Molecular Mediators Research Articles

Forkhead box O1 transcription factor; a therapeutic target for diabetic cardiomyopathy.

Cardiovascular disease including diabetic cardiomyopathy (DbCM) represents the leading cause of death in people with diabetes. DbCM is defined as ventricular dysfunction in the absence of underlying vascular diseases and/or hypertension. The known molecular mediators of DbCM are multifactorial, including but not limited to insulin resistance, altered energy metabolism, lipotoxicity, endothelial dysfunction, oxidative stress, apoptosis, and autophagy. FoxO1, a prominent member of forkhead box O transcription factors, is involved in regulating various cellular processes in different tissues. Altered FoxO1 expression and activity have been associated with cardiovascular diseases in diabetic subjects. Herein we provide an overview of the role of FoxO1 in various molecular mediators related to DbCM, such as altered energy metabolism, lipotoxicity, oxidative stress, and cell death. Furthermore, we provide valuable insights into its therapeutic potential by targeting these perturbations to alleviate cardiomyopathy in settings of type 1 and type 2 diabetes.

Proteomics identifies potential immunological drivers of postinfection brain atrophy and cognitive decline

Infections have been associated with the incidence of Alzheimer disease and related dementias, but the mechanisms responsible for these associations remain unclear. Using a multicohort approach, we found that influenza, viral, respiratory, and skin and subcutaneous infections were associated with increased long-term dementia risk. These infections were also associated with region-specific brain volume loss, most commonly in the temporal lobe. We identified 260 out of 942 immunologically relevant proteins in plasma that were differentially expressed in individuals with an infection history. Of the infection-related proteins, 35 predicted volumetric changes in brain regions vulnerable to infection-specific atrophy. Several of these proteins, including PIK3CG, PACSIN2, and PRKCB, were related to cognitive decline and plasma biomarkers of dementia (Aβ42/40, GFAP, NfL, pTau-181). Genetic variants that influenced expression of immunologically relevant infection-related proteins, including ITGB6 and TLR5, predicted brain volume loss. Our findings support the role of infections in dementia risk and identify molecular mediators by which infections may contribute to neurodegeneration.

Gal-1-mediated cytochrome p450 activation promotes fibroblast into myofibroblast differentiation in pulmonary fibrosis

Pulmonary fibrosis (PF) results from excessive extracellular matrix (ECM) deposition and tissue remodeling after activation of fibroblasts into myofibroblasts. Abnormally deposited fibrotic ECM, in turn, promotes fibroblast activation and accelerates loss of lung structure and function. However, the molecular mediators and exact mechanisms by which fibrotic ECM promotes fibroblast activation are unclear. In a bleomycin-induced PF mouse model, we found Galectin-1 (Gal-1) expression was significantly increased in lung tissue, and overexpression of Gal-1 plasmid-transfected fibroblasts were activated into myofibroblasts. Using the decellularization technique to prepare decellularized fibrotic ECM and constructing a 3D in vitro co-culture system with fibroblasts, we found that decellularized fibrotic ECM induced a high expression of Gal-1 and promoted the activation of fibroblasts into myofibroblasts. Therefore, Gal-1 has been identified as a pivotal mediator in PF. Further, we found that decellularized fibrotic ECM delivered mechanical signals to cells through the Gal-1-mediated FAK-Src-P130Cas mechanical signalling pathway, while the CYP450 enzymes (mainly involved in CYP1A1, CYP24A1, CYP3A4, and CYP2D6 isoforms) acted as a chemical signalling pathway to receive mechanical signals transmitted from upstream Gal-1, thereby promoting fibroblast activation. The Gal-1 inhibitor OTX008 or the CYP1A1 inhibitor 7-Hydroxyflavone prevented PF in mice and inhibited the role of fibrotic ECM in promoting fibroblast activation into myofibroblasts, preventing PF. These results reveal novel molecular mechanisms of lung fibrosis formation and identify Gal-1 and its downstream CYP1A1 as potential therapeutic targets for PF disease treatmnts.

