Metabolic regulation of the Th17/Treg balance in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a long-lasting and inflammatory autoimmune condition affecting the gastrointestinal tract, impacting millions of individuals globally. The balance between T helper 17 (Th17) cells and regulatory T cells (Tregs) is pivotal in the pathogenesis and progression of IBD. This review summarizes the pivotal role of Th17/Treg balance in maintaining intestinal homeostasis, elucidating how its dysregulation contributes to the development and exacerbation of IBD. It comprehensively synthesizes the current understanding of how dietary factors regulate the metabolic pathways influencing Th17 and Treg cell differentiation and function. Additionally, this review presents evidence from the literature on the potential of dietary regimens to regulate the Th17/Treg balance as a strategy for the management of IBD. By exploring the intersection between diet, metabolic regulation, and Th17/Treg balance, the review reveals innovative therapeutic approaches for IBD treatment, offering a promising perspective for future research and clinical practice.

Baicalin restore intestinal damage after early-life antibiotic therapy: the role of the MAPK signaling pathway.

Antibiotic related intestinal injury in early life affects subsequent health and susceptibility. Here, we employed weaned piglets as a model to investigate the protective effects of baicalin against early-life antibiotic exposure-induced microbial dysbiosis. Piglets exposed to lincomycin showed a marked reduction in body weight (p < 0.05) and deterioration of jejunum intestinal morphology, alongside an increase in antibiotic-resistant bacteria such as Staphylococcus, Dolosicoccus, Escherichia-Shigella, and Raoultella. In contrast, baicalin treatment resulted in body weights, intestinal morphology, and microbial profiles that closely resembled those of the control group (p > 0.05), with a significant increase in norank_f_Muribaculaceae and Prevotellaceae_NK3B31_group colonization compared with lincomycin group (p < 0.05). Further analysis through fecal microbial transplantation into mice revealed that lincomycin exposure led to significant alterations in intestinal morphology and microbial composition, notably increasing harmful microbes and decreasing beneficial ones such as norank_Muribaculaceae and Akkermansia (p < 0.05). This shift was associated with an increase in harmful metabolites and disruption of the calcium signaling pathway gene expression. Conversely, baicalin supplementation not only counteracted these effects but also enhanced beneficial metabolites and regulated genes within the MAPK signaling pathway (MAP3K11, MAP4K2, MAPK7, MAPK13) and calcium channel proteins (ORA13, CACNA1S, CACNA1F and CACNG8), suggesting a mechanism through which baicalin mitigates antibiotic-induced intestinal and microbial disturbances. These findings highlight baicalin's potential as a plant extract-based intervention for preventing antibiotic-related intestinal injury and offer new targets for therapeutic strategies.

Hydroxytyrosol attenuates diquat-induced oxidative stress by activating Nrf2 pathway and modulating colonic microbiota in mice.

This study was conducted to investigate the antioxidant effects of hydroxytyrosol (HT) administration in diquat (DQ)-challenged mice. The results showed that HT treatment markedly alleviated DQ-induced oxidative stress, which was indicated by the enhanced total antioxidant capacity (T-AOC), increased activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase and decreased malondialdehyde (MDA) concentration in serum. Additionally, HT increased the mRNA expression levels of NF-E2-related factor 2 (Nrf2) and its downstream genes, including NADPH quinone oxidoreductase 1 (NQO1) and catalase (CAT) in the small intestine of DQ-challenged mice. 16S rRNA gene sequencing results showed that HT treatment increased the relative abundance of Firmicutes and Lactobacillus and decreased the relative abundance of Bacteroidetes. Interestingly, Pearson correlation analysis showed that there were strong association between colonic Firmicutes, Lactobacillus, and Bacteroidetes and the activities of serum antioxidant enzymes. Meanwhile, HT significantly enhanced the colonic butyrate concentration in DQ-challenged mice. Additionally, HT treatment decreased the serum metabolites involving in glycerophospholipid metabolism, pentose, and glucuronate interconversions, which were associated with alleviated oxidative stress. These results indicate that oral administration of 100 mg/kg body weight HT alleviates oxidative stress in DQ-challenged mice, which may involve Nrf2 signaling pathways via modulation of colonic microbiota.

