Nutrition impact on ILC3 maintenance and function centers on a cell-intrinsic CD71-iron axis.

Iron metabolism is pivotal for cell fitness in the mammalian host; however, its role in group 3 innate lymphoid cells (ILC3s) is unknown. Here we show that transferrin receptor CD71 (encoded by Tfrc)-mediated iron metabolism cell-intrinsically controls ILC3 proliferation and host protection against Citrobacter rodentium infection and metabolically affects mitochondrial respiration by switching of oxidative phosphorylation toward glycolysis. Iron deprivation or Tfrc ablation in ILC3s reduces the expression and/or activity of the aryl hydrocarbon receptor (Ahr), a key ILC3 regulator. Genetic ablation or activation of Ahr in ILC3s leads to CD71 upregulation or downregulation, respectively, suggesting Ahr-mediated suppression of CD71. Mechanistically, Ahr directly binds to the Tfrc promoter to inhibit transcription. Iron overload partially restores the defective ILC3 compartment in the small intestine of Ahr-deficient mice, consistent with the compensatory upregulation of CD71. These data collectively demonstrate an under-appreciated role of the Ahr-CD71-iron axis in the regulation of ILC3 maintenance and function.

'Silent' flagellin drives immunotolerance to commensal bacteria.

Distinguishing between commensal and pathogenic bacteria to generate appropriate responses (tolerance vs. immunogenicity) is a key decision that the human immune system must make to maintain homeostasis. Recently, Clasen and colleagues reported a distinct allosteric interaction between bacterial flagellin and host Toll-like receptor 5 (TLR5), which may shed light on these differences.

The ion-imprinted oyster shell material for targeted removal of Cd(II) from aqueous solution.

In order to realize the sustainable utilization of waste oyster shell and develop a targeted removal technology for cadmium. A novel ion-imprinted oyster shell material (IIOS) was prepared by surface imprinting technique. The prepared samples were characterized by scanning electron microscope, Fourier infrared spectrometer, X-ray diffractometer, thermogravimetric analysis and N2 adsorption-desorption. The adsorption performances of IIOS for Cd(II) from aqueous solution were studied by the single factor sequential batch, kinetics, isotherms, selectivity and recycling experiments. The characterization researches showed that IIOS was successfully prepared. The adsorption experiments indicated that the adsorption process reached equilibrium within 240 min; the maximum adsorption capacity was up to 69.1 mg g-1 with the initial Cd(II) concentration of 75 mg L-1 at pH 5; the adsorption process fitted well to the pseudo-second-order model and the Langmuir isotherm model, which revealed the chemisorption characteristic of Cd(II). Moreover, IIOS exhibited a good targeted adsorption of Cd(II) in several binary competition systems owing to the present of these imprinted cavities. The recycling experiment showed that the targeted removal ratio of IIOS for Cd(II) remained above 80% after used six times. The results of this study indicated that it is a promising prospect for waste oyster shell used as IIOS to dispose heavy metals in wastewater.

Receptor Usage of a Novel Bat Lineage C Betacoronavirus Reveals Evolution of Middle East Respiratory Syndrome-Related Coronavirus Spike Proteins for Human Dipeptidyl Peptidase 4 Binding.

Although bats are known to harbor Middle East Respiratory Syndrome coronavirus (MERS-CoV)-related viruses, the role of bats in the evolutionary origin and pathway remains obscure. We identified a novel MERS-CoV-related betacoronavirus, Hp-BatCoV HKU25, from Chinese pipistrelle bats. Although it is closely related to MERS-CoV in most genome regions, its spike protein occupies a phylogenetic position between that of Ty-BatCoV HKU4 and Pi-BatCoV HKU5. Because Ty-BatCoV HKU4 but not Pi-BatCoV HKU5 can use the MERS-CoV receptor human dipeptidyl peptidase 4 (hDPP4) for cell entry, we tested the ability of Hp-BatCoV HKU25 to bind and use hDPP4. The HKU25-receptor binding domain (RBD) can bind to hDPP4 protein and hDPP4-expressing cells, but it does so with lower efficiency than that of MERS-RBD. Pseudovirus assays showed that HKU25-spike can use hDPP4 for entry to hDPP4-expressing cells, although with lower efficiency than that of MERS-spike and HKU4-spike. Our findings support a bat origin of MERS-CoV and suggest that bat CoV spike proteins may have evolved in a stepwise manner for binding to hDPP4.

