Short-chain fatty acids (SCFAs) are the main metabolites produced by bacterial fermentation of dietary fibre in the gastrointestinal tract. The absorption of SCFAs is mediated by substrate transporters, such as monocarboxylate transporter 1 and sodium-coupled monocarboxylate transporter 1, which promote cellular metabolism. An increasing number of studies have implicated metabolites produced by microorganisms as crucial executors of diet-based microbial influence on the host. SCFAs are important fuels for intestinal epithelial cells (IECs) and represent a major carbon flux from the diet, that is decomposed by the gut microbiota. SCFAs play a vital role in multiple molecular biological processes, such as promoting the secretion of glucagon-like peptide-1 by IECs to inhibit the elevation of blood glucose, increasing the expression of G protein-coupled receptors such as GPR41 and GPR43, and inhibiting histone deacetylases, which participate in the regulation of the proliferation, differentiation, and function of IECs. SCFAs affect intestinal motility, barrier function, and host metabolism. Furthermore, SCFAs play important regulatory roles in local, intermediate, and peripheral metabolisms. Acetate, propionate, and butyrate are the major SCFAs, they are involved in the regulation of immunity, apoptosis, inflammation, and lipid metabolism. Herein, we review the diverse functional roles of this major class of bacterial metabolites and reflect on their ability to affect intestine, metabolic, and other diseases.

Intestinal dysbiosis frequently occurs in abdominal radiotherapy and contributes to irradiation (IR)-induced intestinal damage and inflammation. Akkermansia muciniphila (A. muciniphila) is a recently characterized probiotic, which is critical for maintaining the dynamics of the intestinal mucus layer and preserving intestinal microbiota homeostasis. However, the role of A. muciniphila in the alleviation of radiation enteritis remains unknown. In this study, we reported that the abundance of A. muciniphila was markedly reduced in the intestines of mice exposed to abdominal IR and in the feces of patients who received abdominal radiotherapy. Abundance of A. muciniphila in feces of radiotherapy patients was negatively correlated with the duration of diarrhea in patients. Administration of A. muciniphila substantially mitigated IR-induced intestinal damage and prevented mouse death. Analyzing the metabolic products of A. muciniphila revealed that propionic acid, a short-chain fatty acid secreted by the microbe, mediated the radioprotective effect. We further demonstrated that propionic acid bound to G-protein coupled receptor 43 (GRP43) on the surface of intestinal epithelia and increased histone acetylation and hence enhanced the expression of tight junction proteins occludin and ZO-1 and elevated the level of mucins, leading to enhanced integrity of intestinal epithelial barrier and reduced radiation-induced intestinal damage. Metformin, a first-line agent for the treatment of type II diabetes, promoted intestinal epithelial barrier integrity and reduced radiation intestinal damage through increasing the abundance of A. muciniphila. Together, our results demonstrated that A. muciniphila plays a critical role in the reduction of abdominal IR-induced intestinal damage. Application of probiotics or their regulators, such as metformin, could be an effective treatment for the protection of radiation exposure-damaged intestine.

Radiotherapy is an important treatment for abdominal tumors. A critical side effect for this therapy is enteritis. In this review, we aim to summarize recent findings in radiation enteritis, in particular the role of gut microbiota dysbiosis in the development and therapy of the disease. Gut microbiota dysbiosis plays an important role in the occurrence of various diseases, such as radiation enteritis. Abdominal radiation results in changes in the composition of microbiota and reduces its diversity, which is mainly reflected in the decrease of Lactobacillus spp. and Bifidobacterium spp. and increase of Escherichia coli and Staphylococcus spp. Gut microbiota dysbiosis aggravates radiation enteritis, weakens intestinal epithelial barrier function, and promotes inflammatory factor expression. Pathogenic Escherichia coli induce the rearrangement and redistribution of claudin-1, occludin, and ZO-1 in tight junctions, a critical component in intestinal epithelial barrier. In view of the role that microbiome plays in radiation enteritis, we believe that intestinal flora could be a potential biomarker for the disease. Correction of microbiome by application of probiotics, fecal microbiota transplantation (FMT), and antibiotics could be an effective method for the prevention and treatment of radiation-induced enteritis.

Glucose-6-phosphate dehydrogenase (G6PD) is the only rate-limiting enzyme in the pentose phosphate pathway (PPP). Rapidly proliferating cells require metabolites from PPP to synthesize ribonucleotides and maintain intracellular redox homeostasis. G6PD expression can be abnormally elevated in a variety of cancers. In addition, G6PD may act as a regulator of viral replication and vascular smooth muscle function. Therefore, G6PD-mediated activation of PPP may promote tumor and non-neoplastic disease progression. Recently, studies have identified post-translational modifications (PTMs) as an important mechanism for regulating G6PD function. Here, we provide a comprehensive review of various PTMs (e.g., phosphorylation, acetylation, glycosylation, ubiquitination, and glutarylation), which are identified in the regulation of G6PD structure, expression and enzymatic activity. In addition, we review signaling pathways that regulate G6PD and evaluate the role of oncogenic signals that lead to the reprogramming of PPP in tumor and non-neoplastic diseases as well as summarize the inhibitors that target G6PD.