bims-ainimu 2026-03-08 papers

Issue of 2026–03–08
seven papers selected by
Pedro Escoll Guerrero, Institut Pasteur

Front Endocrinol (Lausanne). 2026 ;17 1809151

Correction: Metabolic reprogramming and M2 macrophage depletion define the microenvironment of adenomyosis.

Frontiers Production Office

[This corrects the article DOI: 10.3389/fendo.2025.1602814.].

Keywords: Keratan sulfate; adenomyosis; endometrium; immune infiltration; macrophage; metabolic flux

DOI: https://doi.org/10.3389/fendo.2026.1809151

Microb Pathog. 2026 Mar 02. pii: S0882-4010(26)00150-6. [Epub ahead of print] 108424

Trimethylamine activates the Type III Secretion System of Salmonella to enhance host cell invasion.

Zeyuan Gao, Chunhua Lu, Yuemao Shen.

Epidemiological evidence has revealed that elevated plasma trimethylamine N-oxide (TMAO) levels are associated with the pathogenesis of multiple human diseases. As trimethylamine (TMA) is the key dietary precursor for TMAO biosynthesis in both mice and humans, inhibition of TMA production can effectively lower the risk of these diseases. In the anaerobic intestinal environment, dietary TMAO is enzymatically reduced to TMA by TMAO reductase by Proteobacteria. Here, we demonstrate that endogenously produced TMA potently activates the Type III Secretion System (T3SS) of Salmonella by binding to the transcriptional regulator HilD and enhancing its DNA-binding affinity. This TMA-HilD interaction enhances bacterial invasion of host cells without affecting bacterial growth. Crucially, inhibition of microbial TMAO reductase (TorA) - mediated TMA production can not only attenuates Salmonella virulence by disrupting TMA-HilD-driven T3SS activation but also reduces plasma TMAO levels to alleviate the risk of metabolic diseases. Therefore, targeting TMAO-microbiota-TMA axis represents a promising therapeutic strategy for combating both bacterial infections and metabolic disorders.

Keywords: Salmonella; TMAO reductase; Trimethylamine (TMA); Type III Secretion System (T3SS); Virulence regulation

DOI: https://doi.org/10.1016/j.micpath.2026.108424

Phytomedicine. 2026 Jan 04. pii: S0944-7113(26)00011-5. [Epub ahead of print]153 157774

Dihydroartemisinin facilitates intestinal mucosal healing in inflammatory bowel disease by targeting 11βHSD-1 to reprogram macrophage metabolism.

Xinke Du, Li Liu, Yang Zhang, Bingqi Zhang, Lina Yang, Ming Chu, Liu Zhou, Yuchen Li, Jianshi Zhu, Keshan Dong, Xiaohui Su, Qing Yang, Ying Chen, Xiaoxi Kan, Jiayin Han, Xiaoxin Zhu, Jiang Xu, Qi Li.

BACKGROUND: Mucosal healing is a major clinical challenge and a critical prognostic factor in inflammatory bowel disease (IBD). Achieving mucosal healing requires the functional reprogramming of macrophages to facilitate intestinal stem cells (ISCs)-mediated repair, a process impaired in IBD due to dysregulated macrophage activity. Dihydroartemisinin (DHA), a derivative of artemisinin, shows promise in treating IBD, but its therapeutic potential remains underexplored due to its common classification as an anti-inflammatory agent.
PURPOSE: This study aims to evaluate the efficacy of DHA in promoting mucosal healing in IBD and to elucidate the underlying mechanisms of macrophage reprogramming, thereby expanding the therapeutic potential of DHA beyond its conventional anti-inflammatory actions.
METHODS: The therapeutic efficacy of DHA and its underlying mechanisms were systematically investigated using a DSS-induced colitis mouse model, with a focus on the repair phase. Mucosal healing was assessed through comprehensive histopathological and functional evaluations. DHA's role in macrophage metabolic reprogramming was explored through transcriptomic and metabolic analyses, and its effect on epithelial regeneration was examined using macrophage-organoid co-cultures. A molecular target discovery approach, integrating Mendelian randomization, molecular docking, and direct binding assays, identified 11βHSD-1 as a molecular target of DHA, which was subsequently confirmed through genetic and pharmacological loss-of-function studies in macrophages.
RESULTS: Our findings demonstrated that DHA significantly promoted mucosal healing in a DSS-induced colitis model during the repair phase, as evidenced by reduced disease activity scores, increased colon length, and decreased histological damage. DHA also facilitated the recovery of gut functions, including barrier integrity, absorption, secretion, and motility. Macrophages were found to be essential for therapeutic effects of DHA. Specifically, DHA reprogrammed macrophage metabolism from glycolysis to oxidative phosphorylation, inducing a pro-repair phenotype characterized by enhanced secretion of Relmα and Wnt3a, which promoted the proliferation and differentiation of intestinal organoids. Mechanistically, we found that DHA directly bound to and activated 11βHSD-1, a key metabolic regulator in macrophages. This activation triggered STAT3/6 signaling, establishing a positive feedback loop that reinforced metabolic remodeling and facilitated the release of repair-promoting factors.
CONCLUSION: Our findings demonstrate that DHA promotes intestinal mucosal healing by reprogramming macrophage metabolism, thereby enhancing ISC proliferation and differentiation. These results provide new insights into the potential of DHA in reshaping immune homeostasis, offering promising therapeutic strategies for IBD.