Gut-muscle communication links FGF19 levels to the loss of lean muscle mass following rapid weight loss

ObjectiveOptimal weight loss involves decreasing adipose tissue while preserving lean muscle mass. Identifying molecular mediators that preserve lean muscle mass is therefore a clinically important goal. We have shown that circulating, postprandial FGF19 levels are lower in patients with obesity and decrease further with comorbidities such as type 2 diabetes and MASLD. Preclinical studies have shown that FGF15 (mouse ortholog of human FGF19) is necessary to protect against lean muscle mass loss following metabolic surgery-induced weight loss in a mouse model of diet-induced obesity. We evaluated if non-surgical weight loss interventions also lead to increased systemic levels of FGF19 and whether FGF19 levels are predictive of lean muscle mass following rapid weight loss in human subjects with obesity. Research design and methodsWeight loss was induced in 176 subjects with obesity via a very low-energy diet, VLED (800 kcal/d) in the form of total liquid meal replacement for 3-4 months. We measured plasma FGF19 levels at baseline and following VLED-induced weight loss. Multiple linear regression was performed to assess if FGF19 levels were predictive of lean mass at baseline (obesity) and following VLED. ResultsPostprandial levels of FGF19 increased significantly following VLED-weight loss. Multiple linear regression analysis showed that baseline (obesity) FGF19 levels, but not post VLED FGF19 levels, significantly predicted the percent of lean muscle mass after VLED-induced weight loss, while controlling for age, sex, and the baseline percent lean mass. ConclusionThese data identify gut-muscle communication and FGF19 as a potentially important mediator of the preservation of lean muscle mass during rapid weight loss.

A Mouse Model for Conditional Expression of Activated β-Catenin in Epidermal Keratinocytes.

We report the generation and characterization of the K5: CAT bigenic mouse in which the constitutively activated form of β-catenin (ΔN89 β-catenin) is conditionally expressed in cytokeratin-5 (K5) positive epidermal keratinocytes. Following short-term doxycycline intake during the telogen resting phase, the adult K5: CAT bigenic develops enlarged pilosebaceous units that expand deep into the dermis, an expansion usually observed during the anagen growth phase. Prolonged doxycycline treatment results in significant thickening and folding of the K5: CAT epidermis. During this persistent induction period, there is clear evidence of increased keratinocyte proliferation, particularly in the epidermal basal cell layer and the outer root sheath of the hair follicle. This unscheduled increase in cellular proliferation likely explains the decrease in hair density observed in the K5: CAT mouse following persistent doxycycline intake. Numerous hyperplastic endometrioid cysts, which display cornification toward their lumens, are also observed during this treatment period. Remarkably, de-induction of ΔN89 β-catenin expression through doxycycline withdrawal results in a marked reversal of the skin phenotype, suggesting that these morphological changes are dependent on continued signaling by β-catenin and/or its downstream molecular mediators. Joining a small group of mouse models for conditional β-catenin signaling, our K5: CAT mouse model will be particularly useful in identifying those molecular mediators of β-catenin that are responsible for initiating and maintaining these phenotypic responses in the K5: CAT skin. Such studies are predicted to shed more light on β-catenin signaling in epidermal epithelial morphogenesis, hair follicle cycling, and hair growth pathologies.

Prevention and treatment of peri-implant fibrosis by functionally inhibiting skeletal cells expressing the leptin receptor.

