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HFM-induced visceral hyperalgesia is reversed by rifaximin. (A) Representative electromyogram recordings of responses to colorectal distension in rats fed RC, HFM, or HFM with rifaximin (HFM+Rif). (B) Mean amplitudes of abdominal muscle contractions are expressed as area under the curve (AUC) after baseline subtraction (n = 6 per group). *P < 0.05 compared with RC rats; # P < 0.05 compared with HFM. AUC, area under the curve; EMG, electromyographic activity; HFM, high-FODMAP diet; RC, regular chow. P < 0.05, by 2-tailed Student's t test or 2-way repeated-measures ANOVA.
Source publication
Foods high in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) exacerbate symptoms of irritable bowel syndrome (IBS); however, their mechanism of action is unknown. We hypothesized that a high-FODMAP (HFM) diet increases visceral nociception by inducing dysbiosis and that the FODMAP-altered gut microbial community...
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Context 1
... examine whether TLR4 is involved, rat colon was pre- treated with the intracolonic administration of siRNA targeting TLR4 (10 nmol per rat in 0.3 ml) for 3 days, which resulted in a 40% reduction in TLR4 gene expression in the ascending colon- ic mucosa (Supplemental Figure 2). Pretreatment of TLR4 siRNA prevented visceral hypersensitivity caused by fecal supernatant from HFM rats, indicating the involvement of TLR4 ( Figure ...
Context 2
... next assessed the preventive effect of rifaximin on the development of visceral hyperalgesia in HFM rats. Repeated oral gavage of rifaximin significantly attenuated the increased VMR to CRD induced by HFM at 20, 40, 60, and 80 mmHg (Figure 2, A and B). These data suggest that HFM causes mucosal inflamma- tion and visceral hypersensitivity by inducing dysbiosis, which rifaximin ...
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... the effect of HFM on visceromotor response (VMR) to graded colorectal distension (CRD) was examined. Rats showed pressure-dependent increases in VMR to CRD (Figure 2, A and B). The VMR to 20, 40, 60, and 80 mmHg CRD significantly increased 2.5-, 2.8-, 2.5-, and 2.4-fold after 2-week HFM (P < 0.05, n = 6 per group), suggesting the development of visceral ...
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Citations
... Bacterial activation of TLRs can induce proinflammatory cytokine production and subsequent inflammatory reactions [136][137][138]. Pro-inflammatory cytokine responses in the intestine can precipitate VH through sensitization of nodose ganglia neurons via TLR4 activation and promote chronic inflammatory changes in the gut [34, 139,140]. ...
Disorders of Gut‐Brain Interaction (DGBI) are widely prevalent and commonly encountered in gastroenterology practice. While several peripheral and central mechanisms have been implicated in the pathogenesis of DGBI, a recent body of work suggests an important role for the gut microbiome. In this review, we highlight how gut microbiota and their metabolites affect physiologic changes underlying symptoms in DGBI, with a particular focus on their mechanistic influence on GI transit, visceral sensitivity, intestinal barrier function and secretion, and CNS processing. This review emphasizes the complexity of local and distant effects of microbial metabolites on physiological function, influenced by factors such as metabolite concentration, duration of metabolite exposure, receptor location, host genetics, and underlying disease state. Large‐scale in vitro work has elucidated interactions between host receptors and the microbial metabolome but there is a need for future research to integrate such preclinical findings with clinical studies. The development of novel, targeted therapeutic strategies for DGBI hinges on a deeper understanding of these metabolite‐host interactions, offering exciting possibilities for the future of treatment of DGBI.
... Influence gut microbiota to decrease deleterious LPS levels. [55][56][57] MethanogenesisPathways ...
