Summary Host microbial cross-talk is essential to maintain intestinal homeostasis. However, maladaptation of this response through microbial dysbiosis or defective host defense toward invasive intestinal bacteria can result in chronic inflammation. We have shown that macrophages differentiated in the presence of the bacterial metabolite butyrate display enhanced antimicrobial activity. Butyrate-induced antimicrobial activity was associated with a shift in macrophage metabolism, a reduction in mTOR kinase activity, increased LC3-associated host defense and anti-microbial peptide production in the absence of an increased inflammatory cytokine response. Butyrate drove this monocyte to macrophage differentiation program through histone deacetylase 3 (HDAC3) inhibition. Administration of butyrate induced antimicrobial activity in intestinal macrophages in vivo and increased resistance to enteropathogens. Our data suggest that (1) increased intestinal butyrate might represent a strategy to bolster host defense without tissue damaging inflammation and (2) that pharmacological HDAC3 inhibition might drive selective macrophage functions toward antimicrobial host defense.

Neutralization of IL-22 production from colonic innate lymphoid cells reduces dysplasia in bacterial-induced colon cancer by reducing proliferation of epithelial cells via reduced activation of Stat3.

Cytokine networks are crucial aspects of tumour immunology, particularly for colorectal cancer (CRC), in which inflammation and antitumour immunity are key determinants of disease progression. In this Review, we highlight new insights into the functions of well-known cytokines in CRC, describe recently discovered roles for a growing number of novel players, and emphasize the complexity and therapeutic implications of the cytokine milieu. We also discuss how cancer mutations and epigenetic adaptations influence the oncogenic potential of cytokines, a relatively unexplored area that could yield crucial insights into tumour immunology and facilitate the effective application of cytokine-modulatory therapies for CRC.

SummaryThe role of intestinal eosinophils in immune homeostasis is enigmatic and the molecular signals that drive them from protective to tissue damaging are unknown. Most commonly associated with Th2 cell-mediated diseases, we describe a role for eosinophils as crucial effectors of the interleukin-23 (IL-23)-granulocyte macrophage colony-stimulating factor (GM-CSF) axis in colitis. Chronic intestinal inflammation was characterized by increased bone marrow eosinopoiesis and accumulation of activated intestinal eosinophils. IL-5 blockade or eosinophil depletion ameliorated colitis, implicating eosinophils in disease pathogenesis. GM-CSF was a potent activator of eosinophil effector functions and intestinal accumulation, and GM-CSF blockade inhibited chronic colitis. By contrast neutrophil accumulation was GM-CSF independent and dispensable for colitis. In addition to TNF secretion, release of eosinophil peroxidase promoted colitis identifying direct tissue-toxic mechanisms. Thus, eosinophils are key perpetrators of chronic inflammation and tissue damage in IL-23-mediated immune diseases and it suggests the GM-CSF-eosinophil axis as an attractive therapeutic target.

Aim Decreased cancer incidence and reported changes to clinical management indicate that the COVID‐19 pandemic has delayed cancer diagnosis and treatment. This study aimed to develop and apply a flexible model to estimate the impact of delayed diagnosis and treatment on survival outcomes and healthcare costs based on a shift in the disease stage at treatment initiation. Methods A model was developed and made publicly available to estimate population‐level health economic outcomes by extrapolating and weighing stage‐specific outcomes by the distribution of stages at treatment initiation. It was applied to estimate the impact of 3‐ and 6‐month delays based on Australian data for stage I breast cancer, colorectal cancer, and lung cancer patients, and for T1 melanoma. Two approaches were explored to estimate stage shifts following a delay: (a) based on the relation between time to treatment initiation and overall survival (breast, colorectal, and lung cancer), and (b) based on the tumor growth rate (melanoma). Results Using a conservative once‐off 3‐month delay and considering only shifts from stage I/T1 to stage II/T2, 88 excess deaths and $12 million excess healthcare costs were predicted in Australia over 5 years for all patients diagnosed in 2020. For a 6‐month delay, excess mortality and healthcare costs were 349 deaths and $46 million over 5 years. Conclusions The health and economic impacts of delays in treatment initiation cause an imminent policy concern. More accurate individual patient data on shifts in stage of disease during and after the COVID‐19 pandemic are critical for further analyses.

SummaryInteractions between the host and its microbiota are of mutual benefit and promote health. Complex molecular pathways underlie this dialog, but the identity of microbe-derived molecules that mediate the mutualistic state remains elusive. Helicobacter hepaticus is a member of the mouse intestinal microbiota that is tolerated by the host. In the absence of an intact IL-10 signaling, H. hepaticus induces an IL-23-driven inflammatory response in the intestine. Here we investigate the interactions between H. hepaticus and host immune cells that may promote mutualism, and the microbe-derived molecule(s) involved. Our results show that H. hepaticus triggers early IL-10 induction in intestinal macrophages and produces a large soluble polysaccharide that activates a specific MSK/CREB-dependent anti-inflammatory and repair gene signature via the receptor TLR2. These data identify a host-bacterial interaction that promotes mutualistic mechanisms at the intestinal interface. Further understanding of this pathway may provide novel prevention and treatment strategies for inflammatory bowel disease.

Regulation of the programming of tumour-associated macrophages (TAMs) controls tumour growth and anti-tumour immunity. We examined the role of FGF2 in that regulation. Tumours in mice genetically deficient in low-molecular weight FGF2 (FGF2 LMW) regress dependent on T cells. Yet, TAMS not T cells express FGF receptors. Bone marrow derived-macrophages from Fgf2 LMW−/− mice co-injected with cancer cells reduce tumour growth and express more inflammatory cytokines. FGF2 is induced in the tumour microenvironment following fractionated radiation in murine tumours consistent with clinical reports. Combination treatment of in vivo tumours with fractionated radiation and a blocking antibody to FGF2 prolongs tumour growth delay, increases long-term survival and leads to a higher iNOS + /CD206 + TAM ratio compared to irradiation alone. These studies show for the first time that FGF2 affects macrophage programming and is a critical regulator of immunity in the tumour microenvironment.

Inflammatory bowel disease (IBD) are heterogenous disorders of the gastrointestinal tract caused by a spectrum of genetic and environmental factors. In mice, overlapping regions of chromosome 3 have been associated with susceptibility to IBD-like pathology, including a locus called Hiccs. However, the specific gene that controls disease susceptibility remains unknown. Here we identify a Hiccs locus gene, Alpk1 (encoding alpha kinase 1), as a potent regulator of intestinal inflammation. In response to infection with the commensal pathobiont Helicobacter hepaticus (Hh), Alpk1-deficient mice display exacerbated interleukin (IL)-12/IL-23 dependent colitis characterized by an enhanced Th1/interferon(IFN)-γ response. Alpk1 controls intestinal immunity via the hematopoietic system and is highly expressed by mononuclear phagocytes. In response to Hh, Alpk1−/− macrophages produce abnormally high amounts of IL-12, but not IL-23. This study demonstrates that Alpk1 promotes intestinal homoeostasis by regulating the balance of type 1/type 17 immunity following microbial challenge.