Effects of glyphosate exposure on intestinal microbiota, metabolism and microstructure: a systematic review.

Glyphosate is the most commercialized herbicide in Brazil and worldwide, and this has become a worrying scenario in recent years. In 2015 glyphosate was classified as potentially carcinogenic by the World Health Organization, which opened avenues for numerous debates about its safe use regarding non-target species' health, including humans. This review aimed to observe the impacts of glyphosate and its formulations on the gut microbiota, as well as on the gut microstructure and animal metabolism. A systematic review was conducted based on the PRISMA recommendations, and the search for original articles was performed in Pubmed/Medline, Scopus and Web of Science databases. The risk of bias in the studies was assessed using the SYRCLE strategy. Our findings revealed that glyphosate and its formulations are able to induce intestinal dysbiosis by altering bacterial metabolism, intestinal permeability, and mucus secretion, as well as causing damage to the microvilli and the intestinal lumen. Additionally, immunological, enzymatic and genetic changes were also observed in the animal models. At the metabolic level, damage was observed in lipid and energy metabolism, the circulatory system, cofactor and vitamin metabolism, and replication, repair, and translation processes. In this context, we pointed out that the studies revealed that these alterations, caused by glyphosate-based herbicides, can lead to intestinal and systemic diseases, such as Crohn's disease and Alzheimer's disease.

Can the Evidence-Based Use of Probiotics (Notably Saccharomyces boulardii CNCM I-745 and Lactobacillus rhamnosus GG) Mitigate the Clinical Effects of Antibiotic-Associated Dysbiosis?

Dysbiosis corresponds to the disruption of a formerly stable, functionally complete microbiota. In the gut, this imbalance can lead to adverse health outcomes in both the short and long terms, with a potential increase in the lifetime risks of various noncommunicable diseases and disorders such as atopy (like asthma), inflammatory bowel disease, neurological disorders, and even behavioural and psychological disorders. Although antibiotics are highly effective in reducing morbidity and mortality in infectious diseases, antibiotic-associated diarrhoea is a common, non-negligible clinical sign of gut dysbiosis (and the only visible one). Re-establishment of a normal (functional) gut microbiota is promoted by completion of the clinically indicated course of antibiotics, the removal of any other perturbing external factors, the passage of time (i.e. recovery through the microbiota's natural resilience), appropriate nutritional support, and-in selected cases-the addition of probiotics. Systematic reviews and meta-analyses of clinical trials have confirmed the strain-specific efficacy of some probiotics (notably the yeast Saccharomyces boulardii CNCM I-745 and the bacterium Lactobacillus rhamnosus GG) in the treatment and/or prevention of antibiotic-associated diarrhoea in children and in adults. Unusually for a probiotic, S. boulardii is a eukaryote and is not therefore directly affected by antibiotics-making it suitable for administration in cases of antibiotic-associated diarrhoea. A robust body of evidence from clinical trials and meta-analyses shows that the timely administration of an adequately dosed probiotic (upon initiation of antibiotic treatment or within 48 h) can help to prevent or resolve the consequences of antibiotic-associated dysbiosis (such as diarrhoea) and promote the resilience of the gut microbiota and a return to the pre-antibiotic state. A focus on the prescription of evidence-based, adequately dosed probiotics should help to limit unjustified and potentially ineffective self-medication.

Ivermectin-induced bacterial gut dysbiosis does not increase susceptibility to Pseudomonas aeruginosa lung infection but exacerbates liver damage.