Functional gastrointestinal disorders present diagnostic and therapeutic challenges, and there is a strong need for molecular markers that enable early detection and intervention. Herein, we present an approach to assess an abnormal gut microbiome associated with irritable bowel syndrome using stool-based gut metatranscriptome data from a large adult human population ( n = 80,570). We develop a suite of eight gut microbial functional pathway scores, each of which represents the activity of a set of interacting microbial functional features (based on KEGG orthology) relevant to known gut biochemical activities. We use a normative approach within a subpopulation ( n = 9,350) to define “Good” and “Not Optimal” activities for these functional pathway scores. We hypothesize that Not Optimal scores are associated with irritable bowel syndrome (IBS) and its subtypes (i.e., IBS-Constipation, IBS-Diarrhea, IBS-Mixed Type). We show that Not Optimal functional pathway scores are associated with higher odds of IBS or its subtypes within an independent cohort ( n = 71,220) using both the Rome IV Diagnostic Questionnaire as well as self-reported phenotypes. Rather than waiting to diagnose IBS after symptoms appear, these functional scores can help to provide early health insights into molecular pathways that may lead to IBS. These molecular endpoints could also assist with measuring the efficacy of practical interventions, developing related algorithms, providing personalized nutritional recommendations, diagnostics, and treatments for gastrointestinal disorders like IBS.
Graphical Abstract
... Disruptions in the Gut-Brain Axis (GBA) can lead to conditions like irritable/inflammatory bowel syndrome (IBS), implicating the intestinal microbiome [8]. Dietary triggers, such as fermentable oligosaccharides, contribute to IBS symptoms [9]. IBD introduces additional complexity involving lipopolysaccharide (LPS) [10]. ...
... IBD introduces additional complexity involving lipopolysaccharide (LPS) [10]. Indeed, LPS, at the intestinal level, activates NF-kB, leading to inflammatory cytokine production and increased permeability [9]. This underscores the gut's critical role beyond gastrointestinal concerns, impacting systemic inflammatory responses. ...
Vitamin D3 (VitD3) plays a crucial role in various cellular functions through its receptor interaction. The biological activity of Vitamin D3 can vary based on its solubility and stability. Thus, the challenge lies in maximizing its biological effects through its complexation within cyclodextrin (βNS-CDI 1:4) nanosponges (NS) (defined as VitD3NS). Therefore, its activity has been evaluated on two different gut–brain axes (healthy gut/degenerative brain and inflammatory bowel syndrome gut/degenerative brain axis). At the gut level, VitD3-NS mitigated liposaccharide-induced damage (100 ng/mL; for 48 h), restoring viability, integrity, and activity of tight junctions and reducing ROS production, lipid peroxidation, and cytokines levels. Following intestinal transit, VitD3-NS improved the neurodegenerative condition in the healthy axis and the IBS model, suggesting the ability of VitD3-NS to preserve efficacy and beneficial effects even in IBS conditions. In conclusion, this study demonstrates the ability of this novel form of VitD3, named VitD3-NS, to act on the gut–brain axis in healthy and damaged conditions, emphasizing enhanced biological activity through VitD3 complexation, as such complexation increases the beneficial effect of vitamin D3 in both the gut and brain by about 50%.
... Studies on rodents have indicated that a high FODMAP diet could potentially result in dysbiosis, dysfunction of the colonic barrier, recruitment and activation of mast cells, and the development of visceral hypersensitivity [59][60][61]. Singh et al. demonstrated, using mast cell-deficient rodents with or without mast cell reconstitution, that the loss of the colonic barrier induced by a high FODMAP diet relies on toll-like receptor 4 (TLR4)-dependent mast cell activation [60]. In a previous 2018 study, the same authors fed rats a high FODMAP diet, resulting in increased fecal Gram-negative bacteria, elevated lipopolysaccharides (LPS), and induced intestinal pathology, evidenced by barrier dysfunction and visceral hypersensitivity. ...
... In a previous 2018 study, the same authors fed rats a high FODMAP diet, resulting in increased fecal Gram-negative bacteria, elevated lipopolysaccharides (LPS), and induced intestinal pathology, evidenced by barrier dysfunction and visceral hypersensitivity. The barrier loss was reversed by a low FODMAP diet [61]. The proposed mechanism involves an abundance of Gram-negative bacteria induced by a high FODMAP diet, leading to increased luminal LPS. ...
