: Body weight change; C: Disease activity index (DAI) score; D: Spleen index. Data are expressed as mean ± SD (n = 6). Data were analyzed by one-way ANOVA with Tukey’s post hoc test. *, **, ***, and **** represented significances of p < 0.05, p < 0.01, p < 0.001, and p < 0.0001, respectively

Sample collection and detection

The DAI score and spleen index

The DAI score of mice was calculated according to the previously described methods (Ahn et al. 2014), which include assessing body weight loss, stool consistency, and the presence of blood in feces. On the 15th day, the mice were euthanized, and their spleens were collected and weighed. The spleen index was determined by dividing the weight of the spleen (mg) by the body weight (g) (Shang et al. 2020).

Histological analysis

Following excision from mice, colon tissues were measured for length and subsequently photographed. A portion of the colon tissue was immersed in a 10% formaldehyde solution for 24 h to fixation, and then histological evaluation was performed with hematoxylin and eosin (H&E) staining. The colonic histopathology of mice was observed by a microscope, and the histological score was determined from four aspects: epithelial loss, crypt damage, goblet cell damage, and inflammatory infiltration (Kim et al. 2019).

Detection of inflammatory cytokines level

The concentrations of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-10 (IL-10), and interleukin-1β (IL-1β) in the colons of mice were assessed using the enzyme-linked immunosorbent assay (ELISA) kit, following the manufacturer’s instructions.

Quantitative detection of SCFAs content

The cecal contents were immediately collected after dissecting the mice and stored at − 80 ℃. The SCFAs in feces were quantified with slight modifications based on the method described by a previous report (S. Zhang et al. 2019a, b).

Sample preparation: 50 ± 1 mg sample was extracted with 1 mL distilled water and swirled for 10 s. Homogenized in a ball mill at 40 Hz for 4 min, followed by ultrasound treatment in ice water for 5 min (repeated three times). Centrifuged the mixture at 5000 rpm and 4 °C for 20 min. Transferred the supernatant into a fresh tube, added 50% H2SO4 and 2-Methylvaleric acid (25 mg/L stock in methyl tert-butyl ether) as internal standard, vortex mixed for 10 s, oscillated for 10 min, then ultrasound treated for 5 min (incubated in ice water). Centrifuged again at 10,000 rpm and 4 °C for 15 min, and kept at − 20 °C for 30 min. The resulting supernatant was transferred into a vial for subsequent analysis. Calibration Curve and Quantification: Quantification was performed using an internal standard method. Individual short-chain fatty acid (SCFA) standards (acetic acid, butyric acid, propionic acid, isobutyric acid, valeric acid, isovaleric acid, and hexanoic acid) were accurately weighed to prepare stock solutions. 2-Methylvaleric acid was used as the internal standard. A series of calibration standard solutions, covering the linear quantitative range for each component (e.g., 1–100 mg/L), were prepared by serial dilution of the stock solutions. These calibration standards were processed identically to the samples (including addition of internal standard, acidification, and extraction) to construct the calibration curves. All target SCFAs showed excellent linearity within their respective ranges, with correlation coefficients (R2) greater than 0.998 (for details, see Supplementary Material). The concentration of SCFAs in samples was calculated based on the peak area ratio of the analyte to the internal standard against the daily calibration curve.

Gas chromatography-mass spectrometry (GC-MS) analysis: GC/MS analysis was performed using a SHIMADZU GC2030-QP2020 NX gas chromatography-mass spectrometer with an Agilent HP-FFAP capillary column (30 m × 250 μm × 0.25 μm, J&W Scientific, Folsom, CA, USA). Helium gas served as the carrier gas at a flow rate of 1 mL/min. Injection was performed in split mode at a ratio of 5:1 with an injection volume of 1 µL. The temperatures of injection, ion source, quad, and transfer line were set to 240 ℃, 200 ℃, 150 ℃, and 240 ℃, respectively. The initial temperature program started from 80 ℃ for 1 min, then increased to 200 ℃ at 10 ℃/min for 5 min, finally ramped up to 240 ℃ at 40 ℃/min and held 1 min. The ionization was carried out in the electron impact mode with the electron energy of − 70 eV. After a solvent delay of 3.5 min, the Scan/SIM mode was employed to acquire the mass spectrum data within the m/z range of 33–150.

