Mitochondrial perturbation in the intestine causes microbiota-dependent injury and gene signatures discriminative of inflammatory disease.

Mitochondrial dysfunction is associated with inflammatory bowel diseases (IBDs). To understand how microbial-metabolic circuits contribute to intestinal injury, we disrupt mitochondrial function in the epithelium by deleting the mitochondrial chaperone, heat shock protein 60 (Hsp60Δ/ΔIEC). This metabolic perturbation causes self-resolving tissue injury. Regeneration is disrupted in the absence of the aryl hydrocarbon receptor (Hsp60Δ/ΔIEC;AhR-/-) involved in intestinal homeostasis or inflammatory regulator interleukin (IL)-10 (Hsp60Δ/ΔIEC;Il10-/-), causing IBD-like pathology. Injury is absent in the distal colon of germ-free (GF) Hsp60Δ/ΔIEC mice, highlighting bacterial control of metabolic injury. Colonizing GF Hsp60Δ/ΔIEC mice with the synthetic community OMM12 reveals expansion of metabolically flexible Bacteroides, and B. caecimuris mono-colonization recapitulates the injury. Transcriptional profiling of the metabolically impaired epithelium reveals gene signatures involved in oxidative stress (Ido1, Nos2, Duox2). These signatures are observed in samples from Crohn's disease patients, distinguishing active from inactive inflammation. Thus, mitochondrial perturbation of the epithelium causes microbiota-dependent injury with discriminative inflammatory gene profiles relevant for IBD.

Mitochondrial Metabolism in the Intestinal Stem Cell Niche-Sensing and Signaling in Health and Disease.

Mitochondrial metabolism, dynamics, and stress responses in the intestinal stem cell niche play a pivotal role in regulating intestinal epithelial cell homeostasis, including self-renewal and differentiation. In addition, mitochondria are increasingly recognized for their involvement in sensing the metabolic environment and their capability of integrating host and microbial-derived signals. Gastrointestinal diseases such as inflammatory bowel diseases and colorectal cancer are characterized by alterations of intestinal stemness, the microbial milieu, and mitochondrial metabolism. Thus, mitochondrial function emerges at the interface of determining health and disease, and failure to adapt mitochondrial function to environmental cues potentially results in aberrant tissue responses. A mechanistic understanding of the underlying role of mitochondrial fitness in intestinal pathologies is still in its infancy, and therapies targeting mitochondrial (dys)function are currently lacking. This review discusses mitochondrial signaling and metabolism in intestinal stem cells and Paneth cells as critical junction translating host- and microbe-derived signals into epithelial responses. Consequently, we propose mitochondrial fitness as a hallmark for intestinal epithelial cell plasticity, determining the regenerative capacity of the epithelium.

Changes in Markers of Thrombin Generation and Interleukin-6 During Unicondylar Knee and Total Knee Arthroplasty.

BACKGROUND: Total knee arthroplasty (TKA) is associated with a risk of thromboembolism requiring routine thromboprophylaxis, but there is debate about the risk with unicondylar knee arthroplasty (UKA) as it is a more minor procedure. We sought to investigate the relative risk of thromboembolism with UKA compared to TKA and one-staged bilateral TKA (BTKA) by measuring the increase in circulating biochemical markers of thrombin generation during the procedures. Degree of surgical trauma was also assessed by measuring interleukin-6, a marker of metabolic injury. METHODS: We prospectively studied a total of 75 patients: 25 patients undergoing UKA, unilateral TKA, and BTKA, respectively. All patients had surgery performed with tourniquet and received no tranexamic acid. Blood samples were taken during surgery and assayed for circulating markers of thrombin generation: prothrombin fragment 1+2 (F1+2) and thrombin-antithrombin complexes plus interleukin-6. RESULTS: Thrombin-antithrombin complexes, increased during all time points (P < .001) but was not significantly different between surgical treatment groups. F1+2 also rose significantly during surgery, with no significant difference between UKA and TKA. There was, however, a significant difference in F1+2 between BTKA and UKA or TKA (P < .02). Interleukin-6 rose minimally with UKA but rose significantly with TKA and BTKA (P < .001). CONCLUSION: Based on these data of circulating biochemical markers, patients undergoing UKA are at similar risk of thromboembolism with respect to TKA despite a lower index of metabolic injury. We believe that UKA patients should receive thromboprophylaxis comparable to TKA patients.

Astrocytic exportin-7 responds to ischemia through mediating LKB1 translocation from the nucleus to the cytoplasm.

The superfamily of importin-ß-related proteins is the largest class of nuclear transport receptors and can be generally divided into importins and exportins according to their transport directions. Eleven importins and seven exportins have been identified, and the expression patterns of both classes are important for their functions in nucleocytoplasmic transport activities. This study demonstrates that all of the importins (importin-ß; transportin-1, -2, and -3; and importin-4, -5, -7, -8, -9, -11, and -13) and all the exportins (exportin-1, -2, -4, -5, -6, -7, and -t) are differentially expressed in the cerebral cortex, cerebellum, hippocampus, and brainstem and in primary cultures of cerebral cortical astrocytes and neurons. For astrocytes, we observed that different importins and exportins displayed different expression changes during 0-6 hr of ischemia treatment, especially an increase of both the mRNA and the protein of exportin-7. Immunostaining showed that exportin-7 accumulated inside the nucleus and around the nuclear envelope. In addition, we noticed an increased cytoplasmic distribution of one of the cargo proteins of exportin-7, LKB1, an important element in maintaining energy homeostasis. This increased cytoplasmic distribution was accompanied by an increased expression of exportin-7 under ischemia in astrocytes. We demonstrate that exportin-7 responds to ischemia in astrocytes and that this response involves translocation of LKB1, a protein that plays important roles during metabolic stress, from the nucleus to the cytoplasm.