... Enhanced intestinal permeability is suggested as a potential factor, with ongoing research exploring this aspect [33,61,62]. In a controlled, single-blind study where patients with IBS were randomized to either a low or high FODMAP diet for 3 weeks, it was found that individuals on the low FODMAP diet exhibited reduced urinary histamine levels [63]. ...
The low FODMAP (fermentable oligosaccharide, disaccharide, monosaccharide, and polyol) diet is a beneficial therapeutic approach for patients with irritable bowel syndrome (IBS). However, how the low FODMAP diet works is still not completely understood. These mechanisms encompass not only traditionally known factors such as luminal distension induced by gas and water but also recent evidence on the role of FOMAPs in the modulation of visceral hypersensitivity, increases in intestinal permeability, the induction of microbiota changes, and the production of short-chain fatty acids (SCFAs), as well as metabolomics and alterations in motility. Although most of the supporting evidence is of low quality, recent trials have confirmed its effectiveness, even though the majority of the evidence pertains only to the restriction phase and its effectiveness in relieving abdominal bloating and pain. This review examines potential pathophysiological mechanisms and provides an overview of the existing evidence on the effectiveness of the low FODMAP diet across various IBS subtypes. Key considerations for its use include the challenges and disadvantages associated with its practical implementation, including the need for professional guidance, variations in individual responses, concerns related to microbiota, nutritional deficiencies, the development of constipation, the necessity of excluding an eating disorder before commencing the diet, and the scarcity of long-term data. Despite its recognized efficacy in symptom management, acknowledging these limitations becomes imperative for a nuanced comprehension of the role of a low FODMAP diet in managing IBS. By investigating its potential mechanisms and evidence across IBS subtypes and addressing emerging modulations alongside limitations, this review aims to serve as a valuable resource for healthcare practitioners, researchers, and patients navigating the intricate landscape of IBS.
... Interestingly, food components can interact with the gut microbiota and its metabolites. For example, the intake of FODMAPs and tryptophan can induce the release of neuroactive mediators (e.g., 5-hydroxytryptamine (HT), histamine, proteases, and lipopolysaccharides) that can trigger and increase visceral hypersensitivity through modulation of intestinal nociceptive signaling [90,91]. Further, fecal supernatants of IBS patients were able to cause hypersensitivity in visceral afferents in mice colon. ...
Background:
Disorders of gut-brain interaction (DGBIs) have a complex pathophysiology that is often characterized by a relationship between food ingestion and triggering of symptoms. Understanding of the underlying mechanisms and the role of nutrients as a therapeutic target are rapidly evolving.
Aims and methods:
We performed a narrative review of the literature using the following keywords, their acronyms, and their associations: nutrients, disorders of gut-brain interaction; functional dyspepsia; malabsorption; irritable bowel syndrome; diarrhea; constipation.
Results:
Functional dyspepsia displayed a significant correlation between volume, fat and/or wheat abundance, chemical composition of ingested food and symptoms of early satiety, fullness and weight loss. Carbohydrate malabsorption is related to enzyme deficiency throughout the GI tract. Food composition and richness in soluble vs. non-soluble fibers is related to constipation and diarrhea. The elimination of fermentable oligo-, di-, monosaccharides and polyols (FODMAPs) has a significant and non-unidirectional impact on irritable bowel syndrome (IBS) symptoms.
Conclusions:
Food volume, nutritive and chemical composition, and its malabsorption are associated with symptom generation in DGBIs. Further multicenter, randomized-controlled clinical trials are needed to clarify the underlying pathophysiology.
... It has to kept in mind, though, that the regulation of immunity by LPS is a complex process, with differences of Bacteroides LPS as compared to Escherichia coli LPS related to immunogenicity and endotoxin tolerance 64 . Furthermore, Sudhir et al. reported that low-dose LPS exposure enhanced allergic airway inflammation in OVA-sensitized mice, with higher levels of Th2 66 . This may explain why our study showed that CSU patients with high LPS levels are more likely to have rapid relapse after cessation of controller therapy, suggesting that LPS may be a driver of CSU relapse. ...
... In vivo intestinal permeability was assessed with 4000 Da FITCdextran (46944, Sigma-Aldrich) 66 . In brief, mice were fasted for more than 6 h and were given 4000 Da FITC dextran working solution (200 ul, 50 mg/ml) by gavage. ...