The cellular and molecular mediators of peri-implant fibrosis-a most common reason for implant failure and for surgical revision after the replacement of a prosthetic joint-remain unclear. Here we show that peri-implant fibrotic tissue in mice and humans is largely composed of a specific population of skeletal cells expressing the leptin receptor (LEPR) and that these cells are necessary and sufficient to generate and maintain peri-implant fibrotic tissue. In a mouse model of tibial implantation and osseointegration that mimics partial knee arthroplasty, genetic ablation of LEPR+ cells prevented peri-implant fibrosis and the implantation of LEPR+ cells from peri-implant fibrotic tissue was sufficient to induce fibrosis in secondary hosts. Conditional deletion of the adhesion G-protein-coupled receptor F5 (ADGRF5) in LEPR+ cells attenuated peri-implant fibrosis while augmenting peri-implant bone formation, and ADGRF5 inhibition by the intra-articular or systemic administration of neutralizing anti-ADGRF5 in the mice prevented and reversed peri-implant fibrosis. Pharmaceutical agents that inhibit the ADGRF5 pathway in LEPR+ cells may be used to prevent and treat peri-implant fibrosis.

Exercise Reduces Glucose Intolerance, Cardiac Inflammation and Adipose Tissue Dysfunction in Psammomys obesus Exposed to Short Photoperiod and High Energy Diet.

Circadian disruption causes glucose intolerance, cardiac fibrosis, and adipocyte dysfunction in sand rats (Psammomys obesus). Exercise intervention can improve glucose metabolism, insulin sensitivity, adipose tissue function and protect against inflammation. We investigated the influence of exercise on male P. obesus exposed to a short photoperiod (5 h light:19 h dark) and high-energy diet. Exercise reduced glucose intolerance. Exercise reduced cardiac expression of inflammatory marker Ccl2 and Bax:Bcl2 apoptosis ratio. Exercise increased heart:body weight ratio and hypertrophy marker Myh7:Myh6, yet reduced Gata4 expression. No phenotypic changes were observed in perivascular fibrosis and myocyte area. Exercise reduced visceral adipose expression of inflammatory transcription factor Rela, adipogenesis marker Ppard and browning marker Ppargc1a, but visceral adipocyte size was unaffected. Conversely, exercise reduced subcutaneous adipocyte size but did not affect any molecular mediators. Exercise increased ZT7 Bmal1 and Per2 in the suprachiasmatic nucleus and subcutaneous Per2. Our study provides new molecular insights and histological assessments on the effect of exercise on cardiac inflammation, adipose tissue dysfunction and circadian gene expression in P. obesus exposed to short photoperiod and high-energy diet. These findings have implications for the protective benefits of exercise for shift workers in order to reduce the risk of diabetes and cardiovascular disease.

Mechanisms of Postischemic Stroke Angiogenesis: A Multifaceted Approach.

Ischemic stroke constitutes a significant global health care challenge, and a comprehensive understanding of its recovery mechanisms is imperative for the development of innovative therapeutic strategies. Angiogenesis, a pivotal element of ischemic tissue repair, facilitates the restoration of blood flow to damaged regions, thereby promoting neuronal regeneration and functional recovery. Nevertheless, the mechanisms underlying postischemic stroke angiogenesis remain incompletely elucidated. This review meticulously examines the constituents of the neurovascular unit, ion channels, molecular mediators, and signaling pathways implicated in angiogenesis following stroke. Furthermore, it delves into prospective therapeutic strategies informed by these factors. Our objective is to provide detailed and exhaustive information on the intricate mechanisms governing postischemic stroke angiogenesis, thus providing a robust scientific foundation for the advancement of novel neurorepair therapies.

Single-cell transcriptomics predict novel potential regulators of acute epithelial restitution in the ischemia-injured intestine.

These studies validate an approach to identify and predict upstream regulation of restituting epithelium in a unique pig intestinal ischemic injury model. Identification of potential molecular mediators of restitution, such as CSF-1, will inform the development of targeted therapeutic interventions for medical management of patients with ischemia-mediated intestinal injury.

Cardiac aging: from hallmarks to therapeutic opportunities.

