Comparison of biochemical, microbial and mucosal mRNA expression in bile acid diarrhoea and irritable bowel syndrome with diarrhoea

Camilleri, Michael; Carlson, Paula; BouSaba, Joelle; McKinzie, Sanna; Vijayvargiya, Priya; Magnus, Yorick; Sannaa, Wassel; Wang, Xiao Jing; Zheng, Ting; Maselli, Daniel B.; Atieh, Jessica; Taylor, Ann; Nair, Asha; Nagaraj, Nagaswaroop Kengunte; Johnson, Stephen; Burton, Duane D.; Busciglio, Irene

doi:10.1136/gutjnl-2022-327471

Cited by 25 publications

(18 citation statements)

References 54 publications

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“…Conversely, there was reduced expressions of peptidase inhibitor (PI) PI15 and PI16 genes that inhibit proteases in IBS-D, suggesting vulnerability of the mucosa to the effects of proteases (eg, pancreatic or bacterial) in IBS-D 42. The differential immune activation in ascending colon mucosal biopsies in 11 patients with BAD and 33 controls with IBS-D showed greater activation in BAD43 which is consistent with the detergency and mucosal irritation by bile acids, particularly the di-α hydroxy bile acids, chenodeoxycholic acid and deoxycholic acid 44. There were minimal differences in mucosal expression between ileal biopsies from patients with IBS-C or IBS-D and healthy controls 44.…”

Section: Update On Pathophysiology Of Ibs and Its Diagnosismentioning

confidence: 99%

Irritable bowel syndrome: treatment based on pathophysiology and biomarkers

Camilleri

Boeckxstaens

2022

Gut

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ObjectiveTo appraise the evidence that pathophysiological mechanisms and individualised treatment directed at those mechanisms provide an alternative approach to the treatment of patients with irritable bowel syndrome (IBS).DesignA PubMED-based literature review of mechanisms and treatment of IBS was conducted independently by the two authors, and any differences of perspective or interpretation of the literature were resolved following discussion.ResultsThe availability of several noninvasive clinical tests can appraise the mechanisms responsible for symptom generation in IBS, including rectal evacuation disorders, abnormal transit, visceral hypersensitivity or hypervigilance, bile acid diarrhoea, sugar intolerances, barrier dysfunction, the microbiome, immune activation and chemicals released by the latter mechanism. The basic molecular mechanisms contributing to these pathophysiologies are increasingly recognised, offering opportunities to intervene with medications directed specifically to food components, receptors and potentially the microbiome. Although the evidence supporting interventions for each mechanism is not at the same level of proof, the current state-of-the-art provides the opportunity to advance the practice from treatment based on symptoms to individualisation of treatment guided by pathophysiology and clinically identified biomarkers.ConclusionThese advances augur well for the implementation of evidence-based individualised treatment for patients with IBS based on actionable biomarkers or psychological disturbances.

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Section: Update On Pathophysiology Of Ibs and Its Diagnosismentioning

confidence: 99%

Irritable bowel syndrome: treatment based on pathophysiology and biomarkers

Camilleri

Boeckxstaens

2022

Gut

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“…Patients with BAD showed lower alpha and beta diversity with an increased amount of Firmicutes and decreased expression of bile acid thiol ligase (involved in the transformation of primary to secondary BA) as well as decreased sulfatases. Furthermore, in the same study, biopsies from patients with BAD presented downregulation of BA transporters (SLC44A5 in particular) and upregulation in barrier-weakening genes (such as CLDN2), together with increased inflammatory activity within the lamina propria [82].…”

Section: Bile Acid-induced Diarrhea (Bad)mentioning

confidence: 66%

Bile Acid-Related Regulation of Mucosal Inflammation and Intestinal Motility: From Pathogenesis to Therapeutic Application in IBD and Microscopic Colitis

et al. 2022

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Inflammatory bowel diseases (IBD) and microscopic colitis are chronic immune-mediated inflammatory disorders that affect the gastroenterological tract and arise from a complex interaction between the host’s genetic risk factors, environmental factors, and gut microbiota dysbiosis. The precise mechanistic pathways interlinking the intestinal mucosa homeostasis, the immunological tolerance, and the gut microbiota are still crucial topics for research. We decided to deeply analyze the role of bile acids in these complex interactions and their metabolism in the modulation of gut microbiota, and thus intestinal mucosa inflammation. Recent metabolomics studies revealed a significant defect in bile acid metabolism in IBD patients, with an increase in primary bile acids and a reduction in secondary bile acids. In this review, we explore the evidence linking bile acid metabolites with the immunological pathways involved in IBD pathogenesis, including apoptosis and inflammasome activation. Furthermore, we summarize the principal etiopathogenetic mechanisms of different types of bile acid-induced diarrhea (BAD) and its main novel diagnostic approaches. Finally, we discuss the role of bile acid in current and possible future state-of-the-art therapeutic strategies for both IBD and BAD.