Keywords: 11β Hydroxysteroid dehydrogenase 1; Dihydroartemisinin; Inflammatory bowel disease; Macrophages metabolism; Mucosal healing

DOI: https://doi.org/10.1016/j.phymed.2026.157774

Indian J Med Microbiol. 2026 Feb 28. pii: S0255-0857(26)00043-5. [Epub ahead of print] 101085

Generalized Lymphadenopathy due to Disseminated Non-Typhoidal Salmonella Infection in a 3-Year-old: Unmasking IL-12RB1-Deficient MSMD - A Rare Case Report.

M Shagana, G Vithiya, M Srividhya, P Periyasamy.

IL-12 receptor β1 (IL-12Rβ1) deficiency is the most frequent genetic etiology of Mendelian Susceptibility to Mycobacterial Disease (MSMD), predisposing to severe infections with intracellular pathogens. We report a 3-year-old male with prior BCG adenitis and multidrug-resistant extra-pulmonary tuberculosis who presented with persistent generalized lymphadenopathy. Excisional lymph node biopsy grew Salmonella enterica serovar Typhimurium. Genetic testing revealed a homozygous pathogenic mutation in the IL12RB1 gene. This case illustrates a rare presentation of disseminated non-typhoidal salmonellosis in IL-12Rβ1 deficiency and highlights the importance of early immunological evaluation in children with recurrent, severe, or atypical infections.

Keywords: Generalized lymphadenopathy; MSMD; Non-typhoidal Salmonella.

DOI: https://doi.org/10.1016/j.ijmmb.2026.101085

Sci Rep. 2026 Mar 06.

Transmission of Salmonella clones between different animal species in a horse and cattle breeding region in Japan.

Nobuo Arai, Hidekazu Niwa, Eri Uchida-Fujii, Yuiko Sawa, Yukino Tamamura-Andoh, Yuta Kinoshita, Anna Momoki, Ayako Watanabe-Yanai, Taketoshi Iwata, Midori Kubo, Masahiro Kusumoto.

Sequence type 34 (ST34) Salmonella enterica serovar Typhimurium and its monophasic variant (Salmonella 4,[5],12:i:-) are the most prevalent clones among humans and animals worldwide, including in Japan. Although cross-species transmission may have occurred in the background of global spread, the matter remains unresolved. Here, we conducted high-resolution phylogenetic analysis using whole-genome sequencing data of Salmonella Typhimurium and 4,[5],12:i:- obtained from a horse and cattle breeding district in Japan and identified cases of cross-species transmission of ST34 Salmonella 4,[5],12:i:- between horses and cattle. These isolates were classified into five clusters, core genome single-nucleotide polymorphism (cgSNP) clusters 1-5, based on the SNP distance. To elucidate the genetic background of each cgSNP cluster, we also conducted a phylogenetic analysis of 496 ST34 strains obtained from Japan and other countries. Hierarchical clustering using rhierBAPS revealed three clades. The past ST34 epidemic strains in Japan and cgSNP clusters 1-3 were concentrated in clades 1 and 3, which should be referred to as the Japanese epidemic lineages, whereas cgSNP cluster 5 belonged to clade 2, which should be referred to as the global lineage. These results suggest that ST34 Salmonella may have entered Japan through multiple routes and was transmitted between horses and cattle.

Keywords: Salmonella 4,[5],12:i:-; Cattle; Cross-species transmission; Horse; Sequence type 34

DOI: https://doi.org/10.1038/s41598-026-39311-y

J Antibiot (Tokyo). 2026 Mar 06.

Nanoliposome mediated co-delivery of amoxicillin and tazobactam remediate intracellular infection by a multidrug-resistant Salmonella enterica serovar Typhimurium.