Cardiac aging is an intricate and multifaceted process with considerable impact on public health, especially given the global demographic shift towards aged populations. This review discusses structural, cellular and functional changes associated with cardiac aging and heart failure with preserved ejection fraction (HFpEF). Key molecular mediators are considered within the framework of the established hallmarks of aging, with particular attention to promising therapeutic candidates. We further delineate the differential impacts of aging on cardiac structure and function in men and women, addressing hormonal and chromosomal influences. The protective and mitigating effects of exercise in cardiac aging and HFpEF in particular are discussed, as an inspiration for the identification of pathways that mitigate biological aging. We also emphasize how much remains to be learned and the importance of these efforts in enhancing the cardiac health of aging populations worldwide.

Modulation of the allosteric and vasoregulatory arms of erythrocytic oxygen transport.

Efficient distribution of oxygen (O2) to the tissues in mammals depends on the evolved ability of red blood cell (RBC) hemoglobin (Hb) to sense not only O2 levels, but metabolic cues such as pH, PCO2, and organic phosphates, and then dispense or take up oxygen accordingly. O2 delivery is the product of not only oxygen release from RBCs, but also blood flow, which itself is also governed by vasoactive molecular mediators exported by RBCs. These vascular signals, including ATP and S-nitrosothiols (SNOs) are produced and exported as a function of the oxygen and metabolic milieu, and then fine-tune peripheral metabolism through context-sensitive vasoregulation. Emerging and repurposed RBC-oriented therapeutics can modulate either or both of these allosteric and vasoregulatory activities, with a single molecule or other intervention influencing both arms of O2 transport in some cases. For example, organic phosphate repletion of stored RBCs boosts the negative allosteric effector 2,3 biphosphoglycerate (BPG) as well as the anti-adhesive molecule ATP. In sickle cell disease, aromatic aldehydes such as voxelotor can disfavor sickling by increasing O2 affinity, and in newer generations, these molecules have been coupled to vasoactive nitric oxide (NO)-releasing adducts. Activation of RBC pyruvate kinase also promotes a left shift in oxygen binding by consuming and lowering BPG, while increasing the ATP available for cell health and export on demand. Further translational and clinical investigation of these novel allosteric and/or vasoregulatory approaches to modulating O2 transport are expected to yield new insights and improve the ability to correct or compensate for anemia and other O2 delivery deficits.

Peripheral endotoxin exposure in mice activates crosstalk between phagocytes in the brain and periphery.

Inflammation is a central process of many neurological diseases, and a growing number of studies suggest that non-brain-resident immune cells may contribute to this neuroinflammation. However, the unique contributions of specific immune cell subsets to neuroinflammation are presently unknown, and it is unclear how communication between brain-resident and non-resident immune cells underlies peripheral immune cell involvement in neuroinflammation. In this study, we employed the well-established model of lipopolysaccharide (LPS)-induced neuroinflammation and captured brain-resident and non-resident immune cells from the brain and its vasculature by magnetically enriching cell suspensions from the non-perfused brain for CD45 + cells. Then, we identified immune subtype-specific neuroinflammatory processes using single-cell genomics and predicted the crosstalk between immune cell subtypes by analyzing the simultaneous expression of ligands and receptors. We observed a greater abundance of peripheral phagocytes associated with the brain in this model of neuroinflammation, and report that these professional phagocytes activated similar transcriptional profiles to microglia during LPS-induced neuroinflammation. And, we observed that the probable crosstalk between microglia and peripheral phagocytes was activated in this model while homotypic microglial communication was likely to be decreased. Our novel findings reveal that microglia signaling to non-brain-resident peripheral phagocytes is preferentially triggered by peripheral inflammation, which is associated with brain infiltration of peripheral cells. Overall, our study supports the involvement of peripheral immune cells in neuroinflammation and suggests several possible molecular signaling pathways between microglia and peripheral cells that may facilitate central-peripheral crosstalk during inflammation. Examining these molecular mediators in human disease and other rodent models may reveal novel targets that modify brain health, especially in comorbidities characterized by peripheral inflammation.