Effects of the compound extracts of Caprifoliaceae and Scutellaria baicalensis Georgi on the intestinal microbiota and antioxidant function.

According to the Chinese encyclopedia "Ben Cao Gang Mu" (AD 1552-1578), Caprifoliaceae and Scutellaria baicalensis Georgi are used in traditional Chinese medicine to clear heat, detoxify, and treat wind-heat colds, upper respiratory tract infections, and pneumonia. However, the mechanism and the effects of the compound extracts of Caprifoliaceae and Scutellaria baicalensis Georgi on intestinal health remain unclear. From the perspective of intestinal microbes, this study assessed the antioxidant, anti-inflammatory, and intestinal protective properties of Caprifoliaceae and Scutellaria baicalensis Georgi. Mice received diets with or without Caprifoliaceae and Scutellaria baicalensis Georgi extractive (BCA) for 2 weeks in this study. The results showed that BCA increased body weight gain, feed intake, and catalase (CAT) content in the mice but reduced γ-glutamyl transpeptidase (γ-GT) content in the serum (p < 0.05). BCA improved the Sobs, Chao, and Ace indices, as well as the number of Campylobacterota, Patercibacteria, and Desulfobacterota in the colon microbiota, while it decreased the Firmicutes phylum (p < 0.05). At the genus level, BCA increased Candidatus_Saccharimonas, Helicobacter, unclassified_f_Lachnospiraceae, Alistipes, norank_f_norank_o_Clostridia_vadinBB60_group, norank_f_Ruminococcaceae, unclassified_f_Ruminococcaceae, etc. abundance (p < 0.05), but it significantly decreased Lactobacillus and Lachnospiraceae_UCG_001 abundance (p < 0.05). Moreover, BCA improved the concentration of acetic acid, butyric acid, propionic acid, valeric acid, and isovaleric acid and diminished the concentration of isobutyric acid (p < 0.05). Correlation analysis shows that the changes in short-chain fatty acids and antioxidant and inflammatory indices in the serum were significantly correlated with the BCA-enriched microbiota. This study supplemented a database for the application of Caprifoliaceae and Scutellaria baicalensis Georgi in clinical and animal production.

Baicalin Alleviates Short-Term Lincomycin-Induced Intestinal and Liver Injury and Inflammation in Infant Mice.

The adverse effects of short-term megadose of antibiotics exposure on the gastrointestinal and liver tissue reactions in young children have been reported. Antibiotic-induced intestinal and liver reactions are usually unpredictable and present a poorly understood pathogenesis. It is, therefore, necessary to develop strategies for reducing the adverse effects of antibiotics. Studies on the harm and rescue measures of antibiotics from the perspective of the gut-liver system are lacking. Here, we demonstrate that lincomycin exposure reduced body weight, disrupted the composition of gut microbiota and intestinal morphology, triggered immune-mediated injury and inflammation, caused liver dysfunction, and affected lipid metabolism. However, baicalin administration attenuated the lincomycin-induced changes. Transcriptome analysis showed that baicalin improved immunity in mice, as evidenced by the decreased levels of intestinal inflammatory cytokines and expression of genes that regulate Th1, Th2, and Th17 cell differentiation, and inhibited mucin type O-glycan biosynthesis pathways. In addition, baicalin improved liver function by upregulating the expression of genes involved in bile acid secretion and lipid degradation, and downregulating genes involved in lipid synthesis in lincomycin-treated mice. Bile acids can regulate intestinal immunity and strengthen hepatoenteric circulation. In addition, baicalin also improved anti-inflammatory bacteria abundance (Blautia and Coprobacillus) and reduced pathogenic bacteria abundance (Proteobacteria, Klebsiella, and Citrobacter) in lincomycin-treated mice. Thus, baicalin can ameliorate antibiotic-induced injury and its associated complications such as liver disease.

Effects of chlortetracycline on growth performance and intestinal functions in weaned piglets.

