Ferroptosis plays a role in several diseases such as iron overload-induced liver diseases. Manipulation of ferroptosis has been explored as a potential therapeutic strategy to treat related diseases. Numerous antioxidants have been identified to control ferroptosis but the cell-autonomous mechanisms responsible for regulating ferroptosis remain elusive. In the present study, we found that iron overload promoted ferroptosis in hepatocytes by excessively inducing HO-1 expression, which contributed to the progression of liver injury and fibrosis, accompanied by the upregulation of the FGF21 protein level in vitro and in vivo. Interestingly, both recombinant FGF21 and Fgf21 overexpression significantly protected against iron overload-induced hepatocytes mitochondria damage, liver injury and fibrosis by inhibiting ferroptosis. In contrast, the loss of FGF21 aggravated iron overload-induced ferroptosis. Notably, FGF21-induced HO-1 inhibition (via the promotion of HO-1 ubiquitination and degradation) and NRF2 activation provide a mechanistic explanation for this phenomenon. Taken together, we identified FGF21 as a novel ferroptosis suppressor. Thus, FGF21 activation may provide an effective strategy for the potential treatment of iron overload-induced ferroptosis-related diseases, such as hereditary haemochromatosis (HH).

Betaine is a natural compound present in commonly consumed foods and may have a potential role in the regulation of glucose and lipids metabolism. However, the underlying molecular mechanism of its action remains largely unknown. Here, we show that supplementation with betaine contributes to improved high-fat diet (HFD)-induced gut microbiota dysbiosis and increases anti-obesity strains such as Akkermansia muciniphila, Lactobacillus, and Bifidobacterium. In mice lacking gut microbiota, the functional role of betaine in preventing HFD-induced obesity, metabolic syndrome, and inactivation of brown adipose tissues are significantly reduced. Akkermansia muciniphila is an important regulator of betaine in improving microbiome ecology and increasing strains that produce short-chain fatty acids (SCFAs). Increasing two main members of SCFAs including acetate and butyrate can significantly regulate the levels of DNA methylation at host miR-378a promoter, thus preventing the development of obesity and glucose intolerance. However, these beneficial effects are partially abolished by Yin yang (YY1), a common target gene of the miR-378a family. Taken together, our findings demonstrate that betaine can improve obesity and associated MS via the gut microbiota-derived miR-378a/YY1 regulatory axis, and reveal a novel mechanism by which gut microbiota improve host health.

Weanling pigs, with immature immune system and physiological function, usually experience post-weaning diarrhea. This study determined the effects of dietary Clostridium butyricum supplementation on growth performance, diarrhea, and immunity of weaned pigs challenged with lipopolysaccharide (LPS). In Experiment (Exp.) 1, 144 weaned piglets were weaned at 21 d and randomly assigned to six groups, with six replicates per group and four pigs per replicate, receiving a control diet (CON) or diet supplemented with antibiotics (AB) or C. butyricum (CB) (0.1%, 0.2%, 0.4%, or 0.8%), respectively. All diets in Exp. 1 were a highly digestible basal diet, with 3,000 mg/kg zinc oxide supplied in the first 2 wk only. In Exp. 2, 180 piglets were weaned at 21 d and randomly assigned to five groups, with six replicates per group and six pigs per replicate, receiving CON, AB, or CB (0.2%, 0.4%, or 0.6%) diets. The digestibility of diets was lower than those in Exp. 1, and did not include zinc oxide. At 36 d of Exp. 2, 12 piglets were selected from each of the CON and 0.4% CB groups, six piglets were intraperitoneally injected with LPS (50 μg/kg body weight) and the other six piglets with normal saline; animals were killed at 4 h after injection to collect blood, intestine, and digesta samples for biochemical analysis. In Exp. 1, CB and AB diets had no effect on growth performance of piglets. In Exp. 2, 0.4% CB decreased feed-gain ratio (P < 0.1), diarrhea score (P < 0.05), and increased duodenal, jejunal, and ileal villus height and jejunal villus height/crypt depth (P < 0.05). The 0.4% CB decreased the plasma tumor necrosis factor (TNF) α (P < 0.05) but increased ileal mucosa IL-10 and TLR2 mRNA expression (P < 0.05). Furthermore, 0.4% CB altered the microbial profile, with Bacillus and Ruminococcaceae UGG-003 at genus level and Lactobacillus casei and Parasutterella secunda at species level were higher than CON in colonic content (P < 0.05). Dietary C. butyricum supplementation had positive effects on growth of weaned piglets with less digestible diets. There was a tendency to reduce the feed-gain ratio, which could reduce feed costs in pig production. Moreover, C. butyricum decreased post-weaning diarrhea by improving the intestinal morphology, intestinal microflora profile, and immune function.

