• NF‐κB/NLRP3 inflammasome
• acetic acid‐induced colitis rat model
• hesperetin
• macrophage modulation
• pyroptosis

• Animals
• NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
• Hesperidin/pharmacology
• Hesperidin/therapeutic use
• NF-kappa B/metabolism
• NF-kappa B/antagonists & inhibitors
• Inflammasomes/metabolism
• Rats
• Male
• Colitis/chemically induced
• Colitis/metabolism
• Colitis/pathology
• Colitis/prevention & control
• Colitis/drug therapy
• Signal Transduction/drug effects
• Rats, Sprague-Dawley
• MicroRNAs/metabolism

• The authors received no specific funding for this work.

• Biomarkers
• Inflammation
• Tandem mass spectrometry
• Ulcerative colitis

• Humans
• Colitis, Ulcerative/metabolism
• Colitis, Ulcerative/pathology
• Colitis, Ulcerative/diagnosis
• Intestinal Mucosa/metabolism
• Intestinal Mucosa/pathology
• Proteomics/methods
• Male
• Female
• Adult
• Middle Aged
• Biomarkers/metabolism
• Tandem Mass Spectrometry
• Chromatography, Liquid
• Case-Control Studies
• Prospective Studies

• 2020A1515110036 Natural Science Foundation of Guangdong Province
• 2017A030313578 Natural Science Foundation of Guangdong Province
• 201707010276 Science and Technology Project of Guangzhou
• 81700489 National Natural Science Foundation of China
• 2023A044 Director Foundation of Nanfang Hospital

• Animals
• Humans
• Mice
• Bifidobacterium bifidum/metabolism
• Bifidobacterium bifidum/physiology
• Caco-2 Cells
• Intestinal Mucosa/metabolism
• Intestinal Mucosa/microbiology
• Mice, Inbred C57BL
• Myosin-Light-Chain Kinase/metabolism
• Permeability/drug effects
• PPAR gamma/metabolism
• Probiotics/pharmacology
• Tight Junctions/metabolism
• Toll-Like Receptor 2/metabolism
• Transcription Factor RelA/metabolism
• Tumor Necrosis Factor-alpha/metabolism
• Toll-Like Receptor 6

• R01 DK064165 NIDDK NIH HHS
• R01 DK106072 NIDDK NIH HHS
• R01 DK121073 NIDDK NIH HHS

• Colitis
• ER stress
• Oroxyloside
• PPARγ

• Animals
• PPAR gamma/metabolism
• PPAR gamma/genetics
• Endoplasmic Reticulum Stress/drug effects
• Dextran Sulfate
• Mice
• Endoplasmic Reticulum Chaperone BiP
• Mice, Inbred C57BL
• Reactive Oxygen Species/metabolism
• Colitis/chemically induced
• Colitis/drug therapy
• Male
• Humans
• Protective Agents/pharmacology

• Biologics
• Delivery systems
• Inflammatory bowel diseases
• Mucosal healing
• Stability

• Humans
• Inflammatory Bowel Diseases/drug therapy
• Inflammation
• Drug Delivery Systems
• Cytokines/metabolism
• Biological Products/therapeutic use

• Butyrate-producing microbes
• Clostridia
• Gut-taste receptor
• Inflammatory bowel disease
• Intestinal PPAR-γ
• Taste receptor type 1 member 3
• Western diet
• mTOR signaling

• NRF-2021R1A2C3010280 Ministry of Education
• NRF-2013M3A9D5072550 Institute for Information and Communications Technology Promotion

• Parkinson’s disease
• alpha-synuclein
• exosomes
• gene therapy
• intestine
• spinal cord

• F-1101 Parkinson's UK

Production animals are continuously exposed to environmental and dietary factors that might induce a state of low-grade, chronic intestinal inflammation. This condition compromises the productive performance and well-fare of these animals, requiring studies to understand what causes it and to develop control strategies. An intestinal inflammatory process is generally associated with alterations in the structure and functionality of its wall, resulting in the release of cellular components into the blood and/or feces. These components can act as biomarkers, i.e., they are measured to identify and quantify an inflammatory process without requiring invasive methods. In this review we discuss the mechanisms of low-grade inflammation, its effects on animal production and sustainability, and the identification of biomarkers that could provide early diagnosis of this process and support studies of useful interventional strategies.

