The Impact of Plant Phytochemicals on the Gut Microbiota of Humans for a Balanced Life

The gastrointestinal tract of humans is a complex microbial ecosystem known as gut microbiota. The microbiota is involved in several critical physiological processes such as digestion, absorption, and related physiological functions and plays a crucial role in determining the host’s health. The habitual consumption of specific dietary components can impact beyond their nutritional benefits, altering gut microbiota diversity and function and could manipulate health. Phytochemicals are non-nutrient biologically active plant components that can modify the composition of gut microflora through selective stimulation of proliferation or inhibition of certain microbial communities in the intestine. Plants secrete these components, and they accumulate in the cell wall and cell sap compartments (body) for their development and survival. These compounds have low bioavailability and long time-retention in the intestine due to their poor absorption, resulting in beneficial impacts on gut microbiota population. Feeding diets containing phytochemicals to humans and animals may offer a path to improve the gut microbiome resulting in improved performance and/or health and wellbeing. This review discusses the effects of phytochemicals on the modulation of the gut microbiota environment and the resultant benefits to humans; however, the effect of phytochemicals on the gut microbiota of animals is also covered, in brief.     

Maternal Acetate Supplementation Reverses Blood Pressure Increase in Male Offspring Induced by Exposure to Minocycline during Pregnancy and Lactation

Emerging evidence supports that hypertension can be programmed or reprogrammed by maternal nutrition. Maternal exposures during pregnancy, such as maternal nutrition or antibiotic use, could alter the offspring’s gut microbiota. Short-chain fatty acids (SCFAs) are the major gut microbiota-derived metabolites. Acetate, the most dominant SCFA, has shown its antihypertensive effect. Limited information exists regarding whether maternal acetate supplementation can prevent maternal minocycline-induced hypertension in adult offspring. We exposed pregnant Sprague Dawley rats to normal diet (ND), minocycline (MI, 50 mg/kg/day), magnesium acetate (AC, 200 mmol/L in drinking water), and MI + AC from gestation to lactation period. At 12 weeks of age, four groups (n = 8/group) of male progeny were sacrificed. Maternal acetate supplementation protected adult offspring against minocycline-induced hypertension. Minocycline administration reduced plasma acetic acid level, which maternal acetate supplementation prevented. Additionally, acetate supplementation increased the protein level of SCFA receptor G protein-coupled receptor 41 in the offspring kidneys. Further, minocycline administration and acetate supplementation significantly altered gut microbiota composition. Maternal acetate supplementation protected minocycline-induced hypertension accompanying by the increases in genera Roseburia, Bifidobacterium, and Coprococcus. In sum, our results cast new light on targeting gut microbial metabolites as early interventions to prevent the development of hypertension, which could help alleviate the global burden of hypertension.     

Chronic-Antibiotics Induced Gut Microbiota Dysbiosis Rescues Memory Impairment and Reduces β-Amyloid Aggregation in a Preclinical Alzheimer’s Disease Model

Alzheimer’s disease (AD) is a multifactorial pathology characterized by β-amyloid (Aβ) deposits, Tau hyperphosphorylation, neuroinflammatory response, and cognitive deficit. Changes in the bacterial gut microbiota (BGM) have been reported as a possible etiological factor of AD. We assessed in offspring (F1) 3xTg, the effect of BGM dysbiosisdysbiosis in mothers (F0) at gestation and F1 from lactation up to the age of 5 months on Aβ and Tau levels in the hippocampus, as well as on spatial memory at the early symptomatic stage of AD. We found that BGM dysbiosisdysbiosis with antibiotics (Abx) treatment in F0 was vertically transferred to their F1 3xTg mice, as observed on postnatal day (PD) 30 and 150. On PD150, we observed a delay in spatial memory impairment and Aβ deposits, but not in Tau and pTau protein in the hippocampus at the early symptomatic stage of AD. These effects are correlated with relative abundance of bacteria and alpha diversity, and are specific to bacterial consortia. Our results suggest that this specific BGM could reduce neuroinflammatory responses related to cerebral amyloidosis and cognitive deficit and activate metabolic pathways associated with the biosynthesis of triggering or protective molecules for AD.     