Comprehensive exploration of the enzymes catalysing oxygen-involved reactions and COGs relevant to bacterial oxygen utilization.

To better understand the mechanisms of bacterial adaptation in oxygen environments, we explored the aerobic living-associated genes in bacteria by comparing Clusters of Orthologous Groups of proteins' (COGs) frequencies and gene expression analyses and 38 COGs were detected at significantly higher frequencies (p-value less than 1e-6) in aerobes than in anaerobes. Differential expression analyses between two conditions further narrowed the prediction to 27 aerobe-specific COGs. Then, we annotated the enzymes associated with these COGs. Literature review revealed that 14 COGs contained enzymes catalysing oxygen-involved reactions or products involved in aerobic pathways, suggesting their important roles for survival in aerobic environments. Additionally, protein-protein interaction analyses and step length comparisons of metabolic networks suggested that the other 13 COGs may function relevantly with the 14 enzymes-corresponding COGs, indicating that these genes may be highly associated with oxygen utilization. Phylogenetic and evolutionary analyses showed that the 27 COGs did not have similar trees, and all suffered purifying selection pressures. The divergent times of species containing or lacking aerobic COGs validated that the appearing time of oxygen-utilizing gene was approximately 2.80 Gyr ago. In addition to help better understand oxygen adaption, our method may be extended to identify genes relevant to other living environments.

Immunotherapy Targeting Adenosine Synthase A Decreases Severity of Staphylococcus aureus Infection in Mouse Model.

Staphylococcusaureus is a severe pathogen found in the community and in hospitals. Most notably, methicillin-resistant S. aureus (MRSA) is resistant to almost all antibiotics, which is a growing public health concern. The emergence of drug-resistant strains has prompted the search for alternative treatments such as immunotherapeutic approaches. Previous research showed that S. aureus exploit the immunomodulatory attributes of adenosine to escape host immunity. In this study, we investigated adenosine synthase A (AdsA), an S. aureus cell wall-anchored enzyme as possible targets for immunotherapy. Mice vaccinated with aluminum hydroxide-formulated recombinant AdsA (rAdsA) induced high-titer anti-AdsA antibodies, thereby providing consistent protection in 3 mouse infection models when challenged with 2 S. aureus strains. The importance of anti-AdsA antibody in protection was demonstrated by passive transfer experiments. Moreover, AdsA-specific antisera promote killing S. aureus by immune cells. Altogether, our data demonstrate that the AdsA is a promising target for vaccines and therapeutics development to alleviate severe S. aureus diseases.

Laribacter hongkongensis anaerobic adaptation mediated by arginine metabolism is controlled by the cooperation of FNR and ArgR.

Laribacter hongkongensis is a fish-borne pathogen associated with invasive infections and gastroenteritis. Its adaptive mechanisms to oxygen-limiting conditions in various environmental niches remain unclear. In this study, we compared the transcriptional profiles of L. hongkongensis under aerobic and anaerobic conditions using RNA-sequencing. Expression of genes involved in arginine metabolism significantly increased under anoxic conditions. Arginine was exploited as the sole energy source in L. hongkongensis for anaerobic respiration via the arginine catabolism pathway: specifically via the arginine deiminase (ADI) pathway. A transcriptional regulator FNR was identified to coordinate anaerobic metabolism by tightly regulating the expression of arginine metabolism genes. FNR executed its regulatory function by binding to FNR boxes in arc operons promoters. Survival of isogenic fnr mutant in macrophages decreased significantly when compared with wild-type; and expression level of fnr increased 8 h post-infection. Remarkably, FNR directly interacted with ArgR, another regulator that influences the biological fitness and intracellular survival of L. hongkongensis by regulating arginine metabolism genes. Our results demonstrated that FNR and ArgR work in coordination to respond to oxygen changes in both extracellular and intracellular environments, by finely regulating the ADI pathway and arginine anabolism pathways, thereby optimizing bacterial fitness in various environmental niches.

