Metformin and Probiotics in the Crosstalk between Colitis-Associated Colorectal Cancer and Diabetes in Mice

Parwani

Mediators of Inflammation

et al. 2021

Alcohol-induced liver injury implicates inflammation and oxidative stress as important mediators. Despite rigorous research, there is still no Food and Drug Administration (FDA) approved therapies for any stage of alcoholic liver disease (ALD). Interestingly, metformin (Met) and several probiotic strains possess the potential of inhibiting alcoholic liver injury. Therefore, we investigated the effectiveness of combination therapy using a mixture of eight strains of lactic acid-producing bacteria, commercialized as Visbiome® (V) and Met in preventing the ethanol-induced hepatic injury using in vitro and in vivo models. Human HepG2 cells and male Wistar rats were exposed to ethanol and simultaneously treated with probiotic V or Met alone as well as in combination. Endoplasmic reticulum (ER) stress markers, inflammatory markers, lipid metabolism, reactive oxygen species (ROS) production, and oxidative stress were evaluated, using qRT-PCR, Oil red O staining, fluorimetry, and HPLC. In vitro, probiotic V and Met in combination prevented ethanol-induced cellular injury, ER stress, oxidative stress, and regulated lipid metabolism as well as inflammatory response in HepG2 cells. Probiotic V and Met also promoted macrophage polarization towards the M2 phenotype in ethanol-exposed RAW 264.7 macrophage cells. In vivo, combined administration of probiotic V and Met ameliorated the histopathological changes, inflammatory response, hepatic markers (liver enzymes), and lipid metabolism induced by ethanol. It also improved the antioxidant markers (HO-1 and Nrf-2), as seen by their protein levels in both HepG2 cells as well as liver tissue using ELISA. Hence, probiotic V may act, in addition to the Met, as an effective preventive treatment against ethanol-induced hepatic injury.

Section: Introductionmentioning

confidence: 99%

Metformin and Probiotics Interplay in Amelioration of Ethanol-Induced Oxidative Stress and Inflammatory Response in an In Vitro and In Vivo Model of Hepatic Injury

Parwani

Mediators of Inflammation

et al. 2021

“…A recent study of diabetic and non-diabetic mice with induced colorectal cancer showed that metformin treatment in association with probiotics containing Bifidobacterium species actively prevented inflammatory and carcinogenic processes [ 34 ]. Furthermore a study of H. pylori -related gastric lesions showed a higher relative abundance of Firmicute in gastritis and gastric metaplasia patients [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

“…In diabetic patients, metformin reduced the incidence of adenomas that could transform into colorectal cancer; therefore, metformin may be useful for the prevention of colorectal cancer in patients with type 2 diabetes [ 45 ]. In mice, metformin use in association with probiotics reinforces beneficial effect on colorectal cancer prevention [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Metformin Modifies the Gut Microbiota of Mice Infected with Helicobacter pylori

et al. 2021

Metformin is widely prescribed to treat type 2 diabetes. Diabetes patients treated with metformin have a decreased risk of cancers, including gastric cancer. Among the factors influencing digestive carcinogenesis, gut microbiota interactions have been intensively studied. Metformin exhibits direct antimicrobial activity toward Helicobacterpylori, which plays a crucial role in gastric carcinogenesis. Mice were infected with H. pylori and treated for 12 days with either metformin or phosphate-buffered saline (PBS) as a control. At the end of the treatment period, the mice were euthanized and cecal and intestinal contents and stool were collected. The gut microbiota of the three different digestive sites (stool, cecal, and intestinal contents) were characterized through 16S RNA gene sequencing. In mice infected with H. pylori, metformin significantly decreased alpha diversity indices and led to significant variation in the relative abundance of some bacterial taxa including Clostridium and Lactobacillus, which were directly inhibited by metformin in vitro. PICRUSt analysis suggested that metformin modifies functional pathway expression, including a decrease in nitrate reducing bacteria in the intestine. Metformin significantly changed the composition and predicted function of the gut microbiota of mice infected with H. pylori; these modifications could be implicated in digestive cancer prevention.

“…Immunohistochemistry for CYP4A (1:150, Abcam, Cambridge, MA 02139, USA) was done on paraffin-embedded tissue sections as previously described [ 76 ]. Sections were examined under the light microscope (Olympus CX41 for slide imaging), and analysis of the sections was performed using Image J software version 1.53.…”

Section: Methodsmentioning

confidence: 99%

“…The pathogenesis of fibrosis and inflammation due to iron overload and increase in ROS production was shown by H&E and Masson trichrome staining as previously described [ 76 ].…”

Section: Methodsmentioning

confidence: 99%

CYP450 Mediates Reactive Oxygen Species Production in a Mouse Model of β-Thalassemia through an Increase in 20-HETE Activity

Bou‐Fakhredin

Dia

Ghadieh

et al. 2021

IJMS

Oxidative damage by reactive oxygen species (ROS) is one of the main contributors to cell injury and tissue damage in thalassemia patients. Recent studies suggest that ROS generation in non-transfusion-dependent (NTDT) patients occurs as a result of iron overload. Among the different sources of ROS, the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family of enzymes and cytochrome P450 (CYP450) have been proposed to be major contributors for oxidative stress in several diseases. However, the sources of ROS in patients with NTDT remain poorly understood. In this study, Hbbth3/+ mice, a mouse model for β-thalassemia, were used. These mice exhibit an unchanged or decreased expression of the major NOX isoforms, NOX1, NOX2 and NOX4, when compared to their C57BL/6 control littermates. However, a significant increase in the protein synthesis of CYP4A and CYP4F was observed in the Hbbth3/+ mice when compared to the C57BL/6 control mice. These changes were paralleled by an increased production of 20-hydroxyeicosatetraenoic acid (20-HETE), a CYP4A and CYP4F metabolite. Furthermore, these changes corroborate with onset of ROS production concomitant with liver injury. To our knowledge, this is the first report indicating that CYP450 4A and 4F-induced 20-HETE production mediates reactive oxygen species overgeneration in Hbbth3/+ mice through an NADPH-dependent pathway.