Molecular Effects of Chronic Exposure to Palmitate in Intestinal Organoids: A New Model to Study Obesity and Diabetes

Intestinal cell dysfunctions involved in obesity and associated diabetes could be correlated with impaired intestinal cell development. To date, the molecular mechanisms underlying these dysfunctions have been poorly investigated because of the lack of a good model for studying obesity. The main aim of this study was to investigate the effects of lipotoxicity on intestinal cell differentiation in small intestinal organoid platforms, which are used to analyze the regulation of cell differentiation. Mouse intestinal organoids were grown in the presence/absence of high palmitate concentrations (0.5 mM) for 48 h to simulate lipotoxicity. Palmitate treatment altered the expression of markers involved in the differentiation of enterocytes and goblet cells in the early (Hes1) and late (Muc2) phases of their development, respectively, and it modified enterocytes and goblet cell numbers. Furthermore, the expression of enteroendocrine cell progenitors (Ngn3) and I cells (CCK) markers was also impaired, as well as CCK-positive cell numbers and CCK secretion. Our data indicate, for the first time, that lipotoxicity simultaneously influences the differentiation of specific intestinal cell types in the gut: enterocytes, goblet cells and CCK cells. Through this study, we identified novel targets associated with molecular mechanisms affected by lipotoxicity that could be important for obesity and diabetes therapy.     

Preclinical In Vitro Model to Assess the Changes in Permeability and Cytotoxicity of Polarized Intestinal Epithelial Cells during Exposure Mimicking Oral or Intravenous Routes: An Example of Arsenite Exposure

The gastrointestinal tract (GIT) is exposed to xenobiotics, including drugs, through both: local (oral) and systemic routes. Despite the advances in drug discovery and in vitro pre-clinical models, there is a lack of appropriate translational models to distinguish the impact of these routes of exposure. Changes in intestinal permeability has been observed in different gastrointestinal and systemic diseases. This study utilized one such xenobiotic, arsenic, to which more than 200 million people around the globe are exposed via their food, drinking water, work environment, soil, and air. The purpose of this study was to establish an in vitro model to mimic gastrointestinal tract exposure to xenobiotics via oral or intravenous routes. To achieve this, we compared the route (mimicking oral and intravenous exposure to GIT and the dose response (using threshold approach) of trivalent and pentavalent inorganic arsenic species on the permeability of in vitro cultured polarized T84 cells, an example of intestinal epithelial cells. Arsenic treatment to polarized T84 cells via the apical and basolateral compartment of the trans-well system reflected oral or intravenous routes of exposure in vivo, respectively. Sodium arsenite, sodium arsenate, dimethyl arsenic acid sodium salt (DMA^V), and disodium methyl arsonate hydrate (MMA^V) were assessed for their effects on intestinal permeability by measuring the change in trans-epithelial electrical resistance (TEER) of T-84 cells. Polarized T-84 cells exposed to 12.8 µM of sodium arsenite from the basolateral side showed a marked reduction in TEER. Cytotoxicity of sodium arsenite, as measured by release of lactate dehydrogenase (LDH), was increased when cells were exposed via the basolateral side. The mRNA expression of genes related to cell junctions in T-84 cells was analyzed after exposure with sodium arsenite for 72 h. Changes in TEER correlated with mRNA expression of focal-adhesion-, tight-junction- and gap-junction-related genes (upregulation of Jam2, Itgb3 and Notch4 genes and downregulation of Cldn2, Cldn3, Gjb1, and Gjb2). Overall, exposure to sodium arsenite from the basolateral side was found to have a differential effect on monolayer permeability and on cell-junction-related genes as compared to apical exposure. Most importantly, this study established a preclinical human-relevant in vitro translational model to assess the changes in permeability and cytotoxicity during exposure, mimicking oral or intravenous routes.     

