Microbiota-dependent indole production stimulates the development of collagen-induced arthritis in mice.

Altered tryptophan catabolism has been identified in inflammatory diseases like rheumatoid arthritis (RA) and spondyloarthritis (SpA), but the causal mechanisms linking tryptophan metabolites to disease are unknown. Using the collagen-induced arthritis (CIA) model, we identified alterations in tryptophan metabolism, and specifically indole, that correlated with disease. We demonstrated that both bacteria and dietary tryptophan were required for disease and that indole supplementation was sufficient to induce disease in their absence.

Microbiota-dependent indole production is required for the development of collagen-induced arthritis.

Altered tryptophan catabolism has been identified in inflammatory diseases like rheumatoid arthritis (RA) and spondyloarthritis (SpA), but the causal mechanisms linking tryptophan metabolites to disease are unknown. Using the collagen-induced arthritis (CIA) model we identify alterations in tryptophan metabolism, and specifically indole, that correlate with disease. We demonstrate that both bacteria and dietary tryptophan are required for disease, and indole supplementation is sufficient to induce disease in their absence.

Microbial-derived indoles inhibit neutrophil myeloperoxidase to diminish bystander tissue damage.

During episodes of acute inflammation, polymorphonuclear leukocytes (PMNs) are actively recruited to sites of inflammation or injury where they provide anti-microbial and wound-healing functions. One enzyme crucial for fulfilling these functions is myeloperoxidase (MPO), which generates hypochlorous acid from Cl and hydrogen peroxide. The potential exists, however, that uncontrolled the extracellular generation of hypochlorous acid by MPO can cause bystander tissue damage and inhibit the healing response.

Intestinal Inflammation as a Dysbiosis of Energy Procurement: New Insights into an Old Topic.

Inflammatory bowel disease (IBD) coincides with profound shifts in microbiota and host metabolic energy supply and demand. The gastrointestinal epithelium is anatomically positioned to provide a selective barrier between the anaerobic luminal microbiota and host lamina propria, with the microbiota and epithelium participating in an intricate energy exchange necessary for homeostasis. Maintenance and restoration of the barrier requires high energy flux and places significant demands on available substrates to generate ATP.

Bile acids modulate colonic MAdCAM-1 expression in a murine model of combined cholestasis and colitis.

Primary sclerosing cholangitis (PSC) is a progressive fibrosing cholestatic liver disease that is strongly associated with inflammatory bowel disease (IBD). PSC-associated IBD (PSC-IBD) displays a unique phenotype characterized by right-side predominant colon inflammation and increased risk of colorectal cancer compared to non-PSC-IBD. The frequent association and unique phenotype of PSC-IBD suggest distinctive underlying disease mechanisms from other chronic liver diseases or IBD alone.

Adaptation to inflammatory acidity through neutrophil-derived adenosine regulation of SLC26A3.

Acute intestinal inflammation includes the early accumulation of neutrophils (PMN). Based on recent evidence that PMN infiltration "imprints" changes in the local tissue environment through local oxygen depletion and the release of adenine nucleotides, we hypothesized that the interaction between transmigrating PMN and intestinal epithelial cells (IECs) results in inflammatory acidification of the tissue. Using newly developed tools, we revealed that active PMN transepithelial migration (TEM) significantly acidifies the local microenvironment, a decrease of nearly 2 pH units.

Oral vitamin B supplement is delivered to the distal gut, altering the corrinoid profile and selectively depleting in C57BL/6 mice.

Vitamin B is a critical nutrient for humans as well as microbes. Due to saturable uptake, high dose oral B supplements are largely unabsorbed and reach the distal gut where they are available to interact with the microbiota. The aim of this study was to determine if oral B supplementation in mice alters 1) the concentration of B and related corrinoids in the distal gut, 2) the fecal microbiome, 3) short chain fatty acids (SCFA), and 4) susceptibility to experimental colitis.

Hypoxanthine is a checkpoint stress metabolite in colonic epithelial energy modulation and barrier function.

Intestinal epithelial cells form a selectively permeable barrier to protect colon tissues from luminal microbiota and antigens and to mediate nutrient, fluid, and waste flux in the intestinal tract. Dysregulation of the epithelial cell barrier coincides with profound shifts in metabolic energy, especially in the colon, which exists in an energetically depleting state of physiological hypoxia. However, studies that systematically examine energy flux and adenylate metabolism during intestinal epithelial barrier development and restoration after disruption are lacking.

Microbiota-Derived Indole Metabolites Promote Human and Murine Intestinal Homeostasis through Regulation of Interleukin-10 Receptor.

Interactions between the gut microbiota and the host are important for health, where dysbiosis has emerged as a likely component of mucosal disease. The specific constituents of the microbiota that contribute to mucosal disease are not well defined. The authors sought to define microbial components that regulate homeostasis within the intestinal mucosa.

Microbial-Derived Butyrate Promotes Epithelial Barrier Function through IL-10 Receptor-Dependent Repression of Claudin-2.

Commensal interactions between the enteric microbiota and distal intestine play important roles in regulating human health. Short-chain fatty acids (SCFAs), such as butyrate, produced through anaerobic microbial metabolism represent a major energy source for the host colonic epithelium and enhance epithelial barrier function through unclear mechanisms. Separate studies revealed that the epithelial anti-inflammatory IL-10 receptor α subunit (IL-10RA) is also important for barrier formation.

Effects of iron supplementation on growth, gut microbiota, metabolomics and cognitive development of rat pups.

Background: Iron deficiency is common during infancy and therefore iron supplementation is recommended. Recent reports suggest that iron supplementation in already iron replete infants may adversely affect growth, cognitive development, and morbidity.

Methods: Normal and growth restricted rat pups were given iron daily (30 or 150 μg/d) from birth to postnatal day (PD) 20, and followed to PD56.

Tissue metabolism and the inflammatory bowel diseases.

The intestinal mucosa provides a selective barrier between the anaerobic lumen and a highly metabolic lamina propria. A number of recent studies indicate that acute inflammation of the mucosa can result in tissue hypoxia and associated shifts in tissue metabolism. The activation of hypoxia-inducible factor (HIF) under these conditions has been demonstrated to function as an endogenous molecular cue to promote resolution of inflammation, particularly through the orchestration of barrier repair toward homeostasis.

Effects of postnatal growth restriction and subsequent catch-up growth on neurodevelopment and glucose homeostasis in rats.

Background: There is increasing evidence that poor growth of preterm infants is a risk factor for poor long-term development, while the effects of early postnatal growth restriction are not well known. We utilized a rat model to examine the consequences of different patterns of postnatal growth and hypothesized that early growth failure leads to impaired development and insulin resistance. Rat pups were separated at birth into normal (N, n = 10) or restricted intake (R, n = 16) litters.