Gut microbiota analysis of cecal contents

The cecal contents of mice were collected for microflora analysis. Bacterial DNA in samples was extracted using a TGuide S96 Magnetic Soil/Stool DNA Kit (Tiangen Biotech (Beijing) Co., Ltd.). The concentration and purity of the extracted DNA were determined using the Qubit dsDNA HS Assay Kit with a Qubit 4.0 Fluorometer (Invitrogen, Thermo Fisher Scientific, USA) and a NanoDrop One spectrophotometer (A260/A280 ratios between 1.8 and 2.0), respectively. The V3–V4 region of the 16S rRNA genes was amplified with universal primers (338F: 5′–ACTCCTACGGGAGGCAGCA–3′ and 806R: 5′–GGACTACHVGGGTWTCTAAT–3′). The PCR amplicon was purified, quantified, and pooled in equal amounts and the constructed library was sequenced by Illumina novaseq 6000 (Illumina, Santiago CA, USA). The bioinformatics analysis of this study was conducted using the BMK Cloud (Biomarker Technologies Co., Ltd., Beijing, China) (Lin et al. 2022). Operational classification units (OTUs) were clustered with similarity ≥ 97% by USEARCH, and OTUs with an abundance < 0.005% were filtered (Edgar 2013). Taxonomy annotation of the OTUs was performed based on the Naive Bayes classifier in QIIME2 using the SILVA database (release 132) with a confidence threshold of 70% (Bolyen et al. 2019; Quast et al. 2013). The alpha diversity and beta diversity were used to assess the complexity and similarity of species in different samples. Permutational multivariate analysis of variance (PERMANOVA), implemented using the ADONIS function in the vegan package in R, was applied to assess the statistical significance of beta diversity differences between groups. The analysis was performed with 999 permutations to quantify the effect size of variables explaining the weighted_unifrac distance (Lkhagva et al. 2021). The linear discriminant analysis (LDA) effect size (LEfSe) was used to test the significant taxonomic difference between groups.

Statistical analysis

Data were expressed as mean ± standard deviation. The GraphPad Prism 8.0 software package (GraphPad Prism, San Diego California, USA) was used to perform statistical analysis. Prior to parametric tests, data were assessed for normality (Shapiro–Wilk test) and homogeneity of variances (Brown–Forsythe test). For multiple comparisons meeting these assumptions, ordinary one-way ANOVA was applied to assess the overall effect, followed by Tukey’s test for post hoc analysis if ANOVA was significant. If the assumptions were violated, the non-parametric Kruskal-Wallis test with Dunn’s post hoc test was used instead. Comparisons between two groups were made using unpaired Student’s t-test (for normal data) or the Mann–Whitney U test (for non-normal data). The significance level was set at p < 0.05. The exact sample size (n) for each group is provided in the figure legends.

Results

Evaluation of tolerance and adhesion capabilities of L. plantarum strains in vitro

To evaluate their gastrointestinal tolerance, the viability of six L. plantarum strains was assessed in simulated gastric juice (pH 3.0) and 0.3% bile salt solution. Tolerance to simulated gastric juice varied pronouncedly among the tested strains (Fig. 1A). While most exhibited survival rates below 65%, L. plantarum P16 was a notable exception, demonstrating significantly higher viability (86.19% ± 0.98%). In contrast, all strains showed excellent tolerance to bile salts, achieving survival rates above 70% (Fig. 1A). Specifically, strains P01, P02, and P16 retained remarkable viability rates exceeding 90% after 3 h of incubation. Based on these findings, it could be concluded that L. plantarum P16 possesses exceptional tolerance and holds promising potential in resisting adverse gastrointestinal conditions.

Fig. 1.

Fig. 1

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Tolerance and adhesion ability of L. plantarum P16. A: Tolerance to acid and bile salts; B: Adhesion to Caco-2 cells. Data are expressed as mean ± SD (n = 3). Data were analyzed by one-way ANOVA with Tukey’s post hoc test. There were significant differences between strains represented by different letters (p < 0.05)

The adhesion of probiotics to intestinal epithelial cells forms the fundamental basis for the functionality of probiotics. The adhesion of L. plantarum P16 to Caco-2 cells were determined in this study. L. plantarum P16 exhibited a markedly higher Caco-2 cell adhesion rate of 13.07%, nearly threefold greater than that of Lacticaseibacillus rhamnosus GG (4.65%), underscoring its superior adhesive properties (Fig. 1B, p < 0.05). This observation suggested that L. plantarum P16 possessed potential for colonization within the gastrointestinal tract.