Pancreatic Epithelial IL17/IL17RA Signaling Drives B7-H4 Expression to Promote Tumorigenesis.

IL17 is required for the initiation and progression of pancreatic cancer, particularly in the context of inflammation, as previously shown by genetic and pharmacological approaches. However, the cellular compartment and downstream molecular mediators of IL17-mediated pancreatic tumorigenesis have not been fully identified. This study examined the cellular compartment required by generating transgenic animals with IL17 receptor A (IL17RA), which was genetically deleted from either the pancreatic epithelial compartment or the hematopoietic compartment via generation of IL17RA-deficient (IL17-RA-/-) bone marrow chimeras, in the context of embryonically activated or inducible Kras. Deletion of IL17RA from the pancreatic epithelial compartment, but not from hematopoietic compartment, resulted in delayed initiation and progression of premalignant lesions and increased infiltration of CD8+ cytotoxic T cells to the tumor microenvironment. Absence of IL17RA in the pancreatic compartment affected transcriptional profiles of epithelial cells, modulating stemness, and immunological pathways. B7-H4, a known inhibitor of T-cell activation encoded by the gene Vtcn1, was the checkpoint molecule most upregulated via IL17 early during pancreatic tumorigenesis, and its genetic deletion delayed the development of pancreatic premalignant lesions and reduced immunosuppression. Thus, our data reveal that pancreatic epithelial IL17RA promotes pancreatic tumorigenesis by reprogramming the immune pancreatic landscape, which is partially orchestrated by regulation of B7-H4. Our findings provide the foundation of the mechanisms triggered by IL17 to mediate pancreatic tumorigenesis and reveal the avenues for early pancreatic cancer immune interception. See related Spotlight by Lee and Pasca di Magliano, p. 1130.

Spreading Depolarization Induces a Transient Potentiation of Excitatory Synaptic Transmission

Spreading depolarization (SD) is a slowly propagating wave of prolonged activation followed by a period of synaptic suppression. Some prior reports have shown potentiation of synaptic transmission after recovery from synaptic suppression and noted similarities with the phenomenon of long-term potentiation (LTP). Since SD is increasingly recognized as participating in diverse neurological disorders, it is of interest to determine whether SD indeed leads to a generalized and sustained long-term strengthening of synaptic connections. We performed a characterization of SD-induced potentiation, and tested whether distinctive features of SD, including adenosine accumulation and swelling, contribute to reports of SD-induced plasticity. Field excitatory postsynaptic potentials (fEPSPs) were recorded in the hippocampal CA1 subregion of murine brain slices, and SD elicited using focal microinjection of KCl. A single SD was sufficient to induce a consistent potentiation of slope and amplitude of fEPSPs. Both AMPA- and NMDA-receptor mediated components were enhanced. Potentiation peaked ∼20 min after SD recovery and was sustained for ∼30 min. However, fEPSP amplitude and slope decayed over an extended 2-hour recording period and was estimated to reach baseline after ∼3 h. Potentiation was saturated after a single SD and adenosine A1 receptor activation did not mask additional potentiation. Induction of LTP with theta-burst stimulation was not altered by prior induction of SD and molecular mediators known to block LTP induction did not block SD-induced potentiation. Together, these results indicate an intermediate duration potentiation that is distinct from hippocampal LTP and may have implications for circuit function for 1–2 h following SD.

Molecular mechanisms of poor osseointegration in irradiated bone: In vivo study in a rat tibia model.