Identification and analysis of genomic islands in Burkholderia cenocepacia AU 1054 with emphasis on pathogenicity islands.

BACKGROUND: Genomic islands (GIs) are genomic regions that reveal evidence of horizontal DNA transfer. They can code for many functions and may augment a bacterium's adaptation to its host or environment. GIs have been identified in strain J2315 of Burkholderia cenocepacia, whereas in strain AU 1054 there has been no published works on such regions according to our text mining and keyword search in Medline. RESULTS: In this study, we identified 21 GIs in AU 1054 by combining two computational tools. Feature analyses suggested that the predictions are highly reliable and hence illustrated the advantage of joint predictions by two independent methods. Based on putative virulence factors, four GIs were further identified as pathogenicity islands (PAIs). Through experiments of gene deletion mutants in live bacteria, two putative PAIs were confirmed, and the virulence factors involved were identified as lipA and copR. The importance of the genes lipA (from PAI 1) and copR (from PAI 2) for bacterial invasion and replication indicates that they are required for the invasive properties of B. cenocepacia and may function as virulence determinants for bacterial pathogenesis and host infection. CONCLUSIONS: This approach of in silico prediction of GIs and subsequent identification of potential virulence factors in the putative island regions with final validation using wet experiments could be used as an effective strategy to rapidly discover novel virulence factors in other bacterial species and strains.

Gordonia hongkongensis sp. nov., isolated from blood culture and peritoneal dialysis effluent of patients in Hong Kong.

Two bacterial strains, HKU50T and HKU46, were isolated in Hong Kong from the blood culture and the peritoneal dialysis effluent of two patients. The strains are Gram-stain-positive, acid-fast, non-motile, non-sporulating bacilli. They grow on Columbia agar with 5 % defibrinated sheep blood and brain-heart infusion agar under aerobic conditions with 5 % CO2 at 37 °C as pink-to-orange, non-haemolytic colonies. The strains are catalase-positive and oxidase-negative, and have a unique biochemical profile distinguishable from other closely related species. DNA sequencing revealed that both isolates possessed multiple intra-genomic 16S rRNA gene copies (99.8-100 % sequence identities to Gordonia lacunae NRRL B-24551T and Gordonia terrae NRRL B-16283T). Phylogenetic analysis of the 16S rRNA gene, secA1 and gyrB showed that the two isolates formed a distinct branch within the genus Gordonia and were most closely related to G. lacunae and G. terrae. DNA-DNA hybridization demonstrated ≤53.7 % and ≤49.4 % DNA relatedness between the two isolates and G. lacunae, and between the two isolates and G. terrae, respectively. Hierarchical cluster analysis of MALDI-TOF MS main spectrum profiles showed that strains HKU50T and HKU46 were closely related to each other, but were distinct from G. lacunae, G. terrae, or any other species of the genus Gordonia in the Bruker database. The chemotaxonomic traits of the two strains were highly similar, and the major fatty acids were summed feature 4 (iso-C15 : 0 2-OH/C16 : 1trans-9), C16 : 0, C18 : 1cis-9, and tuberculostearic acid. A novel species named Gordonia hongkongensis sp. nov. is proposed to accommodate strains HKU50T and HKU46, with strain HKU50T (=CCOS 955T=CIP 111027T=NBRC 111234T=NCCP 16210T) as the type strain.

Arginine Metabolism in Bacterial Pathogenesis and Cancer Therapy.