Lactiplantibacillus plantarum P16 alleviated the increase of DAI score and spleen index in DSS-induced colitis mice

The mouse colitis was induced by adding 3% DSS to the drinking water for seven consecutive days (days 8–14 of the experiment). On day 12 of the experiment, a significant weight loss was observed in the DSS and P16 groups, and the body weight maintained a downward trend in the following experiment (Fig. 2B). At the end of the trial, DSS group exhibited an obvious reduction in body weight, whereas the intervention of L. plantarum P16 significantly attenuated the weight loss in mice (P16 group: 5.50% on average vs. DSS group: 13.76% on average). During DSS induction, the trend in DAI scores diverged from that of body weight, with both the DSS and P16 groups showing a concurrent and continuous increase in DAI (Fig. 2C). However, the increased magnitude of DAI score was mitigated by the administration of L. plantarum P16. On the 14th day, the DAI score of the P16 group was close to 1.5, significantly lower than the DSS group (p < 0.0001), which was about 4.

As a key immune organ, the spleen undergoes cellular activation and proliferation in response to external stimuli, leading to morphological changes. In this study, DSS induction triggered significant splenomegaly in mice, which was effectively alleviated by L. plantarum P16 treatment. Compared with the NC group (3.76 mg/g on average), the spleen index of mice in the DSS group (6.65 mg/g on average) was significantly increased (p < 0.01, Fig. 2D). The spleen index in the P16 group was approximately 4.37 mg/g, representing 60% of that observed in the DSS group and exhibiting a closer resemblance to that found in mice under normal feeding conditions.

Lactiplantibacillus plantarum P16 relieved colonic tissue lesions in mice with colitis

Colonic shortening, a hallmark of colitis, was observed in DSS-treated mice. Compared to the NC group, colon length was markedly reduced by DSS induction, but was partially restored with L. plantarum P16 intervention (Fig. 3A). The average length of the colon in the DSS group was about 5.17 cm, which was significantly shorter than that in the NC group (8.84 cm) (Fig. 3B, p < 0.0001). L. plantarum P16 administration effectively mitigated colonic atrophy in mice, as evidenced by an average 18.38% increase in colon length compared to the DSS group. The colonic tissue structure was observed by H&E staining (Fig. 3C), which showed that the colonic mucosa and crypts were intact, and the goblet cells were abundant in the NC group. However, the DSS group displayed severe intestinal tissue damage manifested as mucosal edema, crypt depletion, extensive inflammatory infiltration, and partial mucosal erosion, which resulted in a significantly higher histopathological score than that of other groups (Fig. 3D, p < 0.05). As expected, the mice in the P16 group exhibited a reduction in histological damage, with a complete colonic epithelium, regular crypt structure, and no obvious inflammatory infiltration. Furthermore, the colonic histopathological score of P16 group (6 ± 1.73) was significantly lower in comparison with the DSS group (9.67 ± 1.75) (p < 0.05).

Fig. 3.

Fig. 3

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L. plantarum P16 alleviate the colonic inflammation in mice with colitis. A: Representative photographs of mice colons; B: colonic length; C: H&E staining of colon (magnification 60 × and 150 ×); D: Histopathological score; E: Tumor necrosis factor-α (TNF-α); F: Interleukin-6 (IL-6); G: Interleukin-1β (IL-1β); H: Interleukin-10 (IL-10). Data are expressed as mean ± SD (n = 6). Data were analyzed by one-way ANOVA with Tukey’s post hoc test. *, **, ***, and **** represented significances of p < 0.05, p < 0.01, p < 0.001, and p < 0.0001, respectively. “ns” represented no significant difference between groups

Lactiplantibacillus plantarum P16 regulated cytokine secretion in the colon of mice

The degree of inflammation in mice was further evaluated by measuring the cytokine levels in the colons. DSS treatment significantly increased the concentrations of proinflammatory cytokines, including TNF-α, IL-6, and IL-1β, which were markedly higher than those in the NC group (Fig. 3E–G). The levels of TNF-α, IL-6, and IL-1β in the P16 group exhibited a significant reduction (p < 0.05, p < 0.0001), surpassing a decrease of more than 20% compared to those in the DSS group. Notably, the level of IL-10, an anti-inflammatory factor, exhibited a divergent trend across all groups. It decreased in the DSS group and increased in the P16 group, however, the difference between groups was not statistically significant (p > 0.05, Fig. 3H).

