The human microbiome is a complex and dynamic system that plays important roles in human health and disease. However, there remain limitations and theoretical gaps in our current understanding of the intricate relationship between microbes and humans. In this narrative review, we integrate the knowledge and insights from various fields, including anatomy, physiology, immunology, histology, genetics, and evolution, to propose a systematic framework. It introduces key concepts such as the ‘innate and adaptive genomes’, which enhance genetic and evolutionary comprehension of the human genome. The ‘germ-free syndrome’ challenges the traditional ‘microbes as pathogens’ view, advocating for the necessity of microbes for health. The ‘slave tissue’ concept underscores the symbiotic intricacies between human tissues and their microbial counterparts, highlighting the dynamic health implications of microbial interactions. ‘Acquired microbial immunity’ positions the microbiome as an adjunct to human immune systems, providing a rationale for probiotic therapies and prudent antibiotic use. The ‘homeostatic reprogramming hypothesis’ integrates the microbiome into the internal environment theory, potentially explaining the change in homeostatic indicators post-industrialization. The ‘cell-microbe co-ecology model’ elucidates the symbiotic regulation affecting cellular balance, while the ‘meta-host model’ broadens the host definition to include symbiotic microbes. The ‘health-illness conversion model’ encapsulates the innate and adaptive genomes’ interplay and dysbiosis patterns. The aim here is to provide a more focused and coherent understanding of microbiome and highlight future research avenues that could lead to a more effective and efficient healthcare system.

Biomechanical stress ie, attributable to pressure overload, leads to cardiac hypertrophy and may ultimately cause heart failure. Yet, it is still unclear how mechanical stress is sensed and transduced on the molecular level. To systematically elucidate the underlying signal transduction pathways, we analyzed the gene expression profile of stretched cardiomyocytes on a genome-wide scale in comparison with other inducers of hypertrophy such as pharmacological stimulation. Neonatal rat ventricular cardiomyocytes were either stretched biaxially or stimulated with phenylephrine (PE), both resulting in a similar degree of hypertrophy. Microarray analyses revealed 164 genes >2.0-fold up- and 21 genes <0.5-fold downregulated ( P <0.01). Differential expression was confirmed by real-time polymerase chain reaction. Genes of the “fetal gene program” such as BNP were induced by both stretch (4.2×) and PE (2.9×). We also verified upregulation of known stretch-responsive genes, including HSP70 (20.9×) and c-myc (3.0×). Moreover, several genes were found to be preferentially induced by stretch, such as the cardioprotective cytokine GDF15 (24.8×) and heme oxygenase 1 (Hmox1, 10.8×; both confirmed on protein level). Neither PE nor endothelin-1 upregulated GDF15 and Hmox1, whereas angiotensin II significantly induced both genes. Conversely, the AT ₁ receptor blocker irbesartan markedly blunted stretch-mediated GDF15 and Hmox1 upregulation, suggesting that the angiotensin receptor tranduces the biomechanical induction of these genes. In conclusion, we report a comprehensive gene expression profile of cardiomyocytes subjected to biomechanical stress in comparison with pharmacologically induced hypertrophy. Our data imply that a stretch-specific gene program exists, which is mediated, at least in part, by angiotensin II–dependent signaling.

Background— Osteopontin, a glycoprotein that can be detected in plasma, was found to be upregulated in several animal models of cardiac failure and may thus represent a new biomarker that facilitates risk stratification in patients with heart failure. We therefore tested whether osteopontin plasma levels are elevated in patients with chronic heart failure and whether they provide independent prognostic information. Methods and Results— We analyzed osteopontin plasma levels in 420 patients with chronic heart failure due to significantly impaired left ventricular systolic function and correlated the results with disease stage and prognostic information (median follow-up of 43 months). We found that osteopontin plasma levels were significantly elevated in patients with heart failure as compared with healthy control subjects (532 versus 382 ng/mL, P =0.008), irrespective of heart failure origin (ischemic versus dilated cardiomyopathy). Furthermore, osteopontin levels were higher in patients with moderate to severe heart failure than in patients with no or mild symptoms (672 ng/mL for New York Heart Association class III/IV versus 479 ng/mL for class I/II, P <0.0001). Estimated 4-year death rates in patients with osteopontin levels above or below a cutoff value derived from receiver operating characteristic analyses were 56.5% and 28.4%, respectively (hazard ratio 3.4, 95% confidence interval 2.2 to 5.3, P <0.0001). In a multivariable model that included demographic, clinical, and biochemical parameters such as N-terminal prohormone brain natriuretic peptide, osteopontin emerged as an independent predictor of death (hazard ratio 2.3, 95% confidence interval 1.4 to 3.5, P <0.001). Conclusion— Our findings suggest that osteopontin might be useful as a novel prognostic biomarker in patients with chronic heart failure.

The composition of skeletal muscle, in terms of the relative number of slow- and fast-twitch fibers, is tightly regulated to enable an organism to respond and adapt to changing physical demands. The phosphatase calcineurin and its downstream targets, transcription factors of the nuclear factor of activated T cells (NFAT) family, play a critical role in this process by promoting the formation of slow-twitch, oxidative fibers. Calcineurin binds to calsarcins, a family of striated muscle–specific proteins of the sarcomeric Z-disc. We show here that mice deficient in calsarcin-2, which is expressed exclusively by fast-twitch muscle and encoded by the myozenin 1 (Myoz1) gene, have substantially reduced body weight and fast-twitch muscle mass in the absence of an overt myopathic phenotype. Additionally, Myoz1 KO mice displayed markedly improved performance and enhanced running distances in exercise studies. Analysis of fiber type composition of calsarcin-2–deficient skeletal muscles showed a switch toward slow-twitch, oxidative fibers. Reporter assays in cultured myoblasts indicated an inhibitory role for calsarcin-2 on calcineurin, and Myoz1 KO mice exhibited both an excess of NFAT activity and an increase in expression of regulator of calcineurin 1-4 (RCAN1-4), indicating enhanced calcineurin signaling in vivo. Taken together, these results suggest that calsarcin-2 modulates exercise performance in vivo through regulation of calcineurin/NFAT activity and subsequent alteration of the fiber type composition of skeletal muscle.