Antibacterial resistance to infectious diseases is a significant global concern for health care organizations; along with aging populations and increasing cancer rates, it represents a great burden for government healthcare systems. Therefore, the development of therapies against bacterial infection and cancer is an important strategy for healthcare research. Pathogenic bacteria and cancer have developed a broad range of sophisticated strategies to survive or propagate inside a host and cause infection or spread disease. Bacteria can employ their own metabolism pathways to obtain nutrients from the host cells in order to survive. Similarly, cancer cells can dysregulate normal human cell metabolic pathways so that they can grow and spread. One common feature of the adaption and disruption of metabolic pathways observed in bacterial and cancer cell growth is amino acid pathways; these have recently been targeted as a novel approach to manage bacterial infections and cancer therapy. In particular, arginine metabolism has been illustrated to be important not only for bacterial pathogenesis but also for cancer therapy. Therefore, greater insights into arginine metabolism of pathogenic bacteria and cancer cells would provide possible targets for controlling of bacterial infection and cancer treatment. This review will summarize the recent progress on the relationship of arginine metabolism with bacterial pathogenesis and cancer therapy, with a particular focus on arginase and arginine deiminase pathways of arginine catabolism.

Molecular characterization of arginine deiminase pathway in Laribacter hongkongensis and unique regulation of arginine catabolism and anabolism by multiple environmental stresses.

The betaproteobacterium Laribacter hongkongensis is associated with invasive bacteremic infections and gastroenteritis. Its genome contains two adjacent arc gene cassettes (arc1 and arc2) under independent transcriptional control, which are essential for acid resistance. Laribacter hongkongensis also encodes duplicate copies of the argA and argB genes from the arginine biosynthesis pathway. We show that arginine enhances the transcription of arcA2 but suppresses arcA1 expression. We demonstrate that ArgR acts as a transcriptional regulator of the two arc operons through binding to ARG operator sites (ARG boxes). Upon temperature shift from 20°C to 37°C, arcA1 transcription is upregulated while arcA2, argA2, argB2 and argG are downregulated. The transcription of arcA1 and arcA2 are augmented under anaerobic and acidic conditions. The transcription levels of argA1, argA2, argB1, argB2 and argG are significantly increased under anaerobic and acidic conditions but are repressed by the addition of arginine. Deletion of argR significantly decreases bacterial survival in macrophages, while expression of both arc operons, argR and all five of the anabolic arg genes increases 8 h post-infection. Our results show that arginine catabolism in L. hongkongensis is finely regulated by controlling the transcription of two arc operons, whereas arginine anabolism is controlled by two copies of argA and argB.

The Hybrid Pre-CTXΦ-RS1 Prophage Genome and Its Regulatory Function in Environmental Vibrio cholerae O1 Strains.

The cholera toxin genes of Vibrio cholerae are encoded by CTXΦ, a lysogenic bacteriophage. Infection with this phage plays a determinant role in toxigenicity conversion and the emergence of new clones of pathogenic V. cholerae. Multiple phage alleles, defined by sequence types of the repressor gene rstR, have been found, showing the divergence of phage genomes. Pre-CTXΦ, which is characterized by the absence of toxin genes, is predicted to be the precursor of CTXΦ. We have found a new pre-CTXΦ prophage genome (named pre-CTXZJΦ for its novel rstR allele) in nontoxigenic V. cholerae O1 isolates that were obtained during surveillance of the estuary water of the Zhujiang River. A novel hybrid genome of the helper phage RS1 was identified in an environmental strain carrying pre-CTXZJΦ in this study. The chromosomal integration and genomic arrangement of pre-CTXZJΦ and RS1 were determined. The RS2 of pre-CTXZJΦ was shown to have a function in replication, but it seemed to have lost its ability to integrate. The RstR of pre-CTXZJΦ exerted the highest repression of its own rstA promoter compared to other RstRs, suggesting rstR-specific phage superinfection immunity and potential coinfection with other pre-CTXΦ/CTXΦ alleles. The environmental strain carrying pre-CTXZJΦ could still be infected by CTXETΦ, the most common phage allele in the strains of the seventh cholera pandemic, suggesting that this nontoxigenic clone could potentially undergo toxigenicity conversion by CTXΦ infection and become a new toxigenic clone despite already containing the pre-CTXΦ prophage.

