Modulation of Gut Microbial Biomarkers and Metabolites in Cancer Management by Tea Compounds.

Cancers are causing millions of deaths and leaving a huge clinical and economic burden. High costs of cancer drugs are limiting their access to the growing number of cancer cases. The development of more affordable alternative therapy could reach more patients. As gut microbiota plays a significant role in the development and treatment of cancer, microbiome-targeted therapy has gained more attention in recent years. Dietary and natural compounds can modulate gut microbiota composition while providing broader and more accessible access to medicine. Tea compounds have been shown to have anti-cancer properties as well as modulate the gut microbiota and their related metabolites. However, there is no comprehensive review that focuses on the gut modulatory effects of tea compounds and their impact on reshaping the metabolic profiles, particularly in cancer models. In this review, the effects of different tea compounds on gut microbiota in cancer settings are discussed. Furthermore, the relationship between these modulated bacteria and their related metabolites, along with the mechanisms of how these changes led to cancer intervention are summarized.

Secretin-dependent signals in the ventromedial hypothalamus regulate energy metabolism and bone homeostasis in mice.

Secretin, though originally discovered as a gut-derived hormone, is recently found to be abundantly expressed in the ventromedial hypothalamus, from which the central neural system controls satiety, energy metabolism, and bone homeostasis. However, the functional significance of secretin in the ventromedial hypothalamus remains unclear. Here we show that the loss of ventromedial hypothalamus-derived secretin leads to osteopenia in male and female mice, which is primarily induced by diminished cAMP response element-binding protein phosphorylation and upregulation in peripheral sympathetic activity. Moreover, the ventromedial hypothalamus-secretin inhibition also contributes to hyperphagia, dysregulated lipogenesis, and impaired thermogenesis, resulting in obesity in male and female mice. Conversely, overexpression of secretin in the ventromedial hypothalamus promotes bone mass accrual in mice of both sexes. Collectively, our findings identify an unappreciated secretin signaling in the central neural system for the regulation of energy and bone metabolism, which may serve as a new target for the clinical management of obesity and osteoporosis.

PNPLA3 Genotype and Dietary Fat Modify Concentrations of Plasma and Fecal Short Chain Fatty Acids and Plasma Branched-Chain Amino Acids.

The GG genotype of the Patatin-like phosphatase domain-containing 3 (PNPLA3), dietary fat, short-chain fatty acids (SCFA) and branched-chain amino acids (BCAA) are linked with non-alcoholic fatty liver disease. We studied the impact of the quality of dietary fat on plasma (p) and fecal (f) SCFA and p-BCAA in men homozygous for the PNPLA3 rs738409 variant (I148M). Eighty-eight randomly assigned men (age 67.8 ± 4.3 years, body mass index 27.1 ± 2.5 kg/m2) participated in a 12-week diet intervention. The recommended diet (RD) group followed the National and Nordic nutrition recommendations for fat intake. The average diet (AD) group followed the average fat intake in Finland. The intervention resulted in a decrease in total p-SCFAs and iso-butyric acid in the RD group (p = 0.041 and p = 0.002). Valeric acid (p-VA) increased in participants with the GG genotype regardless of the diet (RD, 3.6 ± 0.6 to 7.0 ± 0.6 µmol/g, p = 0.005 and AD, 3.8 ± 0.3 to 9.7 ± 8.5 µmol/g, p = 0.015). Also, genotype relation to p-VA was seen statistically significantly in the RD group (CC: 3.7 ± 0.4 to 4.2 ± 1.7 µmol/g and GG: 3.6 ± 0.6 to 7.0 ± 0.6 µmol/g, p = 0.0026 for time and p = 0.004 for time and genotype). P-VA, unlike any other SCFA, correlated positively with plasma gamma-glutamyl transferase (r = 0.240, p = 0.025). Total p-BCAAs concentration changed in the AD group comparing PNPLA3 CC and GG genotypes (CC: 612 ± 184 to 532 ± 149 µmol/g and GG: 587 ± 182 to 590 ± 130 µmol/g, p = 0.015 for time). Valine decreased in the RD group (p = 0.009), and leucine decreased in the AD group (p = 0.043). RD decreased total fecal SCFA, acetic acid (f-AA), and butyric acid (f-BA) in those with CC genotype (p = 0.006, 0.013 and 0.005, respectively). Our results suggest that the PNPLA3 genotype modifies the effect of dietary fat modification for p-VA, total f-SCFA, f-AA and f-BA, and total p-BCAA.

Effects of secretin gene knockout on the diversity, composition, and function of gut microbiota in adult male mice.

The gut microbiota plays a vital role in maintaining gastrointestinal homeostasis, however, whether it is influenced by gut hormones remains unknown. Secretin is a well-known gastrointestinal hormone produced by enteroendocrine S cells. This study utilized 16S rRNA amplicon sequencing to characterize the effect of SCT deficiency on the gut microbiota. Our results show that systemic SCT knockout alters the composition and abundance of the mouse gut microbiota but does not affect fecal short-chain fatty acids and lipids concentrations. At the genus level, the abundance of Turicibacter, Bacteroides, Ruminococcu, Romboutsia, Asaccharobacter, and Parasutterella increased in SCT-/- mice, whereas the abundance of Akkermansia and Escherichia decreased. Functional prediction results showed that lack of SCT reduced the abundance of carbohydrate metabolism-related pathways but increased the abundance of linoleic acid metabolism and branched-chain amino acid degradation. Overall, systemic SCT knockout had only minor effects on gut microbiota composition and function in adult male mice fed a standard chow diet.

Zearalenone attenuates colitis associated colorectal tumorigenesis through Ras/Raf/ERK pathway suppression and SCFA-producing bacteria promotion.

The high prevalence of colorectal cancer (CRC) and its leading death causing rate have placed a considerable burden on patients and healthcare providers. There is a need for a therapy that has fewer adverse effects and greater efficiency. Zearalenone (ZEA), an estrogenic mycotoxin, has been demonstrated to exert apoptotic properties when administrated in higher doses. However, it is unclear whether such apoptotic effect remains valid in an in vivo setting. The current study aimed to investigate the effect of ZEA on CRC and its underlying mechanisms in the azoxymethane/ dextran sodium sulfate (AOM/DSS) model. Our results revealed that ZEA significantly lowered the total number of tumours, colon weight, colonic crypt depth, collagen fibrosis and spleen weight. ZEA suppressed Ras/Raf/ERK/cyclin D1 pathway, increasing the expression of apoptosis parker, cleaved caspase 3, while decreasing the expression of proliferative marker, Ki67 and cyclin D1. The gut microbiota composition in ZEA group showed higher stability and lower vulnerability in the microbial community when compared to AOM/DSS group. ZEA increased the abundance of short chain fatty acids (SCFAs) producing bacteria unidentified Ruminococcaceae, Parabacteroidies and Blautia, as well as the faecal acetate content. Notably, unidentified Ruminococcaceae and Parabacteroidies were substantially correlated with the decrease in tumour count. Overall, ZEA demonstrated a promising inhibitory effect on colorectal tumorigenesis and exhibited the potential for further development as a CRC treatment.