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“…H, healthy controls; D, diarrheal piglets; CON, control group; ETEC, E. coli k88 group; Ben, E. coli k88+Ben-α-Gal group Firmicutes and increases in Lactobacillus and Enterobacteria (E. coli at specie level) during flares [24]. A previous study found higher concentrations of PBA CDCA in the stool of patients with bile acid diarrhea and further showed that immune activation or inflammation and increased permeability could conceivably be contributing to the onset of diarrhea [60]. Our study showed a higher PBA CA concentration and decreased levels of SBAs LCA and HDCA in piglets with diarrhea compared to in the healthy controls.…”

Section: Discussionmentioning

confidence: 99%

Mucin O-glycan-microbiota axis orchestrates gut homeostasis in a diarrheal pig model

Xia

Zhong

et al. 2022

Microbiome

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Background Post-weaning diarrhea in piglets reduces growth performance and increases mortality, thereby causing serious economic losses. The intestinal epithelial cells and microbiota reciprocally regulate each other in order to maintain intestinal homeostasis and control inflammation. However, a relative paucity of research has been focused on the host-derived regulatory network that controls mucin O-glycans and thereby changes gut microbiota during diarrhea in infancy. At the development stage just after birth, the ontogeny of intestinal epithelium, immune system, and gut microbiota appear similar in piglets and human infants. Here, we investigated the changes of mucin O-glycans associated with gut microbiota using a diarrheal post-weaned piglet model. Results We found that diarrhea disrupted the colonic mucus layer and caused aberrant mucin O-glycans, including reduced acidic glycans and truncated glycans, leading to an impaired gut microenvironment. Subsequently, the onset of diarrhea, changes in microbiota and bacterial translocation, resulting in compromised epithelial barrier integrity, enhanced susceptibility to inflammation, and mild growth faltering. Furthermore, we found the activation of NLRP3 inflammasome complexes in the diarrheal piglets when compared to the healthy counterparts, triggered the release of proinflammatory cytokines IL-1β and IL-18, and diminished autophagosome formation, specifically the defective conversion of LC3A/B I into LC3A/B II and the accumulation of p62. Additionally, selective blocking of the autophagy pathway by 3-MA led to the reduction in goblet cell-specific gene transcript levels in vitro. Conclusions We observed that diarrheal piglets exhibited colonic microbiota dysbiosis and mucosal barrier dysfunction. Our data demonstrated that diarrhea resulted in the activation of inflammasomes and autophagy restriction along with aberrant mucin O-glycans including reduced acidic glycans and truncated glycans. The results suggested the mucin O-glycans-microbiota axis is likely associated with diarrheal pathogenesis. Our study provides novel insights into the pathophysiology of early-weaning-induced diarrheal disease in piglets and potentially understanding of disease mechanisms of diarrhea for human infants. Understanding the molecular pathology and pathogenesis of diarrhea is a prerequisite for the development of novel and effective therapies. Our data suggest that facilitating O-glycan elongation, modifying the microbiota, and developing specific inhibitors to some key inflammasomes could be the options for therapy of diarrhea including human infants. Graphical abstract

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Comparison of biochemical, microbial and mucosal mRNA expression in bile acid diarrhoea and irritable bowel syndrome with diarrhoea

Cited by 25 publications

References 54 publications

Irritable bowel syndrome: treatment based on pathophysiology and biomarkers

Irritable bowel syndrome: treatment based on pathophysiology and biomarkers

Bile Acid-Related Regulation of Mucosal Inflammation and Intestinal Motility: From Pathogenesis to Therapeutic Application in IBD and Microscopic Colitis

Mucin O-glycan-microbiota axis orchestrates gut homeostasis in a diarrheal pig model

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