AIM: Weaning stress can cause serious damage to piglet's health. Chlortetracycline (CTC) is widely used to ameliorate weaning stress and prevent infectious diseases in weaned piglets. However, antibiotics as growth promoters have to be limited because of increased antimicrobial resistance. In this study, we evaluated the effects of CTC on growth performance and intestinal functions in order to provide evidence for seeking antibiotic substitutes in weaned piglets. METHODS AND RESULTS: A total of 20 weaned piglets were fed a basal diet or a diet supplemented with 75 mg/kg CTC. CTC decreased the crypt depth and increased the ratio of villus height to crypt depth, whilst failing to affect growth performance and serum biochemical parameters and cytokines. 16S rRNA sequencing suggested that CTC supplementation had no effect on the diversity and composition of colonic microbiota. CONCLUSION: We speculated that gut microbiota is no longer sensitive to a low concentration of CTC due to the long-term use and low bioavailability of CTC in weaned piglets.

Time-course alterations of gut microbiota and short-chain fatty acids after short-term lincomycin exposure in young swine.

Increasing evidence suggests that antibiotic administration causes gut injury, negatively affecting nutrient digestion, immune regulation, and colonization resistance against pathogens due to the disruption of gut microbiota. However, the time-course effects of therapeutic antibiotics on alterations of gut microbes and short-chain fatty acids (SCFAs) in young swine are still unknown. In this study, twenty piglets were assigned into two groups and fed commercial diets with or without lincomycin in the first week for a 28-day trial period. Results showed that 1-week lincomycin exposure (LE) did reduce the body weight on day 14 (p = 0.0450) and 28 (p = 0.0362). The alpha-diversity notably reduced after 1-week LE, and then gradually raised and reached the control group level in the second week on cessation of LE, indicated by the variation of Sobs, Chao, Shannon, and ACE index (p < 0.05). Beta-diversity analysis revealed that the distinct microbial cluster existed persistently for the whole trial period between two groups (p < 0.001). The relative abundance of most microbes including fiber-degrading (e.g., Agathobacter and Coprococcus), beneficial (e.g., Lactobacillus and Mitsuokella), or pathogenic bacteria (e.g., Terrisporobacter and Lachnoclostridium) decreased (LDA score > 3), and the concentration of SCFAs also diminished in the feces of 1-week lincomycin-administrated young swine, indicating that therapeutic LE killed most bacteria and reduced SCFA production with gut dysbiosis occurring. After the LE stopped, the state of gut dysbiosis gradually attenuated and formed new gut-microbe homeostasis distinct from microbial homeostasis of young pigs unexposed to lincomycin. The increased presence of potential pathogens, such as Terrisporobacter, Negativibacillus, and Escherichia-Shigella, and decreased beneficial bacteria, such as Lactobacillus and Agathobacter, were observed in new homeostasis reshaped by short-lincomycin administration (LDA score > 3 or p < 0.05), adversely affecting gut development and health of young pigs. Collectively, these results suggested that severe disruption of the commensal microbiota occurred after short-term LE or termination of LE in young swine. KEY POINTS: • Therapeutic lincomycin exposure induced gut dysbiosis, killing most bacteria and reducing short-chain fatty acid production. • Gut dysbiosis gradually attenuated and formed new homeostasis after lincomycin exposure stopped. • The new homeostasis, increased Escherichia-Shigella etc. and decreased Lactobacillus etc., was potentially harmful to gut health.

Dihydroquercetin supplement alleviates colonic inflammation potentially through improved gut microbiota community in mice.

The purpose of the current study was to investigate the effect of dietary dihydroquercetin (DHQ) supplementation on dextran sodium sulfate (DSS)-induced colitis in mice. Mice were given DHQ supplementation (3 g kg-1) throughout the study, starting 14 days prior to DSS treatment for 1 week followed by 2 days without DSS. The results showed that dietary DHQ supplementation restored DSS-induced disease activity index (DAI), colon length and histopathology scores of the colon tissue. Additionally, supplementation with DHQ reduced the pro-inflammatory cytokine levels, and enhanced the level of IL-10 in the serum. qPCR results indicated that DHQ supplementation significantly downregulated IL-1ß, IL-6, and TNF-α, and upregulated IL-10 gene mRNA expression. Western blot results proved that DHQ supplementation upregulated ZO-1 and occludin levels. Using amplicon sequencing technology, 16S rRNA sequencing results showed that DHQ supplementation increased the fecal Firmicutes/Bacteroidetes ratio and the relative abundance of Lactobacillus and Dubosiella, and decreased the relative abundance of Bacteroidetes. Additionally, DHQ supplementation restored the decreased fecal acetic acid and butyric acid concentrations in DSS-induced colitis mice. Besides, Spearman's correlation analysis showed that Dubosiella was positively correlated with the butyric acid level and Bacteroidetes was positively correlated with the mRNA expression of IL-1ß and IL-6. Both Lactobacillus and Dubosiella showed a negative correlation with the mRNA expression of IL-1ß, IL-6, and TNF-α, and Dubosiella was positively correlated with IL-10. In summary, it was found that DHQ supplementation alleviated DSS-induced colitis which may be potentially associated with altered fecal microbiota communities in mice.