The complex interaction between the intestinal mucosa, the gut microbiota, and the diet balances the host physiological homeostasis and is fundamental for the maximal genetic potential of production animals. However, factors such as chemical and physical characteristics of the diet and/or environmental stressors can continuously affect this balance, potentially inducing a state of chronic low-grade inflammation in the gut, where inflammatory parameters are present and demanding energy, but not in enough intensity to provoke clinical manifestations. It’s vital to expand the understanding of inflammation dynamics and of how they compromise the function activity and microscopic morphology of the intestinal mucosa. These morphometric alterations are associated with the release of structural and functional cellular components into the feces and the blood stream creating measurable biomarkers to track this condition. Moreover, the identification of novel, immunometabolic biomarkers can provide dynamic and predictors of low-grade chronic inflammation, but also provide indicators of successful nutritional or feed additive intervention strategies. The objective of this paper is to review the mechanisms of low-grade inflammation, its effects on animal production and sustainability, and the biomarkers that could provide early diagnosis of this process and support studies of useful interventional strategies.

• Inflammation
• Inflammatory bowel disease (IBD)
• PPARGC1A
• Photodynamic therapy (PDT)

Chitosan oligosaccharides (COS) have been shown to have potential protective effects against colitis, but the mechanism underlying this effect has not been fully elucidated. In this study, COS were found to significantly attenuate dextran sodium sulfate-induced colitis in mice by decreasing disease activity index scores, downregulating pro-inflammatory cytokines, and upregulating Mucin-2 levels. COS also significantly inhibited the levels of nitric oxide (NO) and IL-6 in lipopolysaccharide-stimulated RAW 264.7 cells. Importantly, COS inhibited the activation of the NF-κB signaling pathway via activating PPARγ and SIRT1, thus reducing the production of NO and IL-6. The antagonist of PPARγ could abolish the anti-inflammatory effects of COS in LPS-treated cells. COS also activated SIRT1 to reduce the acetylation of p65 protein at lysine 310, which was reversed by silencing SIRT1 by siRNA. Moreover, COS treatment increased the diversity of intestinal microbiota and partly restored the Firmicutes/Bacteroidetes ratio. COS administration could optimize intestinal microbiota composition by increasing the abundance of norank_f_Muribaculaceae, Lactobacillus and Alistipes, while decreasing the abundance of Turicibacte. Furthermore, COS could also increase the levels of propionate and butyrate. Overall, COS can improve colitis by regulating intestinal microbiota and the PPARγ/SIRT1-mediated NF-κB pathway.

• Immune system
• autoimmune diseases
• gene therapy
• inflammatory bowel disease
• rheumatoid arthritis
• type-1 diabetes mellitus

• Biology-based delivery
• Crohn’s disease
• Epithelial/endothelial targeting
• In vitro &in vivo models
• Nanoparticles
• Ulcerative colitis

• Animals
• Cells, Cultured/drug effects
• Drug Delivery Systems
• Humans
• Inflammatory Bowel Diseases/drug therapy
• Intestinal Mucosa/drug effects
• Molecular Targeted Therapy/methods
• Organoids/drug effects
• Organoids/pathology
• Tissue Scaffolds

Inflammatory bowel disease (IBD) has been posed as a great worldwide health threat. Having an onset during early adulthood, IBD is a chronic inflammatory disease characterized by remission and relapse. Due to its enigmatic etiology, no cure has been developed at the moment. Conventionally, steroids, 5-aminosalicylic acid, and immunosuppressants have been applied clinically to relieve patients’ syndrome which, unfavorably, causes severe adverse drug reactions including diarrhea, anemia, and glaucoma. Insufficient therapeutic effects also loom, and surgical resection is mandatory in half of the patients within 10 years after diagnosis. Biologics demonstrated unique and differentiative therapeutic mechanism which can alleviate the inflammation more effectively. However, their application in IBD has been hindered considering their stability and toxicity. Scientists have brought up with the concept of nanomedicine to achieve the targeted drug delivery of biologics for IBD. Here, we provide an overview of biologics for IBD treatment and we review existing formulation strategies for different biological categories including antibodies, gene therapy, and peptides. This review highlights the current trends in oral delivery of biologics with an emphasis on the important role of nanomedicine in the development of reliable methods for biologic delivery in IBD treatment.