Lactiplantibacillus plantarum P16 elevated the SCFAs levels in the feces of mice with colitis

The intestinal immune response is regulated by SCFAs. In this study, GC-MS was utilized to quantify the concentrations of SCFAs in mouse cecal contents. The predominant SCFAs detected in the cecum contents of mice were acetic acid, butyric acid, valeric acid, isobutyric acid, and propionic acid (Fig. 4). Among them, acetic acid and butyric acid exhibited higher levels compared to the others. The concentrations of SCFAs in the feces of DSS-induced colitis mice were significantly lower compared to the NC group, particularly for acetic acid and butyric acid (Fig. 4A and B, p < 0.01, p < 0.001). Oral administration of L. plantarum P16 effectively promoted the production of SCFAs, as evidenced by a significant increase in the concentrations of various organic acids in the P16 group (p < 0.05, p < 0.01), which were more than twice as high as those observed in the DSS group (Fig. 4). Notably, the content of valeric acid and isobutyric acid in the P16 group were significantly elevated compared to both the DSS and NC groups, reaching levels approximately 1.64 times and 1.45 times that of the control group, respectively.

Fig. 4.

Fig. 4

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L. plantarum P16 elevated the SCFAs levels in the feces of mice with colitis. Data are expressed as mean ± SD (n = 6). Data were analyzed by one-way ANOVA with Tukey’s post hoc test. *, **, and *** represented significances of p < 0.05, p < 0.01, and p < 0.001, respectively. “ns” represented no significant difference between groups

Lactiplantibacillus plantarum P16 modulated gut microbiota in mice with colitis

Analysis of gut microbiota revealed that DSS treatment disrupted the composition of microbiota and reduced its diversity. The ACE, Chao 1, Simpson, and Shannon indices of the DSS group were significantly lower than those of the NC group (Fig. 5A–D, p < 0.0001). However, supplementation with L. plantarum P16 partially restored the dysbiosis in mouse intestinal microbiota, as evidenced by a significant increase in ACE, Simpson and Shannon indices observed in the P16 group compared to the DSS group. Nonmetric multidimensional scaling (NMDS) and Permutational multivariate analysis of variance (PERMANOVA) were employed for beta diversity analysis. Both NMDS and PERMANOVA (F (2, 12) = 3.743, R2=0.384, p = 0.003) results demonstrated significant separation of microbial communities among treatment groups, confirming the intervention’s impact on overall composition (Fig. 5E and F). On NMDS plot’s axis NMDS1, sample points from the DSS group were clustered on the left side far away from the other groups, while sample points of the P16 and the NC groups gathered together on the right side. These findings indicate that DSS treatment disrupt the gut microbiota composition, while L. plantarum P16 could facilitate the intestinal microecology homeostasis.

Fig. 5.

Fig. 5

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The effects of L. plantarum P16 on gut microbiota. A: ACE; B: Chao 1; C: Simpson index; D: Shannon index; E: Non-metric multidimensional scaling (NMDS) plot based on weighted_unifrac; F: PERMANOVA results on microbial β-diversity (weighted_unifrac distance); G: The phylum level; H: The relative abundance of Firmicutes; I: The relative abundance of Bacteroidota; J: The Firmicute/Bacteroidota ratio; K: The relative abundance of Verrucomicrobiota. Data are expressed as mean ± SD (n = 5). Data were analyzed by one-way ANOVA with Tukey’s post hoc test. *, **, ***, and **** represented significances of p < 0.05, p < 0.01, p < 0.001, and p < 0.0001, respectively. “ns” represented no significant difference between groups.