From gut microbiota to host appetite: gut microbiota-derived metabolites as key regulators.

Feelings of hunger and satiety are the key determinants for maintaining the life of humans and animals. Disturbed appetite control may disrupt the metabolic health of the host and cause various metabolic disorders. A variety of factors have been implicated in appetite control, including gut microbiota, which develop the intricate interactions to manipulate the metabolic requirements and hedonic feelings. Gut microbial metabolites and components act as appetite-related signaling molecules to regulate appetite-related hormone secretion and the immune system, or act directly on hypothalamic neurons. Herein, we summarize the effects of gut microbiota on host appetite and consider the potential molecular mechanisms. Furthermore, we propose that the manipulation of gut microbiota represents a clinical therapeutic potential for lessening the development and consequence of appetite-related disorders. Video abstract.

Olive Fruit Extracts Supplement Improve Antioxidant Capacity via Altering Colonic Microbiota Composition in Mice.

Oxidative stress, one of the most common biological dysfunctions, is usually associated with pathological conditions and multiple diseases in humans and animals. Chinese olive fruit (Canarium album L.) extracts (OE) are natural plant extracts rich in polyphenols (such as hydroxytyrosol, HT) and with antioxidant, anti-hyperlipidemia, and anti-inflammatory potentials. This study was conducted to investigate the antioxidant capacity of OE supplementation and its related molecular mechanism in mice. Mice (25.46 ± 1.65 g) were treated with 100 mg/kg body weight (BW) OE or saline solution for 4 weeks, and then the antioxidant and anti-inflammatory capacities of mice were examined. The results showed that OE supplement significantly increased the serum antioxidative enzyme activities of total antioxidant activity (T-AOC), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase and decreased the serum malondialdehyde (MDA) level, indicating that OE treatment enhanced the antioxidant capacity in mice. qPCR results showed that the transcriptional expression of antioxidant SOD1, CAT, Gpx1, and Gpx2 were significantly down-regulated in the small intestine (jejunum and ileum) after OE administration. Meanwhile, OE treatment significantly decreased the T-AOC and increased the MDA level in the small intestine. Furthermore, OE administration dramatically reduced the mRNA expression of pro-inflammatory cytokines (TNF-α and IL-1ß), which confirmed its antioxidant and anti-inflammatory capacities with OE administration. Using amplicon sequencing technology, 16S rRNA sequencing results showed that OE supplement significantly increased the colonic Firmicutes/Bacteroidetes ratio, which also had a negative correlation with the serum MDA level and positively correlated with serum GSH-Px activity through Pearson correlation analysis. Besides that, Alloprevotella was negatively correlated with serum T-AOC. Colidextribacter was positively correlated with serum MDA and negatively correlated with serum T-AOC, SOD, and GSH-Px levels. In summary, this study showed that treatment with 100 mg/kg BW polyphenol-rich OE could alter colonic microbiota community, which was strongly associated with improved antioxidant capacity in mice.

Short-Term Lincomycin Exposure Depletion of Murine Microbiota Affects Short-Chain Fatty Acids and Intestinal Morphology and Immunity.