• antibody
• biologics
• gene therapy
• inflammatory bowel disease
• oligonucleotides
• oral drug delivery
• therapeutic peptide

The peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that promote ligand-dependent transcription of target genes that regulate energy production, lipid metabolism, and inflammation. The PPAR superfamily comprises three subtypes, PPARα, PPARγ, and PPARβ/δ, with differential tissue distributions. In addition to their different roles in the regulation of energy balance and carbohydrate and lipid metabolism, an emerging function of PPARs includes normal homeostasis of intestinal tissue. PPARα activation represses NF-κB signaling, which decreases the inflammatory cytokine production by different cell types, while PPARγ ligands can inhibit activation of macrophages and the production of inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and Il-1β. In this regard, the anti-inflammatory responses induced by PPAR activation might restore physiopathological imbalances associated with inflammatory bowel diseases (IBD). Thus, PPARs and their ligands have important therapeutic potential. This review briefly discusses the roles of PPARs in the physiopathology and therapies of the most important IBDs, ulcerative colitis (UC), and Crohn's disease (CD), as well some new experimental compounds with PPAR activity as promising drugs for IBD treatment.

• Crohn's disease
• PPARα
• PPARβ/δ
• PPARγ
• inflammatory bowel diseases
• ulcerative colitis

• Animal studies
• Autoimmune diseases
• Gene modulation
• Immunopathogenesis

• Crohn’s disease
• adipokines
• adipose tissue
• inflammation
• inflammatory bowel disease
• ulcerative colitis obesity

We have shown that exposure of rats to lipopolysaccharide (LPS) during gestation induces autistic-like behaviors in juvenile offspring and pioglitazone post treatment corrects social and communication deficits. The first objective of the present study was to evaluate the cognition of the rats, because this is also a behavioral sphere committed in autism. Second, biomarkers related to pioglitazone pathways and autism were studied to try to understand their mechanisms. We used our rat model of autism and pioglitazone was administered daily to these young offspring. T-maze spontaneous alternations tests, plasma levels of brain-derived neurotrophic factor (BDNF), beta-endorphin, neurotensin, oxytocin, and substance P were all studied. Exposure of rats to LPS during gestation induced cognitive deficits in the young offspring, elevated BDNF levels and decreased neurotensin levels. Daily postnatal pioglitazone treatment abolished cognition impairments as well as BDNF and neurotensin disturbances. Together with our previous studies, we suggest pioglitazone as a candidate for the treatment of autism, because it improved the responses of the three most typical autistic-like behaviors. BDNF and neurotensin also appeared to be related to the autistic-like behaviors and should be considered for therapeutic purposes.

Summary: Exposure of rats to lipopolysaccharide during gestation induced autistic-like behaviors in the juvenile offspring. Daily postnatal pioglitazone treatment abolished cognition impairments as well as brain-derived neurotrophic factor and neurotensin disturbances.

• LPS
• Maternal immune activation
• Neuropeptides
• Prenatal
• T-maze spontaneous alternations test

• Animals
• Anti-Inflammatory Agents/pharmacology
• Anti-Inflammatory Agents/therapeutic use
• Autistic Disorder/drug therapy
• Autistic Disorder/immunology
• Drug Evaluation, Preclinical
• Female
• Interleukin-6/metabolism
• Lipopolysaccharides/pharmacology
• Male
• Pioglitazone
• Rats, Wistar
• Signal Transduction
• Thiazolidinediones/pharmacology
• Thiazolidinediones/therapeutic use
• Vocalization, Animal

• São Paulo Research Foundation (FAPESP)
• Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES/Prêmio)

Bacterial pneumonia is a significant healthcare burden worldwide. Failure to resolve inflammation after infection precipitates lung injury and an increase in morbidity and mortality. Gram-negative bacteria are common in pneumonia and increased levels of the mito-damage-associated molecular pattern (DAMP) cardiolipin can be detected in the lungs. Here we show that mice infected with Klebsiella pneumoniae develop lung injury with accumulation of cardiolipin. Cardiolipin inhibits resolution of inflammation by suppressing production of anti-inflammatory IL-10 by lung CD11b⁺Ly6G^intLy6C^loF4/80⁺ cells. Cardiolipin induces PPARγ SUMOylation, which causes recruitment of a repressive NCOR/HDAC3 complex to the IL-10 promoter, but not the TNF promoter, thereby tipping the balance towards inflammation rather than resolution. Inhibition of HDAC activity by sodium butyrate enhances recruitment of acetylated histone 3 to the IL-10 promoter and increases the concentration of IL-10 in the lungs. These findings identify a mechanism of persistent inflammation during pneumonia and indicate the potential of HDAC inhibition as a therapy.