To investigate the specific effects of DSS and L. plantarum P16 on the composition of gut microbiota in mice, differences in phylum and genus level compositions were analyzed. The dominant bacterial phyla in the cecum of mice were Firmicutes, Bacteroidota, Campylobacterota, Desuifobacterota, Proteobacteria, and Verrucomicrobiota (Fig. 5G). Among them, Firmicutes and Bacteroidota accounting for more than 70% of mouse cecal fecal microbiota (Fig. 5G). Compared to the NC group, the relative abundance of Firmicutes was decreased and Bacteroidota was increased in the DSS group (Fig. 5H and I). Concurrently, our results showed that the ratio of Firmicutes to Bacteroidota (F/B) was reduced by DSS treatment (Fig. 5J). However, after orally administrated L. plantarum P16, the levels of Firmicutes and Bacteroidota as well as F/B ratio were comparable to those in the control group in DSS-exposed mice. Notably, P16 significantly facilitated the accumulation of Verrucomicrobiota, with a substantially higher abundance observed in the P16 group compared to other groups (Fig. 5K, p < 0.05).

At the genus level, Akkermansia demonstrated the most notable response to P16 administration. Its relative abundance, which was low in both the NC and DSS groups, was substantially elevated in the P16 group, far exceeding the levels observed in the NC group (Fig. 6A). The overall shifts in microbial composition revealed that the DSS group exhibited reduced abundance of unclassified_Lachnospiraceae, Lachnospiraceae_NK4A136_group, Candidatus_Saccharimonas, and unclassified_Ruminococcaceae compared to the NC group, while Bacteroides, Helicobacter, and Mucispirillum were enriched (Figs. 6B–H). In contrast, P16 intervention significantly increased the abundance of unclassified_Lachnospiraceae and Lachnospiraceae_NK4A136_group (Fig. 6B and C, p < 0.05, p < 0.001), while markedly reducing Bacteroides and Helicobacter (Fig. 6F and G, p < 0.01, p < 0.001).

Fig. 6.

Fig. 6

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Analysis of gut microbiota composition at the genus level and identification of differentially abundant taxa by Linear discriminant analysis Effect Size (LEfSe). A: Akkermansia; B: Unclassified_Lachnospiraceae; C: Lachnospiraceae_NK4A136_group; D: Candidatus_Saccharimonas; E: unclassified_Ruminococcaceae; F: Bacteroides; G: Helicobacter; H: Mucispirillum; I: LEfSe analysis (LDA > 4.0, p < 0.05). Data are expressed as mean ± SD (n = 5). Data were analyzed by one-way ANOVA with Tukey’s post hoc test. *, **, ***, and **** represented significances of p < 0.05, p < 0.01, p < 0.001, and p < 0.0001, respectively. “ns” represented no significant difference between groups.

LEfSe analysis was employed to study the significant taxonomic differences of mice cecal microorganisms to identify the specific bacteria between the groups. In the NC group, the abundance of Firmicutes was significantly higher; for the DSS group, Bacteroides, Bacteroidaceae, Helicobacter, and Helicobacteraceae significantly increased and became the absolute dominant taxa (Fig. 6I). Oral administration of L. plantarum P16induced a substantial restructuring of the gut microbiota in mice, characterized by a marked increase in the abundance of Verrucomicrobiae and Akkermansia compared to the other two group.

Discussions

IBD is a challenging health problem whose pathogenesis is associated with dysregulation of the host immune response and intestinal microecosystem (Ryan et al. 2020). Probiotics, which are natural inhabitants of the human gut with a high safety profile, represent a promising therapeutic strategy for IBD due to their potential to modulate gut microbiota and enhance immune response (Jakubczyk et al. 2020). In this study, a murine colitis model was established using 3% DSS to investigate the protective effects of L. plantarum P16. The results demonstrate that administration of L. plantarum P16 effectively attenuated DSS-induced body weight loss, colonic inflammation, and histological damage. Furthermore, L. plantarum P16 promoted restoration of microbial homeostasis, suggesting its potential as a novel probiotic intervention for IBD.