Excessive use of medications, including the antiparasitic drug ivermectin, can lead to bacterial gut dysbiosis, an imbalance in the intestinal microbiome, which in turn may increase or decrease susceptibility to infectious processes. To better understand the effects of continuous ivermectin usage on the gut bacterial community, C57BL/6 isogenic mice were treated by gavage with ivermectin or saline. Ivermectin-induced bacterial gut dysbiosis is characterized by a decrease in Bacteroidetes, Firmicutes, Proteobacteria and Tenericutes and an increase in species of the phylum Verrucomicrobia. A pro-inflammatory immunostimulatory caecal content, as well as disruption of caecal tissue organization and liver tissue damage, was observed in mice with gut dysbiosis. However, ivermectin-induced gut dysbiosis did not lead to acute susceptibility to Pseudomonas aeruginosa lung infection: infected mice with and without gut dysbiosis showed similar rates of recovery of viable bacteria in organs, histopathology and differential cytokine expression in the lung. Therefore, an extension of liver damage was observed in ivermectin-treated and P. aeruginosa-infected mice, which was exacerbated by infection.

Pesticides and Their Impairing Effects on Epithelial Barrier Integrity, Dysbiosis, Disruption of the AhR Signaling Pathway and Development of Immune-Mediated Inflammatory Diseases.

The environmental and occupational risk we confront from agricultural chemicals increases as their presence in natural habitats rises to hazardous levels, building a major part of the exposome. This is of particular concern in low- and middle-income countries, such as Brazil, known as a leading producer of agricultural commodities and consumer of pesticides. As long as public policies continue to encourage the indiscriminate use of pesticides and governments continue to support this strategy instead of endorsing sustainable agricultural alternatives, the environmental burden that damages epithelial barriers will continue to grow. Chronic exposure to environmental contaminants in early life can affect crucial barrier tissue, such as skin epithelium, airways, and intestine, causing increased permeability, leaking, dysbiosis, and inflammation, with serious implications for metabolism and homeostasis. This vicious cycle of exposure to environmental factors and the consequent damage to the epithelial barrier has been associated with an increase in immune-mediated chronic inflammatory diseases. Understanding how the harmful effects of pesticides on the epithelial barrier impact cellular interactions mediated by endogenous sensors that coordinate a successful immune system represents a crucial challenge. In line with the epithelial barrier hypothesis, this narrative review reports the available evidence on the effects of pesticides on epithelial barrier integrity, dysbiosis, AhR signaling, and the consequent development of immune-mediated inflammatory diseases.

Lifelong Exposure to a Low-Dose of the Glyphosate-Based Herbicide RoundUp® Causes Intestinal Damage, Gut Dysbiosis, and Behavioral Changes in Mice.

RoundUp® (RUp) is a comercial formulation containing glyphosate (N-(phosphono-methyl) glycine), and is the world's leading wide-spectrum herbicide used in agriculture. Supporters of the broad use of glyphosate-based herbicides (GBH) claim they are innocuous to humans, since the active compound acts on the inhibition of enzymes which are absent in human cells. However, the neurotoxic effects of GBH have already been shown in many animal models. Further, these formulations were shown to disrupt the microbiome of different species. Here, we investigated the effects of a lifelong exposure to low doses of the GBH-RUp on the gut environment, including morphological and microbiome changes. We also aimed to determine whether exposure to GBH-RUp could harm the developing brain and lead to behavioral changes in adult mice. To this end, animals were exposed to GBH-RUp in drinking water from pregnancy to adulthood. GBH-RUp-exposed mice had no changes in cognitive function, but developed impaired social behavior and increased repetitive behavior. GBH-Rup-exposed mice also showed an activation of phagocytic cells (Iba-1-positive) in the cortical brain tissue. GBH-RUp exposure caused increased mucus production and the infiltration of plama cells (CD138-positive), with a reduction in phagocytic cells. Long-term exposure to GBH-RUp also induced changes in intestinal integrity, as demonstrated by the altered expression of tight junction effector proteins (ZO-1 and ZO-2) and a change in the distribution of syndecan-1 proteoglycan. The herbicide also led to changes in the gut microbiome composition, which is also crucial for the establishment of the intestinal barrier. Altogether, our findings suggest that long-term GBH-RUp exposure leads to morphological and functional changes in the gut, which correlate with behavioral changes that are similar to those observed in patients with neurodevelopmental disorders.