Arginine deiminase pathway is far more important than urease for acid resistance and intracellular survival in Laribacter hongkongensis: a possible result of arc gene cassette duplication.

BACKGROUND: Laribacter hongkongensis is a Gram-negative, urease-positive bacillus associated with invasive bacteremic infections in liver cirrhosis patients and fish-borne community-acquired gastroenteritis and traveler's diarrhea. Its mechanisms of adaptation to various environmental niches and host defense evasion are largely unknown. During the process of analyzing the L. hongkongensis genome, a complete urease cassette and two adjacent arc gene cassettes were found. We hypothesize that the urease cassette and/or the arc gene cassettes are important for L. hongkongensis to survive in acidic environment and macrophages. In this study, we tested this hypothesis by constructing single, double and triple non-polar deletion mutants of the urease and two arc gene cassettes of L. hongkongensis using the conjugation-mediated gene deletion system and examining their effects in acidic environment in vitro, in macrophages and in a mouse model. RESULTS: HLHK9∆ureA, HLHK9∆ureC, HLHK9∆ureD and HLHK9∆ureE all exhibited no urease activity. HLHK9∆arcA1 and HLHK9∆arcA2 both exhibited arginine deiminase (ADI) activities, but HLHK9∆arcA1/arcA2 double deletion mutant exhibited no ADI activity. At pH 2 and 3, survival of HLHK9∆arcA1/arcA2 and HLHK9∆ureA/arcA1/arcA2 were markedly decreased (p < 0.001) but that of HLHK9∆ureA was slightly decreased (p < 0.05), compared to wild type L. hongkongensis HLHK9. Survival of HLHK9∆ureA/arcA1/arcA2 and HLHK9∆arcA1/arcA2 in macrophages were also markedly decreased (p < 0.001 and p < 0.01 respectively) but that of HLHK9∆ureA was slightly decreased (p < 0.05), compared to HLHK9, although expression of arcA1, arcA2 and ureA genes were all upregulated. Using a mouse model, HLHK9∆ureA exhibited similar survival compared to HLHK9 after passing through the murine stomach, but survival of HLHK9∆arcA1/arcA2 and HLHK9∆ureA/arcA1/arcA2 were markedly reduced (p < 0.01). CONCLUSIONS: In contrast to other important gastrointestinal tract pathogens, ADI pathway is far more important than urease for acid resistance and intracellular survival in L. hongkongensis. The gene duplication of the arc gene cassettes could be a result of their functional importance in L. hongkongensis.

Mussel byssus-inspired dual-functionalization of zirconia dental implants for improved bone integration.

Zirconia faces challenges in dental implant applications due to its inherent biological inertness, which compromises osseointegration, a critical factor for the long-term success of implants that rely heavily on specific cell adhesion and enhanced osteogenic activity. Here, we fabricated a dual-functional coating that incorporates strontium ions, aimed at enhancing osteogenic activity, along with an integrin-targeting sequence to improve cell adhesion by mussel byssus-inspired surface chemistry. The results indicated that although the integrin-targeting sequence at the interface solely enhances osteoblast adhesion without directly increasing osteogenic activity, its synergistic interaction with the continuously released strontium ions from the coating, as compared to the release of strontium ions alone, significantly enhances the overall osteogenic effect. More importantly, compared to traditional polydopamine surface chemistry, the coating surface is enriched with amino groups capable of undergoing various chemical reactions and exhibits enhanced stability and aesthetic appeal. Therefore, the synergistic interplay between strontium and the functionally customizable surface offers considerable potential to improve the success of zirconia implantation.