Lincomycin, as one of the most commonly used antibiotics, may cause intestinal injury, enteritis and other side effects, but it remains unknown whether these effects are associated with microbial changes and the effects of different doses of lincomycin on infants. Here, 21-day old mice were exposed to 1 and 5 g/L lincomycin to explore the effects of lincomycin on the gut microbiota, metabolites and inflammation. Compared to the control mice, 1 g/L lincomycin exposure decreased the body weight gain of mice (p < 0.05). Both 1 and 5 g/L lincomycin exposure reduced the diversity and microbial composition of mice (p < 0.05). Furthermore, 1 and 5 g/L lincomycin reduced the relative concentrations of acetate, propionate, butyrate, valerate, isobutyric acid and isovaleric acid in the colon chyme of mice (p < 0.05). In addition, 5 g/L lincomycin exposure reduced the villus height, crypt depth, and relative expression of TLR2, TLR3, TLR4, IL-18, TNF-α, and p65 in the jejunum of mice (p < 0.05), while 1 g/L lincomycin exposure reduced the relative expression of TLR2, TLR3, TNF-α, and p65 (p < 0.05). Collectively, these results highlight the depletion effect of short-term lincomycin exposure on microbiota and the further regulatory effect on intestinal morphology and immunosuppression in infant mice.

Effects of Optimal Carbohydrase Mixtures on Nutrient Digestibility and Digestible Energy of Corn- and Wheat-Based Diets in Growing Pigs.

This study aimed to evaluate the effects of optimal carbohydrase mixture (OCM) on macronutrients and amino acid digestibility and the digestible energy (DE) in growing pigs fed the corn-soybean meal-based diet (CSM) and the wheat-soybean meal-based diet (WSM). A total of 36 ileal-cannulated pigs (50.9 ± 4.9 kg initial body weight) were allotted to four dietary treatments randomly, which included CSM and WSM diets, and two diets supplied with corresponding OCM. These OCMs were screened using an in vitro method from our previous study. After the five day adaptation period, fecal samples were collected from d six to seven, and ileal digesta samples were collected on d 8 and 10. Chromic oxide was added as an indigestible marker. The results show that the addition of OCM improved the apparent ileal digestibility (AID) of dry matter (DM), ash, carbohydrate (CHO), neutral detergent fiber, and gross energy (GE) and the apparent total tract digestibility (ATTD) of DM, CHO, and GE in CSM diet (p < 0.05), but reduced the apparent hindgut disappearance (AHD) of DM in CSM diet (p < 0.05). The ATTD of DM, crude protein (CP), ether extract (EE), ash, and GE and the AHD of DM, CP, EE, ash, CHO, and GE in WSM diet were improved by the OCM addition (p < 0.05), whereas the AID of DM, CP, ash, CHO, and GE were decreased (p < 0.05). The respective DE contents in CSM and WSM diets were increased from 15.45 to 15.74 MJ/kg and 15.03 to 15.49 MJ/kg under the effects of OCM (p < 0.05). Similar to the trend of AID of CP, the OCM addition increased the AID and standardized ileal digestibility (SID) of Ile, Thr, and Cys in CSM diet, but decreased the AID and SID of Ile, Phe, Thr, Val, Ala, Pro, Ser, and Tyr in WSM diet. In conclusion, the OCMs screened by an in vitro method could improve the total tract nutrient digestibility and DE for pigs fed corn-based diet or wheat-based diet but had inconsistent effects on the ileal digestibility of nutrients and energy.

Estrogen-related receptor ERRα regulation of human hydroxysteroid sulfotransferase (SULT2A1) gene expression in human Caco-2 cells.

Human hydroxysteroid sulfotransferase, SULT2A1, is important for xenobiotic detoxification and the maintenance of hydroxysteroid homeostasis. Our published report suggested that estrogen-related receptor ERRα downregulates SULT2A1 in Hep G2 cells. The results shown in this study suggest that ERRα upregulates SULT2A1 transcription in Caco-2 cells. The deletion analysis suggested that SULT2A1 promoter region between -65 and -44 is important for this upregulation. Our further investigation suggested that ERRα binding element, ERRE51, mediates ERRα activation of SULT2A1 promoter transcription in Caco-2 cells. The interaction of ERRE51 with ERRα was confirmed by electrophoretic mobility shift assay and chromatin immunoprecipitation analysis. Results also suggest that the difference of constitutive androstane receptor transcription levels in Hep G2 and Caco-2 cells at least partially contribute to the cell type dependent ERRα modulation of SULT2A1 promoter transcription. ERRα regulates human SULT2A1 transcription by competing with other nuclear receptors binding to the DNA-promoter region.

Liver X receptor alpha mediated genistein induction of human dehydroepiandrosterone sulfotransferase (hSULT2A1) in Hep G2 cells.