Ceftriaxone causes dysbiosis and changes intestinal structure in adjuvant obesity treatment.

BACKGROUND: Obesity is still a worldwide public health problem, requiring the development of adjuvant therapies to combat it. In this context, modulation of the intestinal microbiota seems prominent, given that the composition of the intestinal microbiota contributes to the outcome of this disease. The aim of this work is to investigate the treatment with an antimicrobial and/or a potential probiotic against overweight. METHODS: Male C57BL/6J mice were subjected to a 12-week overweight induction protocol. After that, 4-week treatment was started, with mice divided into four groups: control, treated with distilled water; potential probiotic, with Lactobacillus gasseri LG-G12; antimicrobial, with ceftriaxone; and antimicrobial + potential probiotic with ceftriaxone in the first 2 weeks and L. gasseri LG-G12 in the subsequent weeks. RESULTS: The treatment with ceftriaxone in isolated form or in combination with the potential probiotic provided a reduction in body fat. However, such effect is supposed to be a consequence of the negative action of ceftriaxone on the intestinal microbiota composition, and this intestinal dysbiosis may have contributed to the destruction of the intestinal villi structure, which led to a reduction in the absorptive surface. Also, the effects of L. gasseri LG-G12 apparently have been masked by the consumption of the high-fat diet. CONCLUSIONS: The results indicate that the use of a ceftriaxone in the adjuvant treatment of overweight is not recommended due to the potential risk of developing inflammatory bowel disease.

Changes in gut-brain axis parameters in adult rats of both sexes with different feeding pattern that were early nicotine-exposed.

Nicotine is an endocrine disruptor and imprinting factor during breastfeeding that can cause food intake imbalance in the adulthood. As nicotine affects the intestinal microbiota, altering the composition of the bacterial communities and short-chain fatty acids (SCFAs) synthesis in a sex-dependent manner, we hypothesized that nicotine could program the gut-brain axis, consequently modifying the eating pattern of adult male and female rats in a model of maternal nicotine exposure (MNE) during breastfeeding. Lactating Wistar rat dams received minipumps that release 6 mg/kg/day of nicotine (MNE group) or saline for 14 days. The progeny received standard diet from weaning until euthanasia (26 weeks of age). We measured: in vivo electrical activity of the vagus nerve; c-Fos expression in the nucleus tractus solitarius, gastrointestinal peptides receptors, intestinal brain-derived neurotrophic factor (BDNF), SCFAs and microbiota. MNE females showed hyperphagia despite normal adiposity, while MNE males had unchanged food intake, despite obesity. Adult MNE offspring showed decreased Bacteroidetes and increased Firmicutes, Actinobacteria and Proteobacteria. MNE females had lower fecal acetate while MNE males showed higher vagus nerve activity. In summary nicotine exposure through the milk induces long-term intestinal dysbiosis, which may affect eating patterns of adult offspring in a sex-dependent manner.

Effect of Dietary Magnesium Content on Intestinal Microbiota of Rats.

BACKGROUND: Magnesium is a mineral that modulates several physiological processes. However, its relationship with intestinal microbiota has been scarcely studied. Therefore, this study aimed to assess the role of dietary magnesium content to modulate the intestinal microbiota of Wistar male rats. METHODS: Rats were randomly assigned one of three diets: a control diet (C-Mg; 1000 mg/kg), a low magnesium content diet (L-Mg; 60 mg/kg), and a high magnesium content diet (H-Mg; 6000 mg/kg), for two weeks. After treatment, fecal samples were collected. Microbiota composition was assessed by sequencing the V3-V4 hypervariable region. RESULTS: The C-Mg and L-Mg groups had more diversity than H-Mg group. CF231, SMB53, Dorea, Lactobacillus and Turibacter were enriched in the L-Mg group. In contrast, the phyla Proteobacteria, Parabacteroides, Butyricimonas, and Victivallis were overrepresented in the H-Mg group. PICRUSt analysis indicated that fecal microbiota of the L-Mg group were encoded with an increased abundance of metabolic pathways involving carbohydrate metabolism and butanoate metabolism. CONCLUSION: Dietary magnesium supplementation can result in intestinal dysbiosis development in a situation where there is no magnesium deficiency. Conversely, low dietary magnesium consumption is associated with microbiota with a higher capacity to harvest energy from the diet.

