The microbiota-gut-brain axis: A novel nutritional therapeutic target for growth retardation.

Growth retardation (GR), which commonly occurs in childhood, is a major health concern globally. However, the specific mechanism remains unclear. It has been increasingly recognized that changes in the gut microbiota may lead to GR through affecting the microbiota-gut-brain axis. Microbiota interacts with multiple factors such as birth to affect the growth of individuals. Microbiota communicates with the nerve system through chemical signaling (direct entry into the circulation system or stimulation of enteroendocrine cells) and nervous signaling (interaction with enteric nerve system and vagus nerve), which modulates appetite and immune response. Besides, they may also influence the function of enteric glial cells or lymphocytes and levels of systemic inflammatory cytokines. Environmental stress may cause leaky gut through perturbing the hypothalamic-pituitary-adrenal axis to further result in GR. Nutritional therapies involving probiotics and pre-/postbiotics are being investigated for helping the patients to overcome GR. In this review, we summarize the role of microbiota in GR with human and animal models. Then, existing and potential regulatory mechanisms are reviewed, especially the effect of microbiota-gut-brain axis. Finally, we propose nutritional therapeutic strategies for GR by the intervention of microbiota-gut-brain axis, which may provide novel perspectives for the treatment of GR in humans and animals.

Baicalin-Zinc Complex Alleviates Inflammatory Responses and Hormone Profiles by Microbiome in Deoxynivalenol Induced Piglets.

This study aimed to investigate the beneficial effect of baicalin-zinc complex (BZN) on intestinal microorganisms in deoxynivalenol (DON)-challenged piglets and the association between intestinal microorganisms and host immunity and hormone secretion. Forty weaned piglets were randomly divided into four treatments with 10 piglets in each treatment: (1) control (Con) group (pigs fed basal diet); (2) DON group (pigs fed 4 mg DON/kg basal diet); (3) BZN group (pigs fed 0.5% BZN basal diet); and (4) DBZN group (pigs fed 4 mg DON/kg and 0.5% BZN basal diet). The experiment lasted for 14 days. The BZN supplementation in DON-contaminated diets changed the intestinal microbiota composition and increased intestinal microbial richness and diversity of piglets. The BZN supplementation in DON-contaminated diets also alleviated the inflammatory responses of piglets and modulated the secretion of hormones related to the growth axis. Moreover, microbiota composition was associated with inflammatory and hormone secretion. In conclusion, BZN alleviated inflammatory response and hormone secretion in piglets, which is associated with the intestinal microbiome.

Dietary Addition of Antioxidant Complex Packs and Functional Amino Acids Can Improve the Digestion, Absorption, and Immunity of Huanjiang Minipigs.

To study the effect of functional amino acids and the antioxidant function compound package on Huanjiang minipigs and to lay a foundation for the formulation of green and efficient feed for Huanjiang minipigs, we added functional amino acids and the antioxidant function compound package to piglet feed for 28 days. After feeding, we detected the growth performance, biochemical indexes, inflammatory indexes, and intestinal disaccharidase of piglets. It was found that functional amino acids and the antioxidant compound package had certain effects on the growth performance and biochemical indexes of piglets and could reduce the level of IL-6 and increase the level of LZM and SIgA of piglets, and the levels of lactase and maltase in the intestine also increased significantly. The results showed that the compound package of functional amino acids and antioxidation could improve the growth performance and immunity of piglets and promote the digestion and absorption of nutrients in piglets.

Effects of dietary gamma-aminobutyric acid supplementation on amino acid profile, intestinal immunity, and microbiota in ETEC-challenged piglets.