Fecal Microbiota Transplantation Derived from Alzheimer’s Disease Mice Worsens Brain Trauma Outcomes in Wild-Type Controls

Traumatic brain injury (TBI) causes neuroinflammation and neurodegeneration, both of which increase the risk and accelerate the progression of Alzheimer’s disease (AD). The gut microbiome is an essential modulator of the immune system, impacting the brain. AD has been related with reduced diversity and alterations in the community composition of the gut microbiota. This study aimed to determine whether the gut microbiota from AD mice exacerbates neurological deficits after TBI in control mice. We prepared fecal microbiota transplants from 18 to 24 month old 3×Tg-AD (FMT-AD) and from healthy control (FMT-young) mice. FMTs were administered orally to young control C57BL/6 (wild-type, WT) mice after they underwent controlled cortical impact (CCI) injury, as a model of TBI. Then, we characterized the microbiota composition of the fecal samples by full-length 16S rRNA gene sequencing analysis. We collected the blood, brain, and gut tissues for protein and immunohistochemical analysis. Our results showed that FMT-AD administration stimulates a higher relative abundance of the genus Muribaculum and a decrease in Lactobacillus johnsonii compared to FMT-young in WT mice. Furthermore, WT mice exhibited larger lesion, increased activated microglia/macrophages, and reduced motor recovery after FMT-AD compared to FMT-young one day after TBI. In summary, we observed gut microbiota from AD mice to have a detrimental effect and aggravate the neuroinflammatory response and neurological outcomes after TBI in young WT mice.     

Supplementation with SCFAs Re-Establishes Microbiota Composition and Attenuates Hyperalgesia and Pain in a Mouse Model of NTG-Induced Migraine

Migraine is a common brain-disorder that affects 15% of the population. Converging evidence shows that migraine is associated with gastrointestinal disorders. However, the mechanisms underlying the interaction between the gut and brain in patients with migraine are not clear. In this study, we evaluated the role of the short-chain fatty acids (SCFAs) as sodium propionate (SP) and sodium butyrate (SB) on microbiota profile and intestinal permeability in a mouse model of migraine induced by nitroglycerine (NTG). The mice were orally administered SB and SP at the dose of 10, 30 and 100 mg/kg, 5 min after NTG intraperitoneal injections. Behavioral tests were used to evaluate migraine-like pain. Histological and molecular analyses were performed on the intestine. The composition of the intestinal microbiota was extracted from frozen fecal samples and sequenced with an Illumina MiSeq System. Our results demonstrated that the SP and SB treatments attenuated hyperalgesia and pain following NTG injection. Moreover, SP and SB reduced histological damage in the intestine and restored intestinal permeability and the intestinal microbiota profile. These results provide corroborating evidence that SB and SP exert a protective effect on central sensitization induced by NTG through a modulation of intestinal microbiota, suggesting the potential application of SCFAs as novel supportive therapies for intestinal disfunction associated with migraine.     

The Metabolic Role of Gut Microbiota in the Development of Nonalcoholic Fatty Liver Disease and Cardiovascular Disease

The prevalence of metabolic disorders, such as type 2 diabetes (T2D), obesity, and non-alcoholic fatty liver disease (NAFLD), which are common risk factors for cardiovascular disease (CVD), has dramatically increased worldwide over the last decades. Although dietary habit is the main etiologic factor, there is an imperfect correlation between dietary habits and the development of metabolic disease. Recently, research has focused on the role of the microbiome in the development of these disorders. Indeed, gut microbiota is implicated in many metabolic functions and an altered gut microbiota is reported in metabolic disorders. Here we provide evidence linking gut microbiota and metabolic diseases, focusing on the pathogenetic mechanisms underlying this association.     

Gastric Cancer: Advances in Carcinogenesis Research and New Therapeutic Strategies

Gastric cancer’s bad incidence, prognosis, cellular and molecular heterogeneity amongst others make this disease a major health issue worldwide. Understanding this affliction is a priority for proper patients’ management and for the development of efficient therapeutical strategies. This review gives an overview of major scientific advances, made during the past 5-years, to improve the comprehension of gastric adenocarcinoma. A focus was made on the different actors of gastric carcinogenesis, including, Helicobacter pylori cancer stem cells, tumour microenvironment and microbiota. New and recent potential biomarkers were assessed as well as emerging therapeutical strategies involving cancer stem cells targeting as well as immunotherapy. Finally, recent experimental models to study this highly complex disease were discussed, highlighting the importance of gastric cancer understanding in the hard-fought struggle against cancer relapse, metastasis and bad prognosis.