Host dysbiosis negatively impacts IL-9-producing T-cell differentiation and antitumour immunity.

BACKGROUND: Host-microbiota interactions shape T-cell differentiation and promote tumour immunity. Although IL-9-producing T cells have been described as potent antitumour effectors, their role in microbiota-mediated tumour control remains unclear. METHODS: We analysed the impact of the intestinal microbiota on the differentiation of colonic lamina propria IL-9-producing T cells in germ-free and dysbiotic mice. Systemic effects of the intestinal microbiota on IL-9-producing T cells and the antitumour role of IL-9 were analysed in a model of melanoma-challenged dysbiotic mice. RESULTS: We show that germ-free mice have lower frequency of colonic lamina propria IL-9-producing T cells when compared with conventional mice, and that intestinal microbiota reconstitution restores cell frequencies. Long-term antibiotic treatment promotes host dysbiosis, diminishes intestinal IL-4 and TGF-ß gene expression, decreases the frequency of colonic lamina propria IL-9-producing T cells, increases the susceptibility to tumour development and reduces the frequency of IL-9-producing T cells in the tumour microenvironment. Faecal transplant restores intestinal microbiota diversity, and the frequency of IL-9-producing T cells in the lungs of dysbiotic animals, restraining tumour burden. Finally, recombinant IL-9 injection enhances tumour control in dysbiotic mice. CONCLUSIONS: Host-microbiota interactions are required for adequate differentiation and antitumour function of IL-9-producing T cells.

Impact of intestinal dysbiosis-related drugs on the efficacy of immune checkpoint inhibitors in clinical practice.

PURPOSE: Intestinal dysbiosis has emerged as a biomarker of response to immune checkpoint inhibitors (ICIs). It can be caused by antibiotics, although it may also result from the use of other drugs that have been studied to a lesser extent. The objective of our study was to analyze the association between the use of potentially dysbiosis-related drugs and survival in patients treated with ICIs in the clinical practice. MATERIALS AND METHODS: A retrospective, multicenter, cohort study was conducted. Clinicopathological variables were collected and the concomitant use of drugs was analyzed. A descriptive analysis of variables and overall survival, estimated by the Kaplan-Meier method, was performed, and association with various independent variables was assessed using Cox regression. RESULTS: We included 253 patients, mainly with non-small cell lung cancer and melanoma. The most commonly used drugs were acid reducers, prescribed to 55.3% of patients, followed by corticosteroids (37.9%), anxiolytic drugs (35.6%), and antibiotics (20.5%). The use of acid reducers (9 vs. 18 months, P < .0001), antibiotics (7 vs. 15 months, P < .017), anxiolytic drugs (8 vs. 16 months, P < .015), and corticosteroids (6 vs. 19 months, P < .00001) was associated with poorer overall survival. Furthermore, the greater the number of drugs used concomitantly with ICIs, the higher the risk of death (1 drug: hazard ratio, 1.88; CI 95%, 1.07-3.30; 4 drugs: hazard ratio, 4.19; CI9 5%, 1.77-9.92; P < .001). CONCLUSION: Response to ICIs may be influenced by the use of drugs that lead to intestinal dysbiosis. Although a confirmatory prospective controlled study is required, our findings should be taken into account when analyzing ICI efficacy.

Decreased Enteric Bacterial Composition and Diversity in South American Crohn's Disease Vary With the Choice of Treatment Strategy and Time Since Diagnosis.