Enterotoxigenic Escherichia coli (ETEC) infection is the most common cause of diarrhea in piglets, and ETEC could increase intestinal gamma-aminobutyric acid (GABA)-producing bacteria to affect intestinal immunity. However, the effect of GABA on ETEC-infected piglets is still unclear. This study aims at investigating the impact of dietary GABA supplementation on the growth performance, diarrhea, intestinal morphology, serum amino acid profile, intestinal immunity, and microbiota  in the ETEC-infected piglet model. Eighteen piglets were randomly divided into two groups, in which the piglets were fed with a basal diet with 20 mg kg-1 GABA supplementation or not. The experiment lasted for three weeks, and the piglets were challenged with ETEC K88 on the fifteenth day. The results showed that dietary GABA reduced the feed conversion ratio, promoted the kidney organ index but did not affect the diarrheal score and small intestinal morphology in ETEC-challenged piglets. Ileal mucosal amino acids (such as carnosine and anserine) and serum amino acids (including threonine and GABA) were increased upon GABA supplementation. GABA enhanced ileal gene expression of TNF-α, IFN-γ, pIgR, and MUC2, while inhibited the ileal expression of IL-18 in ETEC-challenged piglets. GABA supplementation also highly regulated the intestinal microbiota by promoting community richness and diversity and reducing the abundance of the dominant microbial population of the ileal microbiota. Collectively, GABA improves growth performance, regulates the serum amino acid profile, intestinal immunity, and gut microbiota in ETEC-challenged piglets. This study is a fine attempt to reveal the function of GABA in ETEC-infected piglets. It would contribute to the understanding of the roles of exogenous nutrition on the host response to ETEC infection.

Baicalin-Copper Complex Modulates Gut Microbiota, Inflammatory Responses, and Hormone Secretion in DON-Challenged Piglets.

The present experiment assessed the inflammatory responses, hormone secretion, and gut microbiota of weanling piglets administered baicalin-copper complex (BCU) or deoxynivalenol (DON) supplementation diets. Twenty-eight piglets were randomly assigned to four groups: control diet (Con group), a 4 mg DON/kg diet (DON group), a 5 g BCU/kg diet (BCU group), a 5 g BCU + 4 mg DON/kg diet (DBCU group). After 14 days, the results showed that dietary BCU supplementation remarkably increased the relative abundance of Clostrium bornimense and decreased the relative abundance of Lactobacillus in the DBCU group (p < 0.05). BCU decreased the serum concentration of IgG, IL-2, IFN-γ, and IgA in DON treated piglets (p < 0.05), and promoted the serum concentration of IL-1ß, IgG, IL-2, IFN-γ, IgA, IL-6, IgM, and TNFα in normal piglets (p < 0.05). BCU increased the concentrations of serum IGF1, insulin, NPY, GLP-1, and GH, and decreased the concentrations of serum somatostatin in no DON treated piglets (p < 0.05). Dietary BCU supplementation significantly promoted the secretion of somatostatin, and inhibited the secretion of leptin in piglets challenged with DON (p < 0.05). BCU regulated the expression of food intake-related genes in the hypothalamus and pituitary of piglets. Collectively, dietary BCU supplementation alleviated inflammatory responses and regulated the secretion of appetite-regulating hormones and growth-axis hormones in DON challenged piglets, which was closely linked to changes of intestinal microbes.

Effects of GABA Supplementation on Intestinal SIgA Secretion and Gut Microbiota in the Healthy and ETEC-Infected Weanling Piglets.

Pathogenic enterotoxigenic Escherichia coli (ETEC) has been considered a major cause of diarrhea which is a serious public health problem in humans and animals. This study was aimed at examining the effect of γ-aminobutyric acid (GABA) supplementation on intestinal secretory immunoglobulin A (SIgA) secretion and gut microbiota profile in healthy and ETEC-infected weaning piglets. A total of thirty-seven weaning piglets were randomly distributed into two groups fed with the basal diet or supplemented with 40 mg·kg-1 of GABA for three weeks, and some piglets were infected with ETEC at the last week. According to whether ETEC was inoculated or not, the experiment was divided into two stages (referred as CON1 and CON2 and GABA1 and GABA2). The growth performance, organ indices, amino acid levels, and biochemical parameters of serum, intestinal SIgA concentration, gut microbiota composition, and intestinal metabolites were analyzed at the end of each stage. We found that, in both the normal and ETEC-infected piglets, jejunal SIgA secretion and expression of some cytokines, such as IL-4, IL-13, and IL-17, were increased by GABA supplementation. Meanwhile, we observed that some low-abundance microbes, like Enterococcus and Bacteroidetes, were markedly increased in GABA-supplemented groups. KEGG enrichment analysis revealed that the nitrogen metabolism, sphingolipid signaling pathway, sphingolipid metabolism, and microbial metabolism in diverse environments were enriched in the GABA1 group. Further analysis revealed that alterations in microbial metabolism were closely correlated to changes in the abundances of Enterococcus and Bacteroidetes. In conclusion, GABA supplementation can enhance intestinal mucosal immunity by promoting jejunal SIgA secretion, which might be related with the T-cell-dependent pathway and altered gut microbiota structure and metabolism.