Cytosolic sulfotransferases are one of the major families of phase II drug metabolizing enzymes. Sulfotransferase-catalyzed sulfonation regulates hormone activities, metabolizes drugs, detoxifies xenobiotics, and bioactivates carcinogens. Human dehydroepiandrosterone sulfotransferase (hSULT2A1) plays important biological roles by sulfating endogenous hydroxysteroids and exogenous xenobiotics. Genistein, mainly existing in soy food products, is a naturally occurring phytoestrogen with both chemopreventive and chemotherapeutic potential. Our previous studies have shown that genistein significantly induces hSULT2A1 in Hep G2 and Caco-2 cells. In this study, we investigated the roles of liver X receptor (LXRα) in the genistein induction of hSULT2A1. LXRs have been shown to induce expression of mouse Sult2a9 and hSULT2A1 gene. Our results demonstrate that LXRα mediates the genistein induction of hSULT2A1, supported by Western blot analysis results, hSULT2A1 promoter driven luciferase reporter gene assay results, and mRNA interference results. Chromatin immunoprecipitation (ChIP) assay results demonstrate that genistein increase the recruitment of hLXRα binding to the hSULT2A1 promoter. These results suggest that hLXRα plays an important role in the hSULT2A1 gene regulation. The biological functions of phytoestrogens may partially relate to their induction activity toward hydroxysteroid SULT.

Influenza A virus infection activates cholesterol sulfotransferase (SULT2B1b) in the lung of female C57BL/6 mice.

Cytosolic sulfotransferases (SULTs) catalyze the sulfation of hormones, neurotransmitters, and xenobiotics, increasing their water solubility. SULTs are not only important for xenobiotic detoxification but they also play important biological roles in the regulation of the activities of various biosignaling molecules and other cellular functions. In this study, we investigated the effects of influenza A virus lung infection on the expression of SULTs in the lung, brain, and liver of female C57BL/6 mice. Our results demonstrate for the first time that SULT2B1b enzyme activity and protein expression are significantly up-regulated in the lung and brain of female mice in response to lung influenza A virus infection. Real-time quantitative PCR results are consistent with Western blot and enzymatic activity data. In mouse liver, mSULT2B1b is not significantly changed. Enzyme activities, protein expression, and mRNA expression of SULT1A1 and SULT2A1 in the lung, brain, and liver of mice were not significantly affected by the infection. The induction of SULT2B1b may be used to inactivate natural liver X receptor ligands and activate the proliferation of T cells in response to influenza A virus infection in the lung and brain of mice. Our results raise the possibility that regulation of SULT2B1b may influence acquired immune responses to infectious diseases.

Biochanin A induction of sulfotransferases in rats.

Biochanin A (BCA) is a dietary isoflavone present in red clover (Trifoliumn pretense) and many herbal products. BCA has been reported to have chemopreventive actions against various cancers including prostate, breast, colon cancer, and so on. Sulfotransferases are a family of phase II drug-metabolizing enzymes, which are important for xenobiotic detoxification and regulation of biological signaling molecule biological activities. Sulfotransferase gene expressions are regulated by different hormones and xenobiotics. Improper regulation of sulfotransferases leads to improper functions of biological signaling molecules, which in turn can cause cancer or other diseases. BCA inhibits the enzyme activities of the phase I drug-metabolizing enzymes CYP1A1 and CYP1B1 in Chinese hamster ovary cells and induces the phase II drug-metabolizing enzymes UDP-glucuronosyltransferases in human prostate cancer cells. BCA induction of sulfotransferases has not been studied. This investigation evaluates the in vivo regulation of sulfotransferases at protein and mRNA levels in the liver and intestine of Sprague-Dawley rats treated with BCA (0, 2, 10, and 50 mg/kg/day) for 7 days. Our experimental results demonstrate for the first time that chronic BCA treatment can significantly induce the expression of rat sulfotransferase 1A1 (rSULT1A1, AST-IV), sulfotransferase 2A1 (rSULT2A1, STa), and rat estrogen sulfotransferase (rSULT1E1, EST) in rat liver and intestine. Our Western blot results are in good agreement with real-time RT-PCR data, suggesting that BCA induction of sulfotransferases occurs at the transcriptional level.