Non-resolving bacterial pneumonia results in lung tissue damage owing to overactive inflammation. Here the authors show that the mitochondrial DAMP cardiolipin contributes to persistent inflammation by SUMOylating PPARγ, which promotes binding of the corepressor NCOR/HDAC3 complex to the IL-10 promoter.

• Animals
• Colitis/drug therapy
• Colitis/etiology
• Disease Models, Animal
• Humans

• Cell cycle progression
• Chronic inflammation
• Colon carcinogenesis
• Myeloid-derived suppressor cells
• Processed Aloe vera gel

• chronic obstructive pulmonary disease
• lung inflammation
• nuclear factor-kB
• peroxisome proliferator-activating receptor-γ
• rosiglitazone

• aerobic glycolysis
• inflammation
• iron
• lipid
• macrophages
• metabolism
• polarization

• Animals
• Antigens, CD1d/immunology
• Carrier Proteins/metabolism
• Colitis/immunology
• Colitis/pathology
• Disease Models, Animal
• Epithelial Cells/immunology
• Epithelial Cells/metabolism
• Female
• HSP110 Heat-Shock Proteins/genetics
• HSP110 Heat-Shock Proteins/metabolism
• Humans
• Immunity, Mucosal/immunology
• Inflammation/immunology
• Inflammation/pathology
• Inflammatory Bowel Diseases/immunology
• Inflammatory Bowel Diseases/pathology
• Interleukin-10/genetics
• Interleukin-10/immunology
• Intestinal Mucosa/cytology
• Intestinal Mucosa/immunology
• Male
• Mice
• Natural Killer T-Cells/immunology
• Natural Killer T-Cells/metabolism
• Oxazolone
• STAT3 Transcription Factor/metabolism

• R37 DK044319 NIDDK NIH HHS
• R56 AI050950 NIAID NIH HHS
• R01 DK088199 NIDDK NIH HHS
• R01 DK051362 NIDDK NIH HHS
• DK0034854 NIDDK NIH HHS
• R01 DK053056 NIDDK NIH HHS
• R01 AI050950 NIAID NIH HHS
• HL38180 NHLBI NIH HHS
• P30DK52574 NIDDK NIH HHS
• HL59561 NHLBI NIH HHS
• P30 CA013696 NCI NIH HHS
• 260961 European Research Council
• DK088199 NIDDK NIH HHS
• DK034854 NIDDK NIH HHS
• P30CA013696 NCI NIH HHS
• DK051362 NIDDK NIH HHS
• R01 HL038180 NHLBI NIH HHS
• DK044319 NIDDK NIH HHS
• P30 DK034854 NIDDK NIH HHS
• AI50950 NIAID NIH HHS
• P 21530 Austrian Science Fund FWF
• P01 HL059561 NHLBI NIH HHS
• R37 HL038180 NHLBI NIH HHS
• R01 DK044319 NIDDK NIH HHS
• R01 DK056260 NIDDK NIH HHS
• P30 DK052574 NIDDK NIH HHS
• DK053056 NIDDK NIH HHS
• R56 DK053056 NIDDK NIH HHS
• DK56260 NIDDK NIH HHS