Mycolyltransferase is important for biofilm formation and pathogenesis of Tsukamurella keratitis.

AbstractTsukamurella, a group of multi-drug resistant, Gram-positive, aerobic and partially acid-fast bacteria, are emerging causes of bacterial conjunctivitis and keratitis. However, the pathogenesis of Tsukamurella keratitis is largely unknown. To address this, we used New Zealand White rabbits to develop the first eye infection model and conducted in vitro tests to study the pathogenesis mechanisms of Tsukamurella. There is increasing evidence that biofilms play a significant role in ocular infections, leading us to hypothesize that biofilm formation is crucial for effective Tsukamurella infection. In order to look for potential candidate genes which are important in biofilm formation and Tsukamurella keratitis. We performed genome sequencing of two ocular isolates, T. pulmonis-PW1004 and T. tyrosinosolvens-PW899, to identify potential virulence factors. Through in vitro and in vivo studies, we characterized their biological roles in mediating Tsukamurella keratitis. Our findings confirmed that Tsukamurella is an ocular pathogen by fulfilling the Koch's postulates, and using genome sequence data, we identified tmytC, encoding a mycolyltransferase, as a crucial gene in biofilm formation and causing Tsukamurella keratitis in the rabbit model. This is the first report demonstrating the novel role of mycolyltransferase in causing ocular infections. Overall, our findings contribute to a better understanding of Tsukamurella pathogenesis and provide a potential target for treatment. Specific inhibitors targeting TmytC could serve as an effective treatment option for Tsukamurella infections.

The aryl hydrocarbon receptor cell intrinsically promotes resident memory CD8+ T cell differentiation and function.

The Aryl hydrocarbon receptor (Ahr) regulates the differentiation and function of CD4+ T cells; however, its cell-intrinsic role in CD8+ T cells remains elusive. Herein we show that Ahr acts as a promoter of resident memory CD8+ T cell (TRM) differentiation and function. Genetic ablation of Ahr in mouse CD8+ T cells leads to increased CD127-KLRG1+ short-lived effector cells and CD44+CD62L+ T central memory cells but reduced granzyme-B-producing CD69+CD103+ TRM cells. Genome-wide analyses reveal that Ahr suppresses the circulating while promoting the resident memory core gene program. A tumor resident polyfunctional CD8+ T cell population, revealed by single-cell RNA-seq, is diminished upon Ahr deletion, compromising anti-tumor immunity. Human intestinal intraepithelial CD8+ T cells also highly express AHR that regulates in vitro TRM differentiation and granzyme B production. Collectively, these data suggest that Ahr is an important cell-intrinsic factor for CD8+ T cell immunity.

Group 3 innate lymphoid cell pyroptosis represents a host defence mechanism against Salmonella infection.

Group 3 innate lymphoid cells (ILC3s) produce interleukin (IL)-22 and coordinate with other cells in the gut to mount productive host immunity against bacterial infection. However, the role of ILC3s in Salmonella enterica serovar Typhimurium (S. Typhimurium) infection, which causes foodborne enteritis in humans, remains elusive. Here we show that S. Typhimurium exploits ILC3-produced IL-22 to promote its infection in mice. Specifically, S. Typhimurium secretes flagellin through activation of the TLR5-MyD88-IL-23 signalling pathway in antigen presenting cells (APCs) to selectively enhance IL-22 production by ILC3s, but not T cells. Deletion of ILC3s but not T cells in mice leads to better control of S. Typhimurium infection. We also show that S. Typhimurium can directly invade ILC3s and cause caspase-1-mediated ILC3 pyroptosis independently of flagellin. Genetic ablation of Casp1 in mice leads to increased ILC3 survival and IL-22 production, and enhanced S. Typhimurium infection. Collectively, our data suggest a key host defence mechanism against S. Typhimurium infection via induction of ILC3 death to limit intracellular bacteria and reduce IL-22 production.

