Obesity and hypertension are interrelated global health challenges sharing common pathophysiological mechanisms, including insulin resistance, chronic inflammation and neurohormonal dysregulation. Emerging evidence highlights the gut microbiome as a crucial mediator in this interplay, influencing intestinal barrier integrity, systemic inflammation and metabolic homeostasis. In this narrative review, we critically examine the interplay between obesity‐induced hypertension and the gut microbiome, evaluating current evidence, therapeutic implications and future research priorities. Obesity‐associated gut dysbiosis disrupts the intestinal epithelial barrier, increasing translocation of bacterial products like lipopolysaccharides into circulation, promoting systemic inflammation that exacerbates insulin resistance, adipose dysfunction and hypertension. Current treatments targeting obesity, from lifestyle modification to bariatric surgery, show beneficial effects on blood pressure, but microbiome‐targeted interventions are an evolving therapeutic frontier. Prebiotics, probiotics, synbiotics and faecal microbiota transplantation have demonstrated potential antihypertensive effects in preclinical and clinical studies, although findings are heterogeneous and require confirmation in larger randomised trials. Methodological challenges remain, including the need for advanced microbial sampling techniques beyond faecal analysis to fully capture disease‐relevant microbiota alterations. This review synthesises current knowledge on gut microbiome involvement in obesity‐induced hypertension, evaluates microbiome‐based therapeutic strategies and identifies critical research gaps to guide future investigations aimed at mitigating the dual pandemics of obesity and hypertension.

Rheumatoid arthritis (RA) is an autoimmune systemic disease in which pain remains a major and often refractory symptom even after clinical remission of the disease. Although historically attributed to joint inflammation, recent evidence reveals a multifactorial pathogenesis of RA pain, involving peripheral sensitization, central sensitization, and neuroimmune crosstalk. In these mechanisms, interleukin‐6 (IL‐6) plays a central role not only as one of the inflammatory mediators but also as a classic and trans‐signaling modulator for pain. This review synthesizes current mechanistic and clinical evidence on IL‐6 inhibitors, particularly sarilumab and tocilizumab, concerning their effect on pain in RA. Preclinical studies have already demonstrated that IL‐6 enhances the excitability of nociceptors through the upregulation of ion channels in dorsal root ganglia; it also promotes glial activation within the spinal cord; however, chronic pain sustains these processes. Blockade of IL‐6 receptor reverses these changes and alleviates mechanical hyperalgesia as well as allodynia in different models of diseases. Clinical trials of IL‐6 inhibitors have shown that these compounds provide major pain relief, sometimes better than tumor necrosis factor (TNF) inhibitors, most explicitly for patients with elevated baseline C‐reactive protein (CRP) or who do not respond to TNF inhibitors. Differences in their pharmacokinetics, receptor binding, and suppression of CRP may translate into differences in their analgesic profiles. However, it is analyzed that a subset of patients with persistently painful rheumatoid arthritis despite IL‐6 inhibition demonstrates the existence of non‐inflammatory drivers like nociplastic pain and the inadequacy of conventional indices of disease activity to capture the burden of pain.

Shigellosis remains a significant global cause of infectious colitis, increasingly complicated by multidrug-resistant strains and the microbiota-disrupting effects of broad-spectrum antibiotics. Although conventional antimicrobial therapy can reduce symptom duration and bacterial shedding, it also contributes to gut dysbiosis, loss of colonization resistance, and further selection for antimicrobial resistance. These challenges have renewed interest in precision antimicrobial strategies, particularly bacteriophage therapy, which provides strain-level specificity and preserves the gut microbiota. This narrative review evaluates the biological rationale, preclinical and early clinical evidence, safety considerations, and translational challenges associated with bacteriophage therapy targeting Shigella spp. The historical development and mechanistic basis of phage therapy are summarized, with emphasis on the advantages of obligately lytic phages, receptor-specific targeting, self-amplification at infection sites, and activity against both planktonic and biofilm-associated bacteria. Recent microbiota research indicates that shigellosis is closely associated with early and persistent disruption of gut ecology, including depletion of short-chain fatty acids-producing taxa and reduced microbial resilience. Phage-based approaches may reduce pathogen burden while preserving beneficial microbial communities. Evidence from in vitro systems, animal models, human intestinal organoids, and a Phase 1 clinical trial demonstrates targeted efficacy and favorable safety profiles for Shigella-specific phages and phage cocktails. Major barriers to clinical adoption include immune interactions, phage resistance dynamics, genomic safety screening, regulatory classification, and the need for standardized susceptibility testing. Future directions emphasize the development of personalized phage therapy platforms that integrate rapid diagnostics, phage libraries, metagenomics, and artificial intelligence-assisted matching to enable scalable, precision treatment.