Our body is colonized by more than a hundred trillion commensals, represented by viruses, bacteria and fungi. This complex interaction has shown that the microbiome system contributes to the host’s adaptation to its environment, providing genes and functionality that give flexibility of diet and modulate the immune system in order not to reject these symbionts. In the intestine, specifically, the microbiota helps developing organ structures, participates of the metabolism of nutrients and induces immunity. Certain components of the microbiota have been shown to trigger inflammatory responses, whereas others, anti-inflammatory responses. The diversity and the composition of the microbiota, thus, play a key role in the maintenance of intestinal homeostasis and explain partially the link between intestinal microbiota changes and gut-related disorders in humans. Tight junction proteins are key molecules for determination of the paracellular permeability. In the context of intestinal inflammatory diseases, the intestinal barrier is compromised, and decreased expression and differential distribution of tight junction proteins is observed. It is still unclear what is the nature of the luminal or mucosal factors that affect the tight junction proteins function, but the modulation of the immune cells found in the intestinal lamina propria is hypothesized as having a role in this modulation. In this review, we provide an overview of the current understanding of the interaction of the gut microbiota with the immune system in the development and maintenance of the intestinal barrier.

• Microbiota
• Immune system
• Lamina propria
• Intestinal barrier

To be able to colonize its host, invading Salmonella enterica serovar Typhimurium must disrupt and severely affect host-microbiome homeostasis. Here we report that S. Typhimurium induces acute infectious colitis by inhibiting peroxisome proliferator-activated receptor gamma (PPARγ) expression in intestinal epithelial cells. Interestingly, this PPARγ down-regulation by S. Typhimurium is independent of TLR-4 signaling but triggers a marked elevation of host innate immune response genes, including that encoding the antimicrobial peptide lipocalin-2 (Lcn2). Accumulation of Lcn2 stabilizes the metalloproteinase MMP-9 via extracellular binding, which further aggravates the colitis. Remarkably, when exposed to S. Typhimurium, Lcn2-null mice exhibited a drastic reduction of the colitis and remained protected even at later stages of infection. Our data suggest a mechanism in which S. Typhimurium hijacks the control of host immune response genes such as those encoding PPARγ and Lcn2 to acquire residence in a host, which by evolution has established a symbiotic relation with its microbiome community to prevent pathogen invasion.

Enteric pathogens like S. Typhimurium convert the host intestine into an inflamed environment in which they are well adapted to thrive. However, the precise strategy that this pathogen employs to achieve such favorable conditions for its survival remains unclear. Here, we uncovered a novel mechanism whereby S. Typhimurium inhibits the expression of the transcription factor PPARγ in the host intestine, surprisingly without TLR-4 involvement; this inhibition worsened the severity of the host's colitis. Subsequent detailed analysis revealed that colitis severity was coupled with elevated levels of antimicrobials like Lcn2, which stabilized the pro-inflammatory endopeptidase MMP-9 in the intestinal milieu. Combination of this escalated antimicrobial action together with enhanced protease activity disrupted the intestinal homeostasis, promoting an inflamed environment suitable for S. Typhimurium. Interestingly, using Lcn2 mutant mice we show that lack of Lcn2 effectively reduced tissue damage and the degree of inflammation, thus supporting a pivotal role of Lcn2 and MMP-9 in infectious colitis. Our data suggests a model whereby the pathogenesis of S. Typhimurium involves manipulation of the host innate immune and protease system, here illustrated by PPARγ, Lcn2 and MMP-9, to establish colonization and infection within the host.

The intestinal mucosa is the major site of contact with antigens, and it houses the largest lymphoid tissue in the body. In physiological conditions, microbiota and dietary antigens are the natural sources of stimulation for the gut-associated lymphoid tissues (GALT) and for the immune system as a whole. Germ-free models have provided some insights on the immunological role of gut antigens. However, most of the GALT is not located in the large intestine, where gut microbiota is prominent. It is concentrated in the small intestine where protein absorption takes place. In this review, we will address the involvement of food components in the development and the function of the immune system. Studies in mice have already shown that dietary proteins are critical elements for the developmental shift of the immature neonatal immune profile into a fully developed immune system. The immunological effects of other food components (such as vitamins and lipids) will also be addressed. Most of the cells in the GALT are activated and local pro-inflammatory mediators are abundant. Regulatory elements are known to provide a delicate yet robust balance that maintains gut homeostasis. Usually antigenic contact in the gut induces two major immune responses, oral tolerance and production of secretory IgA. However, under pathological conditions mucosal homeostasis is disturbed resulting in inflammatory reactions such as food hypersensitivity. Food allergy development depends on many factors such as genetic predisposition, biochemical features of allergens, and a growing array of environmental elements. Neuroimmune interactions are also implicated in food allergy and they are examples of the high complexity of the phenomenon. Recent findings on the gut circuits triggered by food components will be reviewed to show that, far beyond their role as nutrients, they are critical players in the operation of the immune system in health and disease.