To study the effects of maternal dietary fiber composition during gestation on offspring antioxidant capacity, inflammation, and gut microbiota composition, we randomly assigned 64 gilts to four treatments and administered diets with an insoluble/soluble fiber ratio of 3.89 (R1), 5.59 (R2), 9.12 (R3), and 12.81 (R4). Sow samples (blood and feces at gestation 110) and neonatal samples (blood, liver, and colonic contents) were collected. The results showed that sows and piglets in R1 and R2 had higher antioxidant enzyme activity and lower pro-inflammatory factor levels than those in R3 and R4. Moreover, piglets in R1 and R2 had higher liver mRNA expression of Nrf2 and HO-1 and lower NF-κB than piglets in R4. Interestingly, maternal fiber composition not only affected the production of short-chain fatty acids (SCFAs) in sow feces but also influenced the concentrations of SCFAs in the neonatal colon. Results of high-throughput sequencing showed that piglets as well as sows in R1 and R2 had microbial community structures distinct from those in R3 and R4. Therefore, the composition of dietary fiber in pregnancy diet had an important role in improving antioxidant capacity and decreasing inflammatory response of mothers and their offspring through modulating the composition of gut microbiota.

It takes several hours for mammalian sperm to migrate from the ejaculation or insemination site to the fertilization site in the female reproductive tract in which glucose, amino acids, and fatty acids are regarded as the primary substrates for ATP generation. The present study was designed to investigate whether oleic acid and palmitic acid were beneficial to boar sperm in vitro; and if yes, to elucidate the mechanism that regulates sperm motility. Therefore, the levels of oleic acid and palmitic acid, motility, membrane integrity, acrosome integrity, and apoptosis of sperm were evaluated. Moreover, the enzymes involved in mitochondrial β-oxidation (CPT1: carnitine palmitoyltransferase 1; ACADVL: long-chain acyl-coenzyme A dehydrogenase) were detected with immunofluorescence and Western blotting. Consequently, the ATP content and the activities of CPT1, ACADVL, malate dehydrogenase (MDH), and succinate dehydrogenase (SDH) were also measured. We observed that CPT1 and ACADVL were expressed in boar sperm and localized in the midpiece. The levels of oleic acid and palmitic acid were decreased during storage at 17 °C. The addition of oleic acid and palmitic acid significantly increased sperm motility, progressive motility, straight-line velocity (VSL), membrane integrity, and acrosome integrity with a simultaneous decrease in sperm apoptosis after seven days during storage. When sperm were incubated with oleic acid and palmitic acid at 37 °C for 3 h, the activities of CPT1 and ACADVL, the ATP level, the mitochondrial membrane potential, the activities of MDH and SDH, as well as sperm motility patterns were significantly increased compared to the control (p < 0.05). Moreover, the addition of etomoxir to the diluted medium in the presence of either oleic acid or palmitic acid and the positive effects of oleic acid and palmitic acid were counteracted. Together, these data suggest that boar sperm might utilize oleic acid and palmitic acid as energy substrates for ATP production via β-oxidation. The addition of these acids could improve sperm quality.

Background: This study aimed to investigate the impacts of guar gum and cellulose as the source of dietary fiber during gestation on the reproductive performance of sows. Methods: A total of 210 sows (parities 3–6) were randomly allocated into six diets (n = 35) throughout gestation to feed graded levels of dietary fiber (DF), including a corn-soybean meal-based control diet with no wheat bran inclusion (CON, 12.5% DF), a wheat bran-rich diet (DF1, 17.4% DF), and another 4 diets (DF2, 17.7% DF; DF3, 18.1% DF; DF4, 18.4% DF; DF5, 18.8% DF) in which wheat bran were equally substituted by 1%, 2%, 3% and 4% purified FIBER MIX (guar gum and cellulose, 1:4). All sows received similar DE and other nutrients throughout gestation. Results: DF treatment during gestation resulted in normal fecal score (1 to 5 with 1 = dry and 5 = watery) in sows compared with those received the CON diet (P < 0.05). The number of total born piglets had a tendency to be affected by dietary treatment (P = 0.07), and correlation analysis revealed a linear response of total born to dietary fiber levels during gestation (P < 0.01). Sows received the DF2, DF3, and DF5 diets during gestation had a greater ADFI during lactation compared with those in the CON group (P < 0.05) without affecting the daily body weight gain of suckling piglets. Gut microbiota compositions were dramatically changed by the gestation stage and some of those were changed by DF inclusion. Fecal acetate, propionate, and butyrate of sows were markedly increased in late gestation, and butyrate contents in feces of gestating sows were significantly affected by DF levels (P < 0.01). Serum concentrations of pro-inflammatory TNF-α were decreased and anti-inflammatory IL-10 was increased on day 30 of gestation by DF levels (P < 0.05). Conclusions: In summary, increasing dietary fiber levels by guar gum and cellulose during gestation improved the reproductive performance of sows, which might be related to changes in immunity and gut microbiota of sows.