Gastrointestinal tolerance serves as a crucial indicator for in vitro probiotic screening. For probiotics to exert beneficial effects, they must first survive and colonize the gastrointestinal tract (Plessas et al. 2017). A primary challenge is the low pH of gastric juice, which severely limits survival during stomach passage. Additionally, bile salts in the intestine present cytotoxicity, making bile tolerance another crucial requirement (Li et al. 2020a, b, c). To ensure sufficient activity and vitality through the gastrointestinal tract, probiotics should be resistant to acid and bile salts. The superior survival rate of L. plantarum P16 in the artificial gastric juice and the simulated intestinal fluid suggested its potential for high activity in the gastrointestinal tract. In addition to the ability to survive in harsh gastrointestinal environments, the ability of microorganisms to adhere to intestinal epithelial cells is also an important condition of probiotic screening. In general, strains exhibit enhanced adhesion ability and enable prolonged residence in the intestine, thereby repelling pathogens and interacting with host epithelial cells to improve intestinal health (Poimenidou et al. 2023). The adhesion rate of L. plantarum P16 to Caco-2 cells was 13.07%, exhibiting superior adhesive capabilities compared to LGG and other strains of L. plantarum (Ramos et al. 2013). The results indicated that L. plantarum P16 exhibited favorable gastrointestinal tolerance and possessed the ability to colonize the intestine. Consequently, further investigation was conducted to explore its potential functionality using a BALB/c mouse colitis model induced by DSS.

The DSS-induced mice colitis model is widely utilized in research due to its operational simplicity, rapid disease induction, and clearly discernible symptoms, including significant weight loss, fecal occult blood, diarrhea, elevated DAI score, as well as splenomegaly (Cao et al. 2022; Niu et al. 2022; Zhang et al. 2019a, b, 2022). In the present study, our observations align with these established pathological features, confirming the successful establishment of the colitis model. However, intervention with L. plantarum P16 demonstrated protective effects, as evidenced by the attenuation of weight loss, reduction in hematochezia and diarrhea, decreased DAI scores, and a lower spleen index. These results provide preliminary evidence supporting the protective and preventive effects of L. plantarum P16 against DSS-induced UC in mice. Similarly, both L. plantarum AR113 and L. plantarum L15 have demonstrated efficacy in alleviating colitis in murine models, exhibiting superior effects in maintaining body weight and reducing DAI scores in mice (Xia et al. 2020; Yu et al. 2020). Histopathological examination further revealed that colonic tissue damage, including colon shortening, depletion of goblet cells, and marked inflammatory infiltration (Hu et al. 2020). This damage was significantly mitigated in the P16 group. Compared to the DSS group, P16 group exhibited less damage to the colonic mucosa and crypt compared to the DSS group, displaying a more intact tissue structure and reduced pathological scores. These protective effects were in line with observations made for other lactic acid bacteria, including Lacticaseibacillus paracasei and Limosilactobacillus gasseri (Kim et al. 2019; Zhang et al. 2022), collectively underscoring the potential of probiotic interventions in managing experimental colitis.

Furthermore, L. plantarum P16 attenuates inflammatory responses through modulation of cytokine secretion, notably by suppressing the production of pro-inflammatory factors (TNF-α, IL-6, IL-1β) while enhancing the release of anti-inflammatory cytokine IL-10. Cytokines play a pivotal role in immune response, and their dysregulation is to be the primary etiology of IBD. Elevated levels of pro-inflammatory cytokines including TNF-α, TNF-γ, IL-12, IL-1β, and IL-6 have been observed in both IBD patients and mice with DSS-induced colitis (Bank et al. 2019; Hu et al. 2020; Zhang et al. 2022). TNF-α can disrupt intestinal tight junction proteins and the intestinal barrier integrity, thereby exacerbating inflammatory infiltration leading to diarrhea and promoting IBD pathogenesis (Zou et al. 2020). Furthermore, TNF-α can activate the NF-κB pathway, stimulating the secretion of other pro-inflammatory cytokines such as IL-6 and IL-1β (Kim et al. 2019). Under normal conditions, IL-6 plays a vital role in maintaining intestinal barrier function, while excessive release of it can contribute to inflammation (Sato et al. 2020). Conversely, anti-inflammatory effects are positively correlated with increased levels of IL-10 (Wu et al. 2022). The strains of L. plantarum C2, C3, and P8 can decrease the levels of IL-17 A, IL-17 F, IL-6, IL-22, and TNF-α while increasing TGF-β and IL-10, leading to a reduction in intestinal inflammation (Khan et al. 2022), which was in line with the results obtained from our study. While the L. plantarum CBT LP3 shows prophylactic potential against colitis through modulation of T helper cell subsets and suppression of pro-inflammatory cytokine production (Kim et al. 2020). Based on the above, our findings suggest that the regulatory effects of L. plantarum P16 on cytokines may be one of the major protective effects against DSS-induced colitis However, the precise mechanism underlying the interaction between L. plantarum P16 and the host immune system necessitates further investigation.

