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).

Based on previous studies about microflora regulation and immunity enhancement activities of polysaccharides from Codonopsis pilosula Nannf. var. modesta (Nannf.) L. T. Shen (CPP), there is little study on intestinal mucosal immunity, which is a possible medium for contacting microflora and immunity. In the present study, the BALB/c mice were divided into five groups (eight mice in each group), including a normal group (Con), a model control group (Model), and model groups that were administered CPP (50, 100, 200 mg/kg/d) orally each day for seven days after intraperitoneal injection of 60 mg/kg BW/d cyclophosphamide (CP) for three days. CPP recovered the spleen index and restored the levels of IFN-γ, IL-2, IL-10, as well as serum IgG. In addition, it elevated ileum secretory immunoglobulin A (sIgA), the number of Lactobacillus and acetic acid content in cecum. These results indicated that CPP plays an important role in the protection against immunosuppression, especially mucosa immune damage, and the inhibition of pathogenic bacteria colonization, which could be considered a potential natural source of immunoregulator.

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.