Dietary glutamine, glutamate, and aspartate supplementation improves hepatic lipid metabolism in post-weaning piglets.

A previous study has demonstrated that early weaning significantly suppressed hepatic glucose metabolism in piglets. Glutamate (Glu), aspartate (Asp) and glutamine (Gln) are major metabolic fuels for the small intestine and can alleviate weaning stress, and therefore might improve hepatic energy metabolism. The objective of this study was to investigate the effects of administration of Glu, Asp and Gln on the expression of hepatic genes and proteins involved in lipid metabolism in post-weaning piglets. Thirty-six weaned piglets were assigned to the following treatments: control diet (Control; basal diet + 15.90 g/kg alanine); Asp, Gln and Glu-supplemented diet (Control + AA; basal diet + 1.00 g/kg Asp + 5.00 g/kg Glu + 10.00 g/kg Gln); and the energy-restricted diet supplemented with Asp, Gln and Glu (Energy- + AA; energy deficient diet + 1.00 g/kg Asp + 5.00 g/kg Glu + 10.00 g/kg Gln). Liver samples were obtained on d 5 and 21 post-weaning. Piglets fed Energy- + AA diet had higher liver mRNA abundances of acyl-CoA oxidase 1 (ACOX1), succinate dehydrogenase (SDH), mitochondrial transcription factor A (TFAM) and sirtuin 1 (SIRT1), as well as higher protein expression of serine/threonine protein kinase 11 (LKB1), phosphor-acetyl-CoA carboxylase (P-ACC) and SIRT1 compared with piglets fed control diet (P < 0.05) on d 5 post-weaning. Control + AA diet increased liver malic enzyme 1 (ME1) and SIRT1 mRNA levels, as well as protein expression of LKB1 and P-ACC on d 5 post-weaning (P < 0.05). On d 21 post-weaning, compared to control group, Glu, Gln and Asp supplementation up-regulated the mRNA levels of ACOX1, ME1 and SIRT1 (P < 0.05). These findings indicated that dietary Glu, Gln and Asp supplementation could improve hepatic lipid metabolism to some extent, which may provide nutritional intervention for the insufficient energy intake after weaning in piglets.

Dietary Baicalin Zinc Supplementation Alleviates Oxidative Stress and Enhances Nutrition Absorption in Deoxynivalenol Challenged Pigs.