SCFAs are the primary metabolites of intestinal microbial communities, derived from the fermentation of dietary fiber and carbohydrates by gut microbiota (Louis and Flint 2017). SCFAs play a crucial role in providing energy to intestinal epithelial cells and enhancing intestinal barrier function. Moreover, they regulate immune cell function, influence cellular proliferation, differentiation, and gene expression, exhibiting a close correlation with IBD (Parada Venegas et al. 2019). The levels of SCFAs were decreased in the feces of IBD patients compared with controls (Zhuang et al. 2019); a similar reduction was observed in DSS-induced UC mice in the present study, consistent with previous report (Khan et al. 2022). L. plantarum P16 administration significantly elevated the levels of acetic acid, butyric acid, valeric acid, isobutyric acid, and propionic acid compared to the DSS group. The increase in SCFAs production likely explains why colitis symptoms improved. Butyrate and propionate, in particular, are well-established mediators of colonic health. Among them, butyrate and propionate, as well-studied immunomodulatory SCFAs, can inhibit the activity of histone deacetylases, promote histone acetylation, and thereby regulate cell proliferation, suppress the production of pro-inflammatory cytokines (e.g., TNF-α, IL-12), and promote the expression of anti-inflammatory cytokines (e.g., IL-10) (Parada Venegas et al. 2019; Säemann et al. 2000). These actions are crucial for maintaining epithelial integrity and ameliorating, which is consistent with the observed efficacy of butyrate enemas in patients with UC (Khan et al. 2019). However, a standout finding of this study is that L. plantarum P16 uniquely and significantly elevated valeric acid. Unlike propionate and butyrate, valeric acid has received relatively less attention in probiotic-related research. Emerging evidence suggests that compared with healthy controls, the levels of valeric acid are reduced in individuals with UC, while valeric acid supplementation can alleviate colitis in mice, suggesting its potential as a therapeutic agent for UC management (Liu et al. 2024). Therefore, the action of L. plantarum P16 extends beyond conferring broad anti-inflammatory and barrier-protective effects via the enhancement of conventional beneficial SCFAs such as butyrate and propionate. It also specifically supplies valeric acid, a metabolite with direct therapeutic potential.