Chimeric Antigen Receptors (CAR) T-cell therapy is a ground-breaking discovery in immunotherapy, mainly known for its exceptional results in treating haematological malignancies. The latest research has revealed that the potential of CAR T-cell therapy extends far beyond its current capabilities and could represent a novel therapeutic approach for treating various cancers. This review aims to summarize the latest innovations in CAR T-cell therapy applied in cancer treatment, including multiple myeloma, osteosarcoma, glioblastoma, melanoma and various childhood malignancies. However, several challenges limit success of CAR T-cell therapy, including the antigen escape phenomenon, 'on-target off-tumour' toxicity, penetration into solid tumour tissue, alongside the cost-effectiveness concerns. The improvement of cancer immunotherapies currently available requires an increase in the effectiveness of CAR T-cells in managing refractory and solid cancers. This could be achieved by using CAR T-cells to target various antigens, enhancing their local delivery and tumour infiltration capabilities and utilizing CAR T-cells in combination with checkpoint blockade and immunotherapy, such as PD-1 blockade and CD19 CAR T-cell combined therapy. Although CAR T-cell treatment offers a lot of promise, its cost needs to be taken into account, especially in healthcare systems with limited funding. More importantly, frameworks for Health Technology Assessment (HTA) must adapt to incorporate ethical, sociological and psychological aspects. Reducing CAR T-cell toxicity is also essential, as it remains among biggest obstacles to their widespread application in clinical practice. Future research should therefore focus on enhancing our understanding of CAR T-cell therapy and expanding the application of immunotherapy in treatment.

Steatosis extends beyond the liver to the pancreas, heart, and skeletal muscle, yet prevailing definitions remain narrowly organ-focused. This narrative review introduces the Metabolic Steatotic Axis (MSA) as a framework that captures the dynamic, bidirectional interactions among these organs, driving systemic metabolic dysfunction. We synthesize evidence linking lipotoxicity, inflammatory signaling, and endocrine cross-talk into a self-amplifying network accelerating insulin resistance, β-cell failure, and cardiometabolic risk. The MSA concept provides a rationale for axis-based staging systems and composite biomarker panels to quantify cumulative disease burden better and refine risk stratification. We highlight phenotypic heterogeneity within MSA stages, the possible hierarchy of organ vulnerability, and the implications for prognosis and therapy. Viewing pharmacological and lifestyle interventions through the MSA lens reframes them as systemic modulators rather than organ-specific treatments, underscoring the need for multi-organ endpoints in clinical trials. Finally, we outline priorities for longitudinal imaging, multi-omics integration, and global harmonization to translate the MSA from a conceptual construct to a clinically actionable paradigm. By unifying fragmented observations into a systemic model, the MSA has the potential to reshape disease classification, therapeutic strategies, and precision medicine in metabolic disorders.

ABSTRACT Introduction Interindividual variability in drug response remains a significant clinical challenge, leading to therapeutic failure and toxicity. Much of this variability is unexplained by classical host-centric pharmacokinetic (PK) models, highlighting a critical gap in understanding of drug disposition. This review addresses this gap by establishing the gut microbiome as an important determinant of drug fate. Areas covered This narrative review with scoping approach examines how microbial enzymes affect therapeutics through comprehensive analysis of mechanistic and clinical studies. Key examples discussed include irinotecan, digoxin, and sulfasalazine. We highlight specific situations where the influence of gut bacteria is particularly significant, such as with low-bioavailability drugs and in patients with an ileocolonic anastomosis, where gut bacteria directly impact drug absorption and metabolism. Additionally, we address the limitations of current PK models and explore the potential of new integrated approaches. Expert opinion We propose that the gut microbiome should be recognized as a ‘fifth pillar’ of PKs. This shift in perspective is crucial for advancing personalized medicine. In this new model, a ‘PK profile card’ integrating microbial, genomic, and clinical data will help guide dosing. We anticipate microbiome analysis to become a standard clinical tool to optimize drug efficacy and safety.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation and destruction of cartilage, as well as by extra-articular manifestations. Rheumatoid nephropathy is a common complication of RA and its principal target is the renal corpuscle. Vitamin D and its analogs exert immunomodulatory actions throughout the body due to the widespread of their receptors. Our study aimed to compare the effects of cholecalciferol (vitamin D3) and alfacalcidol on renal corpuscle changes in pristane-induced RA model following a 28-day treatment, using geometric morphometrics. Forty female Wistar rats (190–210 g; 12–13 weeks old) were randomly assigned to four groups: the control (Cont) group (n = 10) received saline i.c., the PIA group (n = 10) was administered pristane i.c., PIA-ALF group (n = 10) was administered pristane i.c. and alfacalcidol orally, and the PIA-CH group (n = 10) was injected i.c. with pristane and received cholecalciferol orally. Pristane administration was used for RA induction. At the end of the experiment, the left kidneys were removed and processed by standard histological procedures for geometric morphometric analysis. Geometric morphometric analysis demonstrated that, compared with the control group, the architecture of the renal corpuscles was altered in the PIA (p < 0.0001) and PIA-CH (p = 0.0065) groups. In contrast, no statistically significant differences were observed in the PIA-ALF group (p = 0.3011). Geometric morphometric analysis demonstrated that alfacalcidol, but not cholecalciferol, exertedaprotective effect on the renal corpuscle architecture in pristane-induced rheumatoid arthritis in rats.

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