Radiotherapy is associated with cell depletion and loss of blood supply, which are linked to compromised bone healing. However, the molecular events underlying these effects at the tissue-implant interface have not been fully elucidated. This study aimed to determine the major molecular mediators associated with compromised osseointegration due to previous exposure to radiation. Titanium implants were placed in rat tibiae with or without pre-exposure to 20 Gy irradiation. Histomorphometric, biomechanical, quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay analyses were performed at 1 and 4 weeks after implantation. The detrimental effects of irradiation were characterized by reduced bone-implant contact and removal torque. Furthermore, pre-exposure to radiation induced different molecular dysfunctions such as (i) increased expression of pro-inflammatory (Tnf) and osteoclastic (Ctsk) genes and decreased expression of the bone formation (Alpl) gene in implant-adherent cells; (ii) increased expression of bone formation (Alpl and Bglap) genes in peri-implant bone; and (iii) increased expression of pro-inflammatory (Tnf) and pro-fibrotic (Tgfb1) genes in peri-implant soft tissue. The serum levels of pro-inflammatory, bone formation and bone resorption proteins were greater in the irradiated rats. Irradiation causes the dysregulation of multiple biological activities, among which perturbed inflammation seems to play a common role in hindering osseointegration.

Transcriptome analysis reveals molecular targets of erythrocyte invasion phenotype diversity in natural Plasmodium falciparum isolates from Cameroon

Further understanding of the molecular mediators of alternative RBC invasion phenotypes in endemic malaria parasites will support malaria blood-stage vaccine or drug development. This study investigated the prevalence of sialic acid (SA)-dependent and SA-independent RBC invasion pathways in endemic Plasmodium falciparum parasites from Cameroon and compared the schizont stage transcriptomes in these two groups to uncover the wider repertoire of transcriptional variation associated with the use of alternative RBC invasion pathway phenotypes. A two-color flow cytometry-based invasion-inhibition assay against RBCs treated with neuraminidase, trypsin, and chymotrypsin and deep RNA sequencing of schizont stages harvested in the first ex vivo replication cycle in culture were employed in this investigation. RBC invasion phenotypes were determined for 63 isolates from asymptomatic children with uncomplicated malaria. Approximately 80% of the isolates invaded neuraminidase-treated but not chymotrypsin-treated RBCs, representing SA-independent pathways of RBC invasion. The schizont transcriptome profiles of 16 isolates with invasion phenotypes revealed a total of 5,136 gene transcripts, with 85% of isolates predicted at schizont stages. Two distinct transcriptome profile clusters belonging to SA-dependent and SA-independent parasites were obtained by data reduction with principal component analysis. Differential analysis of gene expression between the two clusters implicated, in addition to the well-characterized adhesins, the upregulation of genes encoding proteins mediating merozoite organelle discharges as well as several conserved, virulent, merozoite-associated, and exported proteins. The latter majority have been shown to have structural and physiological relevance to RBC surface remodeling and immune evasion in malaria and thus have potential as anti-invasion targets.

The translational value of calcium pyrophosphate deposition disease experimental mouse models

The deposition of calcium pyrophosphate (CPP) crystals in joint tissues causes acute and chronic arthritis that commonly affect the adult and elderly population. Experimental calcium pyrophosphate deposition disease (CPPD) models are divided into genetically modified models and crystal-induced inflammation models. The former do not reproduce phenotypes overlapping with the human disease, while in the latter, the direct injection of crystals into the ankles, dorsal air pouch or peritoneum constitutes a useful and reliable methodology that resembles the CPP induced-inflammatory condition in humans. The translational importance of the induced model is also strengthened by the fact that the key molecular and cellular mediators involved in inflammation are shared between humans and laboratory rodents. Although, in vivo models are indispensable tools for studying the pathogenesis of the CPPD and testing new therapies, their development is still at an early stage and major efforts are needed to address this issue. Here, we analyze the strenghts and limitations of each currently available CPPD in vivo model, and critically discuss their translational value.