Glucose promotes regulatory T cell differentiation to maintain intestinal homeostasis.

Glucose, the critical energy source in the human body, is considered a potential risk factor in various autoimmune diseases when consumed in high amounts. However, the roles of glucose at moderate doses in the regulation of autoimmune inflammatory diseases and CD4+ T cell responses are controversial. Here, we show that while glucose at a high concentration (20% w/v) promotes intestinal inflammation, it suppresses colitis at a moderate dose (6% w/v), which increases the proportion of intestinal regulatory T (Treg) cells but does not affect effector CD4+ T cells. Glucose treatment promotes Treg cell differentiation but it does not affect Treg stability. Feeding glucose alters gut microbiota compositions, which are not involved in the glucose induction of Treg cells. Glucose promotes aryl hydrocarbon receptor (AhR) activation to induce Treg polarization. These findings reveal the different effects of glucose at different doses on the intestinal immune response.

Effect of bevacizumab combined with first-line chemotherapy on metastatic colorectal cancer.

BACKGROUND: To investigate the effect of bevacizumab combined with chemotherapy on the metastasis response rate, survival time of patients with metastatic colorectal cancer (mCRC), the incidence of complications, and the efficacy and safety of bevacizumab for mCRC were recorded. METHODS: Of 87 patients with mCRC, 42 were treated without bevacizumab (control group, CG) and 45 were treated with bevacizumab (observation group, OG). Baseline characteristics, resectability of metastases, quality of life (QOL), and short- and long-term curative effect were compared to evaluate the safety of the treatment plan in the two groups. RESULTS: After 6 months of treatment, the overall response rate (ORR) and disease control rate (DCR) of the CG were 28.57% and 59.52%, respectively, whereas the ORR and DCR of the OG were notably higher at 48.89% and 86.67%, respectively (P < 0.05). The resectability rate of metastases in the OG increased from 8.89% pretreatment to 40.00% posttreatment, whereas that of metastases in the CG increased from 11.90% pretreatment to 23.81% posttreatment. In the OG, the median survival time was 23.0 (range, 19.7-26.3) months, and the median progression-free survival (PFS) was 11.0 (range, 9.4-12.6) months. These results were all superior to those of the CG, which were 14.0 (range, 12.6-15.4) months and 6.0 (range, 4.9-7.2) months, respectively. CONCLUSION: Bevacizumab combined with first-line chemotherapy can significantly prolong survival and PFS, improve QOL, increase the resectability rate of metastases, and improve survival outcomes of patients with mCRC.

Mitochondrial transcription factor A in RORγt+ lymphocytes regulate small intestine homeostasis and metabolism.

RORγt+ lymphocytes, including interleukin 17 (IL-17)-producing gamma delta T (γδT17) cells, T helper 17 (Th17) cells, and group 3 innate lymphoid cells (ILC3s), are important immune regulators. Compared to Th17 cells and ILC3s, γδT17 cell metabolism and its role in tissue homeostasis remains poorly understood. Here, we report that the tissue milieu shapes splenic and intestinal γδT17 cell gene signatures. Conditional deletion of mitochondrial transcription factor A (Tfam) in RORγt+ lymphocytes significantly affects systemic γδT17 cell maintenance and reduces ILC3s without affecting Th17 cells in the gut. In vivo deletion of Tfam in RORγt+ lymphocytes, especially in γδT17 cells, results in small intestine tissue remodeling and increases small intestine length by enhancing the type 2 immune responses in mice. Moreover, these mice show dysregulation of the small intestine transcriptome and metabolism with less body weight but enhanced anti-helminth immunity. IL-22, a cytokine produced by RORγt+ lymphocytes inhibits IL-13-induced tuft cell differentiation in vitro, and suppresses the tuft cell-type 2 immune circuit and small intestine lengthening in vivo, highlighting its key role in gut tissue remodeling.