BACKGROUND AND AIMS: The symptomology of Crohn's disease [CD], a chronic inflammatory disease of the digestive tract, correlates poorly with clinical, endoscopic or immunological assessments of disease severity. The prevalence of CD in South America is rising, reflecting changes in socio-economic stability. Many treatment options are available to CD patients, including biological agents and corticosteroids, each of which offers variable efficacy attributed to host genetics and environmental factors associated with alterations in the gut microbiota. METHODS: Based on 16S rRNA gene sequencing and taxonomic differences, we compared the faecal microbial population of Brazilian patients with CD treated with corticosteroid or anti-tumour necrosis factor [anti-TNF] immunotherapy. Faecal calprotectin and plasma sCD14 levels were quantified as markers for local and systemic inflammation, respectively. RESULTS: Anti-TNF treatment led to an increased relative abundance of Proteobacteria and a decreased level of Bacteroidetes. In contrast, corticoid treatment was associated with an increase in the relative abundance of Actinobacteria, which has been linked to inflammation in CD. Disruption of the faecal microbiota was related to decreased bacterial diversity and composition. Moreover, the choice of clinical regimen and time since diagnosis modulate the character of the resulting dysbiosis. CONCLUSIONS: Enteric microbial populations in CD patients who have been treated are modulated by disease pathogenesis, local inflammatory microenvironment and treatment strategy. The dysbiosis that remains after anti-TNF treatment due to decreased bacterial diversity and composition abates restoration of the microbiota to a healthy state, suggesting that the identification and development of new clinical treatments for CD must include their capacity to normalize the gut microbiota.

Guarana (Paullinia cupana Mart.) alters gut microbiota and modulates redox status, partially via caffeine in Wistar rats.

Microbiota alterations are observed in pathological conditions, and their regulation is a subject of great interest. Gut microbes are affected by diet, and plant polyphenols may have positive effect on gut microbiota; however, plant-derived extracts may have toxic effects. Guarana (Paullinia cupana Mart.) is a nontraditional medicinal plant applied worldwide. Guarana yields an alkaloid and polyphenol-rich seed with antimicrobial, antioxidant, and anti-inflammatory properties, where caffeine is the major compound. We evaluated the effects of guarana seed powder (GSP) and purified caffeine on gut microbial composition and redox and inflammatory parameters in Wistar rats after 21 days of treatment. Fecal microbiota was analyzed utilizing 16S rDNA sequencing. Antioxidant enzymes activities from liver, kidney, and colon, as well as oxidative damage markers, were evaluated. Total nonenzymatic antioxidant potential was also evaluated. Microbiota was altered by both treatments, GSP and caffeine, without loss of diversity. In the liver, the kidney, and the colon, we observed a decrease in the antioxidant enzymes activities in the GSP group with no increase in the expression of oxidative damage markers, although some enzymes were also regulated by caffeine. Taken together, these results suggested that GSP ameliorates redox parameters but negatively affected gut microbiota, partially via caffeine.

Sugars and beyond. The role of sugars and the other nutrients and their potential impact on caries.

The traditional concept of caries as a multifactorial transmittable and infectious disease has been challenged. Novel conceptual ideas have come to add to the complexity of this highly prevalent disease worldwide. Current etiological understanding of the disease has emphasized the pivotal role of sugars in caries. In fact, current definition points toward an ecological disease caused by the commensal microbiota that under ecological imbalances, mainly due to high and or frequent sugars consumption, creates a state of dysbiosis in the dental biofilm. This modern conceptual idea, however, tends to underrate a key issue. As humans are omnivore and consume a mix diet composed by a multitude of substances, the role of the diet in caries must not be restricted only to the presence of fermentable sugars. This review explores the contribution of other food components, ubiquitous to the diet, mostly as potentially protective factors. Anticaries nutrients might determine an environmental change, affecting the ecology of the oral microbiome and partially mitigating the effect of sugars. Understanding the function of the food usually consumed by the people will contribute new knowledge on the mechanisms associated with the onset of caries, on new caries risk variables and on potential novel strategies for the prevention and treatment of the disease.