Background: Bisphenol A (BPA) is an environmental contaminant with endocrine-disrupting properties that induce fetal growth restriction (FGR). Previous studies on pregnant ewes revealed that BPA exposure causes placental apoptosis and oxidative stress (OS) and decreases placental efficiency, consequently leading to FGR. Nonetheless, the response of gut microbiota to BPA exposure and its role in aggravating BPA-mediated apoptosis, autophagy, mitochondrial dysfunction, endoplasmic reticulum stress (ERS), and OS of the maternal placenta and intestine are unclear in an ovine model of gestation. Results: Two pregnant ewe groups (n = 8/group) were given either a subcutaneous (sc) injection of corn oil (CON group) or BPA (5 mg/kg/day) dissolved in corn oil (BPA group) once daily, from day 40 to day 110 of gestation. The maternal colonic digesta and the ileum and placental tissue samples were collected to measure the biomarkers of autophagy, apoptosis, mitochondrial dysfunction, ERS, and OS. To investigate the link between gut microbiota and the BPA-induced FGR in pregnant ewes, gut microbiota transplantation (GMT) was conducted in two pregnant mice groups (n = 10/group) from day 0 to day 18 of gestation after removing their intestinal microbiota by antibiotics. The results indicated that BPA aggravates apoptosis, ERS and autophagy, mitochondrial function injury of the placenta and ileum, and gut microbiota dysbiosis in pregnant ewes. GMT indicated that BPA-induced ERS, autophagy, and apoptosis in the ileum and placenta are attributed to gut microbiota dysbiosis resulting from BPA exposure. Conclusions: Our findings indicate the underlying role of gut microbiota dysbiosis and gut-placental axis behind the BPA-mediated maternal intestinal and placental apoptosis, OS, and FGR. The findings further provide novel insights into modulating the balance of gut microbiota through medication or probiotics, functioning via the gut-placental axis, to alleviate gut-derived placental impairment or FGR.

Studies have shown that exogenous thiamine (THI) supplementation can alleviate inflammation and promote rumen epithelial development in goats and cows. This research aimed to evaluate the effect of THI supplementation on LPS-induced inflammation and energy metabolic dysregulation in RECs of goats. Cells were stimulated with either 5 μg/mL THI for 18 h (THI group) or with 5 μg/mL LPS for 6 h (LPS group). The CON group was stimulated with DMEM/F-12 medium without THI for 18 h. The LPTH group was pretreated with THI for 18 h, followed by LPS stimulation for 6 h. THI supplementation decreased the ROS content (p < 0.05), as well as the ratios of phosphorylated (p)-p65 to p65 (p < 0.05) and p-AMPKα to AMPKα (p < 0.05). Interestingly, when the p38 gene was overexpressed in the LPTH group, the ratio of p-p65 to p65 and p-AMPKα to AMPKα proteins significantly increased, and ATP content decreased (p < 0.05). Our results suggest that THI possesses anti-inflammatory and metabolic-modulatory effects in RECs. The mechanism is largely related to the suppression of the NF-κB/p38 MAPK/AMPK signaling pathway. Additionally, we also revealed that THI supplementation can inhibit LPS-induced oxidative damage and apoptosis to protect mitochondrial function in RECs.

During pregnancy, the regulation of autophagy and ferroptosis dynamically supports placental development and fetal health. Both processes—autophagy, clearing damaged organelles to maintain placental function, and ferroptosis, driven by iron-dependent lipid peroxidation—are involved in pathological conditions such as preeclampsia. Emerging evidence suggests that gut microbiota-derived metabolites act as key regulators of this balance, yet their specific roles across different trimesters remain unclear. This review compiles evidence on how gut microbiota metabolites, like short-chain fatty acids and trimethylamine N-oxide, serve as trimester-specific modulators of the autophagy–ferroptosis balance during pregnancy. We explain how these metabolites influence pregnancy outcomes by regulating placental autophagy and ferroptosis. Furthermore, we explore potential diagnostic and therapeutic approaches for pregnancy complications, focusing on metabolite-based biomarkers and interventions that target microbial–metabolic interactions.

The endoplasmic reticulum is a complex and dynamic organelle that initiates unfolded protein response and endoplasmic reticulum stress in response to the accumulation of unfolded or misfolded proteins within its lumen. Autophagy is a paramount intracellular degradation system that facilitates the transportation of proteins, cytoplasmic components, and organelles to lysosomes for degradation and recycling. Preeclampsia and intrauterine growth retardation are two common complications of pregnancy associated with abnormal trophoblast differentiation and placental dysfunctions and have a major impact on fetal development and maternal health. The intricate interplay between endoplasmic reticulum stress, and autophagy and their impact on pregnancy outcomes, through mediating trophoblast differentiation and placental development, has been highlighted in various reports. Autophagy controls trophoblast regulation through a variety of gene expressions and signaling pathways while excessive endoplasmic reticulum stress triggers downstream apoptotic signaling, culminating in trophoblast apoptosis. This comprehensive review delves into the intricacies of placental development and explores the underlying mechanisms of preeclampsia and intrauterine growth retardation. In addition, this review will elucidate the molecular mechanisms of endoplasmic reticulum stress and autophagy, both individually and in their interplay, in mediating placental development and trophoblast differentiation, particularly highlighting their roles in preeclampsia and intrauterine growth retardation development. This research seeks to the interplay between endoplasmic reticulum stress and impaired autophagy in the placental trophoderm, offering novel insights into their contribution to pregnancy complications.

Although high-protein diets are widespread, the fate of dietary protein, its fermentation by gut microbiota, and the resulting effects on intestinal health are not yet fully understood. This article provides a comprehensive overview of microbial protein fermentation and its impact on intestinal health. We focus on the bacterial anabolic and catabolic pathways involved in microbial protein metabolism and the generation of metabolites such as ammonia, biogenic amines (BAs), and short-chain fatty acids (SCFAs). This review also examines how excessive dietary protein affects intestinal health. Elevated protein levels may disrupt microbial homeostasis, promoting the proliferation of pathogenic bacteria while reducing beneficial microbiota. Furthermore, enhanced bacterial metabolic activity can lead to greater production of harmful compounds such as BAs. These alterations are associated with impaired intestinal barrier function, immune dysregulation, and elevated inflammatory responses. Further research is necessary to clarify the metabolism of high-protein diets and their consequences for intestinal health.