Chronic spontaneous urticaria (CSU) comes with gut dysbiosis, but its relevance remains elusive. Here we use metagenomics sequencing and short-chain fatty acids metabolomics and assess the effects of human CSU fecal microbial transplantation, Klebsiella pneumoniae, Roseburia hominis, and metabolites in vivo. CSU gut microbiota displays low diversity and short-chain fatty acids production, but high gut Klebsiella pneumoniae levels, negatively correlates with blood short-chain fatty acids levels and links to high disease activity. Blood lipopolysaccharide levels are elevated, link to rapid disease relapse, and high gut levels of conditional pathogenic bacteria. CSU microbiome transfer and Klebsiella pneumoniae transplantation facilitate IgE-mediated mast cell(MC)-driven skin inflammatory responses and increase intestinal permeability and blood lipopolysaccharide accumulation in recipient mice. Transplantation of Roseburia hominis and caproate administration protect recipient mice from MC-driven skin inflammation. Here, we show gut microbiome alterations, in CSU, may reduce short-chain fatty acids and increase lipopolysaccharide levels, respectively, and facilitate MC-driven skin inflammation.
... Increased Gram-negative Enterobacteriaceae and decreased acetic acid-producing bacteria (such as Bifidobacteria) associated with T2D resulted in increased LPS release and decreased acetic acid, respectively. Then, LPS from the gut lumen binds Toll-like receptor 4 (TLR4) to damage the intestinal barrier (145), and serum LPS moderately increases, which is an inflammatory state of prediabetes (146,147). However, EECs increased the incretion of GLP-1 after sensing LPS as compensation (41). ...
Gut microbiota exert influence on gastrointestinal mucosal permeability, bile acid metabolism, short-chain fatty acid synthesis, dietary fiber fermentation, and farnesoid X receptor/Takeda G protein-coupled receptor 5 (TGR5) signal transduction. The incretin glucagon-like peptide 1 (GLP-1) is mainly produced by L cells in the gut and regulates postprandial blood glucose. Changes in gut microbiota composition and function have been observed in obesity and type 2 diabetes (T2D). Meanwhile, the function and rhythm of GLP-1 have also been affected in subjects with obesity or T2D. Therefore, it is necessary to discuss the link between the gut microbiome and GLP-1. In this review, we describe the interaction between GLP-1 and the gut microbiota in metabolic diseases. On the one hand, gut microbiota metabolites stimulate GLP-1 secretion, and gut microbiota affect GLP-1 function and rhythm. On the other hand, the mechanism of action of GLP-1 on gut microbiota involves the inflammatory response. Additionally, we discuss the effects and mechanism of various interventions, such as prebiotics, probiotics, antidiabetic drugs, and bariatric surgery, on the crosstalk between gut microbiota and GLP-1. Finally, we stress that gut microbiota can be used as a target for metabolic diseases, and the clinical application of GLP-1 receptor agonists should be individualized.
... Additionally, a balanced gastrointestinal ora plays a pivotal role in the establishment, maturation, and defense against pathogenic invasion of the intestinal immune system 11 . The potential mechanisms through which dysbacteriosis impacts GERD may involve the production of lipopolysaccharide (LPS) by certain gram-negative bacteria in the intestine, which can activate Toll-like receptor-4 (TLR-4) and induce the production of proin ammatory cytokines, ultimately resulting in visceral hypersensitivity 12 . On the other hand, it is important to highlight that LPS produced by the intestinal microbiota possess the ability to activate the nuclear factor-κB (NF-κB) signaling pathway, thereby promoting the synthesis of cyclooxygenase-2 (COX-2) and inducing the expression of nitric oxide synthase, eventually leading to relaxation of the lower esophageal sphincter 13,14 . ...
Background
Despite previous research indicating a strong correlation between gut microbiota (GM) and gastroesophageal reflux disease (GERD), the exact causal relationship between these factors remains uncertain. Consequently, we conducted an extensive investigation utilizing a two-sample Mendelian randomization (MR) study to elucidate the influence of GM on the susceptibility to developing GERD.