Trisha Sackey, Unnikrishnan Kannan, Satwik Majumder, Jojy John, Charles Viau, Zhixuan Feng, Marie Odile Benoit-Biancamano, Jennifer Ronholm, Saji George.

Multidrug-resistant (MDR) Salmonella enterica serovar Typhimurium (S. Typhimurium) poses a growing threat to food safety and animal health, particularly in the swine industry. In this study, we characterized a highly resistant ST strain isolated from a Quebec swine farm using whole-genome sequencing and phenotypic assays. The isolate harbored two plasmids, one of which encoded resistance to seven major antibiotic classes, including β-lactams, aminoglycosides, and sulfonamides, along with multiple virulence factors. To counteract these resistance mechanisms, we developed a nano-enabled antibacterial combination therapy (NeACT) by co-encapsulating amoxicillin (AMOX) and the β-lactamase inhibitor tazobactam into cyclodextrin encapsulated in liposomes (LP-CAT). Physicochemical analysis confirmed optimal particle size, charge, and stability, while checkerboard assays demonstrated strong drug synergism. The LP-CAT formulation drastically restored antimicrobial efficacy, reducing the AMOX minimum inhibitory concentration (MIC) from >2000 µg/mL to ~60 µg/mL. Using porcine intestinal epithelial (IPEC-J2) cells as an intracellular infection model, our study showed the potential of LP-CAT to remove >94% of intracellular bacteria with no cytotoxic effect. The ability of LP-CAT to resolve intestinal infection was further verified in Caenorhabditis elegans (C. elegans) intestinal infection model. These findings establish LP-CAT as a safe and effective strategy to revive antibiotic potency against intracellular MDR pathogens, offering a novel tool for combating antimicrobial resistance in livestock and safeguarding public health.

DOI: https://doi.org/10.1038/s41429-026-00903-5

J Trace Elem Med Biol. 2026 Feb 28. pii: S0946-672X(26)00038-6. [Epub ahead of print]94 127852

Cytotoxic, genotoxic, and apoptotic effects of manganese nitrate on RAW264.7 macrophages via reactive oxygen species accumulation and mitochondrial injury.

Ping-Kun Tsai, Sheng-Wen Wu, Yen-Ju Lee, Yi-Ting Hsieh, Yung-Chuan Ho, Shiuan-Shinn Lee, Yu-Hsiang Kuan.

BACKGROUND: Manganese (Mn) is an essential trace element involved in multiple physiological processes. However, excessive Mn exposure is well known to induce neurotoxicity and has been extensively studied in neuronal and glial models. In contrast, the effects of manganese nitrate (Mn(NO₃)₂) on innate immune cells, particularly macrophages, remain poorly understood. Given the critical role of macrophages in immune regulation and inflammation, this study investigated the cytotoxic, genotoxic, and apoptotic effects of Mn(NO₃)₂ in RAW264.7 macrophages, with emphasis on oxidative stress, mitochondrial injury, and apoptotic signalling pathways.
METHODS: Macrophages were treated with various concentrations of Mn(NO₃)₂. Cell viability was assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and genotoxic effects were analysed using micronucleus and comet assays. Apoptosis was quantified using sub-G1 DNA analysis, Annexin V/PI staining, and the TUNEL assay. Furthermore, intracellular reactive oxygen species (ROS) generation, mitochondrial membrane potential, caspase activities, and apoptosis-related protein (BCL2, BAD, Fas, and TNFR1) expression were evaluated.
FINDINGS: Mn(NO₃)₂ exposure was associated with concentration-dependent reductions in cell viability, along with increases in micronucleus formation, DNA strand breaks, and nuclear fragmentation. Elevated ROS generation and mitochondrial depolarisation levels were also observed. Moreover, BCL2 downregulation, BAD upregulation, and caspase-3, caspase-8, and caspase-9 activation were observed. Fas and TNFR1 upregulation confirmed the involvement of both intrinsic and extrinsic apoptotic pathways.
CONCLUSION: In conclusion, the findings demonstrate that Mn(NO₃)₂ induces cytotoxicity, genotoxicity, and apoptosis in RAW264.7 macrophages through ROS-mediated mitochondrial dysfunction. Mn(NO₃)₂ activates both intrinsic and extrinsic apoptotic pathways, as evidenced by caspase-3/caspase-9 and caspase-8 activation along with BCL2 downregulation, BAD upregulation, and Fas and TNFR1 expression alterations. These findings provide new mechanistic insights into Mn-induced immunotoxicity.

Keywords: Apoptosis; Cytotoxicity; Genotoxicity; Macrophage; Manganese; ROS

DOI: https://doi.org/10.1016/j.jtemb.2026.127852