CCR2+ monocytes promote white matter injury and cognitive dysfunction after myocardial infarction

Survivors of myocardial infarction are at increased risk for vascular dementia. Neuroinflammation has been implicated in the pathogenesis of vascular dementia, yet little is known about the cellular and molecular mediators of neuroinflammation after myocardial infarction. Using a mouse model of myocardial infarction coupled with flow cytometric analyses and immunohistochemistry, we discovered increased monocyte abundance in the brain after myocardial infarction, which was associated with increases in brain-resident perivascular macrophages and microglia. Myeloid cell recruitment and activation was also observed in post-mortem brains of humans that died after myocardial infarction. Spatial and single cell transcriptomic profiling of brain-resident myeloid cells after experimental myocardial infarction revealed increased expression of monocyte chemoattractant proteins. In parallel, myocardial infarction increased crosstalk between brain-resident myeloid cells and oligodendrocytes, leading to neuroinflammation, white matter injury, and cognitive dysfunction. Inhibition of monocyte recruitment preserved white matter integrity and cognitive function, linking monocytes to neurodegeneration after myocardial infarction. Together, these preclinical and clinical results demonstrate that monocyte infiltration into the brain after myocardial infarction initiate neuropathological events that lead to vascular dementia.

A keratinocyte-adipocyte signaling loop is reprogrammed by loss of BTG3 to augment skin carcinogenesis

Obesity is endemic to many developed countries. Overweight or obesity is associated with an increased risk of developing cancer. Dysfunctional adipose tissue alters cancer cell proliferation and migration; however, whether and how neoplastic epithelial cells communicate with adipose tissue and the underlying mechanism are less clear. BTG3 is a member of the anti-proliferative BTG/Tob family and functions as a tumor suppressor. Here, we demonstrated that BTG3 levels are downregulated in basal cell carcinoma and squamous cell carcinoma compared to normal skin tissue, and Btg3 knockout in mice augmented the development of papilloma in a mouse model of DMBA/TPA-induced skin carcinogenesis. Mechanistically, BTG3-knockout keratinocytes promoted adipocyte differentiation mainly through the release of IL1α, IL10, and CCL4, as a result of elevated NF-κB activity. These adipocytes produced CCL20 and FGF7 in a feedback loop to promote keratinocyte migration. Thus, our findings showcased the role of BTG3 in guarding the interplay between keratinocytes and adjacent adipocytes, and identified the underlying neoplastic molecular mediators that may serve as possible targets in the treatment of skin cancer.

Colorectal Cancer in Inflammatory Bowel Disease: A Review of the Role of Gut Microbiota and Bacterial Biofilms in Disease Pathogenesis.

The risk of colorectal cancer [CRC] is increased in patients with inflammatory bowel disease [IBD], particularly in extensive ulcerative colitis [UC] and Crohn's colitis. Gut microbiota have been implicated in the pathogenesis of CRC via multiple mechanisms, including the release of reactive oxygen species and genotoxins, and induction of inflammation, as well as activation of the immune response. Gut microbiota can enhance their carcinogenic and proinflammatory properties by organising into biofilms, potentially making them more resistant to the host's immune system and to antibiotics. Colonic biofilms have the capacity to invade colonic tissue and accelerate tumorigenesis in tumour-prone models of mice. In the context of IBD, the prevalence of biofilms has been estimated to be up to 95%. Although the relationship between chronic inflammation and molecular mediators that contribute to IBD-associated CRC is well established, the role of gut microbiota and biofilms in this sequence is not fully understood. Because CRC can still arise in the absence of histological inflammation, there is a growing interest in identifying chemopreventive agents against IBD-associated CRC. Commonly used in the treatment of UC, 5-aminosalicylates have antimicrobial and anticarcinogenic properties that might have a role in the chemoprevention of CRC via the inhibition or modulation of carcinogenic gut microbiota and potentially of biofilm formation. Whether biologics and other IBD-targeted therapies can decrease the progression towards dysplasia and CRC, via mechanisms independent of inflammation, is still unknown. Further research is warranted to identify potential new microbial targets in therapy for chemoprevention of dysplasia and CRC in IBD.