• CLA
• diet
• food allergy
• food aversion
• nutrition
• oral tolerance
• vitamin A

• bacteraemia
• inflammatory bowel diseases
• interferon-gamma
• liver
• oral streptococci

Several biological activities of pomegranate have been widely described in the literature, but the anti-inflammatory effect in the gastrointestinal tract has not been reviewed till now. The aim of the present paper is to summarize the evidence for or against the efficacy of pomegranate for coping with inflammatory conditions of the gastro-intestinal tract. The paper has been organized in three parts: (1) the first one is devoted to the modifications of pomegranate active compounds in the gastro-intestinal tract; (2) the second one considering the literature regarding the anti-inflammatory effect of pomegranate at gastric level; (3) the third part considers the anti-inflammatory effect of pomegranate in the gut. In vivo studies performed on the whole fruit or juice, peel, and flowers demonstrate antiulcer effect in a variety of animal models. Ellagic acid was the main responsible for this effect, although other individual ellagitannins could contribute to the biological activity of the mixture. Different preparations of pomegranate, including extracts from peels, flowers, seeds, and juice, show a significant anti-inflammatory activity in the gut. No clinical studies have been found, thus suggesting that future clinical studies are necessary to clarify the beneficial effects of pomegranate in the gastrointestinal tract.

• mouse
• aom
• dss
• colitis cancer
• apc

Studies in animal models and humans suggest anti-inflammatory roles on the N-acylethanolamide (NAE)-peroxisome proliferators activated receptor alpha (PPARα) system in inflammatory bowel diseases. However, the presence and function of NAE-PPARα signaling system in the ulcerative colitis (UC) of humans remain unknown as well as its response to active anti-inflammatory therapies such as 5-aminosalicylic acid (5-ASA) and glucocorticoids. Expression of PPARα receptor and PPARα ligands-biosynthetic (NAPE-PLD) and -degrading (FAAH and NAAA) enzymes were analyzed in untreated active and 5-ASA/glucocorticoids/immunomodulators-treated quiescent UC patients compared to healthy human colonic tissue by RT-PCR and immunohistochemical analyses. PPARα, NAAA, NAPE-PLD and FAAH showed differential distributions in the colonic epithelium, lamina propria, smooth muscle and enteric plexus. Gene expression analysis indicated a decrease of PPARα, PPARγ and NAAA, and an increase of FAAH and iNOS in the active colitis mucosa. Immunohistochemical expression in active colitis epithelium confirmed a PPARα decrease, but showed a sharp NAAA increase and a NAPE-PLD decrease, which were partially restored to control levels after treatment. We also characterized the immune cells of the UC mucosa infiltrate. We detected a decreased number of NAAA-positive and an increased number of FAAH-positive immune cells in active UC, which were partially restored to control levels after treatment. NAE-PPARα signaling system is impaired during active UC and 5-ASA/glucocorticoids treatment restored its normal expression. Since 5-ASA actions may work through PPARα and glucocorticoids through NAE-producing/degrading enzymes, the use of PPARα agonists or FAAH/NAAA blockers that increases endogenous PPARα ligands may yield similar therapeutics advantages.

• Adolescent
• Adult
• Aged
• Amidohydrolases/genetics
• Amidohydrolases/metabolism
• Anti-Inflammatory Agents/therapeutic use
• Colitis, Ulcerative/drug therapy
• Colitis, Ulcerative/genetics
• Colitis, Ulcerative/metabolism
• Colon/metabolism
• Ethanolamines/metabolism
• Female
• Gene Expression
• Glucocorticoids/therapeutic use
• Humans
• Intestinal Mucosa/metabolism
• Intestinal Mucosa/pathology
• Male
• Mesalamine/therapeutic use
• Middle Aged
• Nitric Oxide Synthase Type II/genetics
• Nitric Oxide Synthase Type II/metabolism
• PPAR alpha/genetics
• PPAR alpha/metabolism
• PPAR gamma/genetics
• PPAR gamma/metabolism
• Phospholipase D/genetics
• Phospholipase D/metabolism
• Young Adult