Accumulating evidence has demonstrated that the gut microbiota imbalance compromises both intestinal barrier integrity and immune homeostasis, playing a central role in the pathogenesis of IBD (Wang et al. 2020). In line with previous reports, our study confirmed that DSS treatment significantly reduced microbial richness and diversity, lowered α-diversity indices, and disrupted overall microbiome structure (Jing et al. 2018; Yang et al. 2017). While supplementation with lactobacillus such as LGG, L. paracasei KBL382, and L. plantarum AR113 can partially restore the gut microbiota dysbiosis induced by DSS (Kim et al. 2019; Tong et al. 2021; Xia et al. 2020). Consistent with these findings, L. plantarum P16 supplementation not only elevated the Chao1, Simpson, and Shannon indices but also restored a homeostatic microbial community structure in colitis mice, suggesting its efficacy in driving microbial re-equilibration. At the phylum level, ulcerative colitis is commonly associated with a decreased abundance of Firmicutes and an increased abundance of Bacteroidota, resulting in a reduced Firmicutes/Bacteroidota (F/B) ratio (Bian et al. 2020; Wong et al. 2022), which consistent with our findings. The F/B ratio is considered an important indicator of intestinal microecological balance (Stojanov et al. 2020). Interestingly, the alteration of the F/B ratio in UC mice does not exhibit a consistent trend; elevated ratio has also been reported (Li et al. 2020). Despite these divergent reports, L. plantarum P16 intervention effectively normalized the F/B ratio in DSS-induced mice, further supporting its role in facilitating structural and functional recovery of the gut microbiota. Further analysis revealed that L. plantarum P16 modulated the gut microbiota by promoting beneficial bacteria and suppressing harmful ones, thereby fostering intestinal homeostasis. The relative abundance of Bacteroides, Bacteroidaceae, Helicobacter, and Helicobacteraceae in the DSS group was significantly higher than that in other groups. It suggested that the proliferation of these particular microbial taxa may have contributed to the development of colitis in mice. According to previous reports, Bacteroides and Helicobacter showed a positive association with IL-6 and TNF-α while exhibiting a negative correlation with IL-10 (Li et al. 2020a, b, c). The genus Bacteroides is commonly abundant within mammals, where it plays a crucial role in maintaining gut health. However, excessive accumulation of this genus contributes to damage in the intestinal immune system, promoting IBD (Zhang et al. 2017). Helicobacter belongs to the Proteobacteria phylum and is a pathogenic microorganism in the gastrointestinal tract that exacerbates inflammation in mice with colitis (Alkarkoushi et al. 2020; Li et al. 2020c). However, there is an epidemiological correlation between Enterohepatic Helicobacter species and the development of IBD (Alkarkoushi et al. 2020). Surprisingly, a prior study found a lower prevalence of Helicobacter pylori infection in IBD patients compared with control individuals (Rokkas et al. 2015). Therefore, a definitive conclusion cannot be drawn regarding the relationship between Helicobacter pylori and colitis, necessitating further research. Oral administration of L. plantarum P16 modulated the gut microbiota composition, notably increasing the relative abundance of the Firmicutes phylum—a group known for carbohydrate fermentation and production of beneficial SCFAs like butyrate, which contributes to anti-inflammatory effects (Sun et al. 2018). Crucially, the P16 intervention specifically and significantly increased the abundance of Akkermansiaceae and Akkermansia, a genus within the Verrucomicrobiota phylum. Akkermansia is considered a next-generation probiotic candidate (Wang et al. 2022), whose abundance is frequently decreased in patients with IBD compared to healthy individuals (Png et al. 2010). Akkermansia muciniphila can enhances intestinal barrier function by upregulating tight junction proteins and produces metabolites such as acetate and propionate, mechanisms known to alleviate experimental colitis (Ansaldo et al. 2019; Bian et al. 2019). In the DSS group, we observed a marked reduction in the abundance of Lachnospiraceae_NK4A136_group compared to the NC group, consistent with previous reports (Huang et al. 2022). However, oral administration of L. plantarum P16 dramatically increased its abundance. As a known SCFA producer, Lachnospiraceae_NK4A136_group may contribute to inflammation reduction (Li et al. 2020a, b, c). These findings indicate that the protective effect of L. plantarum P16 in UC mice may be mediated by remodeling the gut microbiota, particularly the targeted enrichment of Akkermansia, which enhances SCFA production and immune regulation to confer strain-specific therapeutic efficacy against colitis.

Conclusions

In summary, L. plantarum P16 exhibited favorable gastrointestinal tolerance and adhesion ability. In vivo experiments have confirmed its potential to improve UC by protecting intestinal barrier function, inhibiting inflammatory cytokine secretion, promoting the production of SCFAs, and regulating gut microbiota. These findings showed the protective effect of L. plantarum P16 on DSS-induced colitis in mice, suggesting its potential as a candidate for IBD treatment. While these results are promising, further validation in clinically relevant models and human trials is needed to account for physiological differences between species and to clarify the underlying mechanisms.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary Material 1 (14.8KB, docx)

Author contributions

Zhixian Chen contributed to investigation, methodology, data curation, writing - original draft, and funding acquisition. Qian Cheng and Xiaoli Zhang contributed to methodology, formal analysis, and validation. Zhouhuang Sheng and Lei Shi were responsible for software development and writing-review & editing. Yan Zhang contributed to investigation, conceptualization, supervision, and writing-review & editing.

Funding

This study is supported by National Key Research and Development Program of China (2023YFF1104403).

Data availability

The raw data supporting the conclusions of this article will be made available by the authors on reasonable request. The raw data for 16 S rRNA sequence in this study are available in NCBI, the accession number is PRJNA1365342.

Declarations

Ethics approval and consent to participate

The experimental procedures were approved by the Animal Management and Use Committee of the Hubei Provincial Center for Disease Control and Prevention (Anping Centre (Fu) No. 202210220), and conducted in strict accordance with the Guide for the Care and Use of Laboratory Animals issued by the National Research Council of China.

Consent for publication

All authors approved the final version of the manuscript and consent for publication.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Material 1 (14.8KB, docx)

Data Availability Statement

The raw data supporting the conclusions of this article will be made available by the authors on reasonable request. The raw data for 16 S rRNA sequence in this study are available in NCBI, the accession number is PRJNA1365342.

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