BACKGROUND: Deoxynivalenol contamination is increasing worldwide, presenting great challenges to food security and causing great economic losses in the livestock industry. OBJECTIVE: This study was conducted to determine the protective effect of baicalin zinc as a dietary supplement on pigs fed with a deoxynivalenol contaminated diet. METHODS: A total of 40 weaned pigs (21 d of age; 6.13 ± 0.42 kg average BW) were randomly assigned (10 pigs/group) to 4 dietary treatments: basal diet (Con group), basal diet + 4 mg/kg DON (DON group), basal diet + 5 g/kg BZN (BZN group), and basal diet + 5 g/kg BZN + 4 mg/kg DON (DBZN group) for a 14-d period. Seven randomly-selected pigs from each treatment were killed for blood and tissue sampling. RESULTS: The results showed that piglets challenged with DON exhibited significantly reduced levels of ADG, ADFI, and F/G (p < 0.05). BZN supplemented diets significantly suppressed the protein expression of p-Nrf2, p-NF-kB, and HO-1 in the jejunum of DON challenged piglets (p < 0.05). In liver, DON markedly increased the mRNA expression of P70S6K and HSP70 in piglets fed the basal diet, but significantly reduced that of HO-1, NQO-1, NF-kB, AMPKα2 and HSP70 in piglets fed the BZN supplemented diet (p < 0.05). Dietary supplementation with BZN markedly increased the T-AOC level of serum in weaned piglets (p < 0.05). In jejunum, dietary supplementation with BZN activated the mRNA expression of ZIP4 in piglets (p < 0.05), BZN supplementation significantly suppressed the activity of sucrose and increased the protein concentration in chyme (p < 0.05). CONCLUSION: BZN can play a protective role by reducing oxidative stress and enhancing nutrient absorption in pigs fed DON-contaminated diets.

The Evaluation of the Antioxidant and Intestinal Protective Effects of Baicalin-Copper in Deoxynivalenol-Challenged Piglets.

The present study was performed to evaluate the antioxidant and intestinal protective effects of baicalin-copper on deoxynivalenol-challenged piglets. Forty weaned piglets were randomly divided into four groups and assigned to different diets: (1) basal diet (Con), (2) 4 mg/kg deoxynivalenol of basal diet (DON), (3) 5 g/kg baicalin-copper of basal diet (BCU); and (4) 4 mg/kg deoxynivalenol + 5 g/kg baicalin-copper of basal diet (DBCU). The results showed that the ADFI and ADG of piglets in the DON group were markedly lower than those in the Con group, but the ADFI and ADG of the DBCU group were not significantly different from those of the Con group. In piglets fed a DON-contaminated diet, dietary supplementation with BCU significantly decreased the mRNA levels of P70S6K, 4E-BP1, and HSP70 in the liver, the protein expression of HO-1 in the jejunum, and the expression of p-Nrf2 and p-NF-κB in the ileum but increased Mn-SOD activity in serum. Dietary supplementation with BCU increased jejunal maltase, ZIP4 and MT mRNA levels, and serum concentrations of Arg, Val, Ile, Leu, Lys, and Tyr in DON-contaminated piglets. In summary, BCU can alleviate the growth impairment induced by DON and enhance antioxidant capacity and nutrition absorption in piglets fed DON-contaminated diets.

Effects of dietary gamma-aminobutyric acid supplementation on the intestinal functions in weaning piglets.

This study aims to investigate the effects of dietary gamma-aminobutyric acid (GABA) supplementation on the growth performance, intestinal immunity, intestinal GABAergic system, amino acid profiles and gut microflora of the weaned piglets. Totally sixteen healthy piglets were randomly assigned into two groups to be fed with the basal diet (Con group) or the basal diet with GABA (20 mg kg-1) supplementation. Body weights and feed intakes were monitored weekly. Piglets were sacrificed after 3 weeks of GABA supplementation to collect the blood, ileum, ileal mucosa and luminal content. Immune-associated factors, GABAergic system, amino acid profiles, and microbiota in the ileum and serum amino acid profiles were explored. The results showed that GABA supplementation improved the growth performance and modulated the intestinal immunity with inhibiting the gene expressions of IL-22, proinflammatory cytokines (IL-1 and IL-18), and Muc1, but promoted the expressions of anti-inflammatory cytokines (IFN-γ, IL-4, and IL-10), TLR6 and MyD88. GABA regulated a few components of the intestinal GABAergic system, increased the levels of most amino acids in the ileal mucosa but reduced the serum amino acid profiles. GABA regulated the population and diversity of intestinal microbiota, such as the abundances of the dominant microbial populations, the community richness, and diversity of the ileal microbiota. In conclusion, GABA supplementation modulated the intestinal functions, including intestinal immunity, intestinal amino acid profiles and gut microbiota, and the results can be helpful for understanding the functions of GABA in the intestine.