Method
This study utilized instrumental variables derived from 211 GM taxa obtained from the Genome Wide Association Study (GWAS) data. Subsequently, a MR study was conducted to evaluate the impact of GM on GERD, utilizing data from the IEU open GWAS summary data repository, which included 129,080 cases and 473,524 controls. The primary method employed to analyze causality in this study was the inverse variance weighted (IVW) approach, and a range of sensitivity analyses were conducted to ensure the reliability and consistency of the findings.
Results
The IVW method revealed a positive association between the class Mollicutes (OR: 1.0976, 95% CI: 1.0046–1.1992, p = 0.0393), genus Coprococcus2 (OR 1.0620, 95% CI: 1.0026–1.1248, p = 0.0405), and phylum Tenericutes (OR 1.0976, 95% CI: 1.0043–1.1996, p = 0.0400) with the risk of GERD. However, the weighted median method did not support genus Coprococcus2 (OR 1.0672, 95% CI: 0.9893–1.1512, p = 0.0928) as a risk factor for GERD. Sensitivity analyses further validated the reliability of the MR findings.
Conclusion
Our study contributes evidence to the close relationship between the GM and GERD. Future research should focus on developing microbiome-oriented therapeutic approaches for managing GERD.
... The establishment and development of the human gut microbiota is a complex process, just like human life, the microbiota also undergoes development and establishment, maturity, and stability, and then eventually aging. Studies have shown that the developing intestinal microbiome undergoes three distinct phases of microbiome progression: a developmental phase (months 3-14), a transitional phase (months [15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30], and a stable phase (months 31-46) in human infants and childhood [20]. That is to say, adolescence is a period when the intestinal flora of children is relatively stable. ...
... Therefore, the higher the ratio of Bacteroidetes/Firmicutes, the greater the exposure of LPS. Current knowledge supports that increasing the number of Gram-negative bacteria in the rats' intestine can increase LPS and induce intestinal pathologies, such as inflammation, barrier dysfunction, and visceral hypersensitivity [25,26]. LPS binding protein (LBP) recognizes and binds LPS to activate the transmembrane receptor TLR4, which would initiate the downstream NF-κB signaling [27], and secretion of inflammatory cytokines [28,29]. ...
Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal disorder, however, its effect on gut microbiota during the periadolescent period remains unclear. In this study, our objective was to investigate the characteristics of gut microbiota in male periadolescent rats with IBS induced by neonatal maternal separation (NMS). We evaluated visceral sensitivity by electromyography (EMG), analyzed gut microbiota composition using 16S rDNA gene sequencing, and examined intestinal pathological changes between control and IBS-like groups. The IBS-like group had significantly higher discharge amplitude of the external oblique muscle of the abdomen during colorectal distension (CRD) at 40- and 60 mmHg pressures. We observed differences in gut microbiota composition, with an increase in Bacteroidetes abundance and a decrease in Firmicutes in IBS-like rats. Beta-diversity analysis revealed the gut microbiota of the IBS-like group displayed higher consistent, while that of the control group exhibited substantial variation. Linear discriminant analysis effect size (LEfSe) detected 10 bacterial taxonomic clades showing statistically significant differences (7 increased and 3 decreased) in the IBS-like group. Functional analysis revealed that aminoacyl-tRNA biosynthesis and fatty acid biosynthesis were significantly altered, leading to changes in gene expression. Our findings demonstrate a definite correlation between gut microbiota dysbiosis and IBS during the male periadolescent period, with Alloprevotella and Bacteroide positively associated with high risk of IBS. The effects of specific bacterial genera may provide new insights for the development of treatments for IBS.
... The symptoms of lactose intolerance vary with doses of lactose which may be alleviated with a low FODMAP diet (Misselwitz et al., 2019). Further, FODMAPs also augments visceral nociception by causing dysbiosis, thereby, resulting in intestinal infections like inflammation and visceral hypersensitivity (Zhou et al., 2018). Patel (2021) reported colonic distension owing to visceral hypersensitivity in animal models. ...
