by resulting in histamine generation only in intestinal regions en- riched for histamine H2 receptors. Oral administration of hista- mine may cause adverse outcomes, but the careful selection of microbes that colonize specific areas of the small or large intestine may maximize histamine H2 receptor signaling in the intestinal epithelium. Conversely, provision of L -histidine in the diet en- ables luminal conversion and luminal histamine generation by hdc gene cluster-positive microbes. Another consideration is the relative instability of histamine in vivo. Histamine is unstable in vivo and could be quickly metabolized by histamine N-methyltransferase or diamine oxidase (45). Lower concentra- tions of histamine might be protective, whereas higher concentra- tions might be detrimental to epithelial protection from infection (27). The continuous production of small amounts of histamine by the gut microbiome may result in suppression of intestinal inflammation. With respect to bacterial genetics of histamine pro- duction, the current study did not include an hdcA complemen- tation strain because antibiotic consumption by mice to maintain FIG 4 Inactivation of the L. reuterihistidine decarboxylase gene diminishes its ability to suppress intestinal inflammation. The anti-inflammatory effects of hdcA within an isogenic mutant which does not produce histamine were compared with those of wild-typeL. reuteri 6475 using the TNBS colitis model. The wild-type strain attenuated colitis compared with the medium-control group (MRS/TNBS), whereas thehdcA mutant yielded diminished effects in terms of weight loss (A), Wallace scores (B), and SAA concentrations (C).
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Peripheral inflammation has been suggested as a risk factor for developing mood, psychotic disorder, and cog- nitive impairment  and can also affect hippocampal neurogenesis. Acute administration of LPS results in long-lasting effects on neurogenesis and spatial memory in rodents, induces depression-like behavior and anxiety, and suppresses proliferation and survival of new neurons in the SGZ [72,73]. Moreover, early life inflammatory chal- lenge (for example, LPS injection) produces long-lasting anxiety and depression-like behavior and spatial memory impairment and suppresses neurogenesis [16,74,75]. Our results suggest that chronic intestinal inflammation can also negatively impact proliferation and maturation of neuronal precursors eventually resulting in the reduction of DG granular cell population and can thereby influence the properties and functioning of hippocampal circuits. Given the purported role of hippocampal neurogenesis in cognitive function and depression, its reduction during chronic intestinal inflammation might be the cause of be- havioral changes including cognitive symptoms and mood disorders that occur in patients with IBD.
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Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory disease of the intestine. IBD is a multifactorial disorder, and IBD-associated genes are critical in innate immune response, inflammatory response, autophagy, and epithelial barrier integrity. Moreover, epithelial oxygen tension plays a critical role in intestinal inflammation and resolution in IBD. The intestines have a dynamic and rapid fluctuation in cellular oxygen tension, which is dysregulated in IBD. Intestinal epithelial cells have a steep oxygen gradient where the tips of the villi are hypoxic and the oxygenation increases at the base of the villi. IBD results in heightened hypoxia throughout the mucosa. Hypoxia signals through a well-conserved family of transcription factors, where hypoxia-inducible factor (HIF)-1 α and HIF-2 α are essential in maintaining intestinal homeostasis. In inflamed mucosa, HIF-1 α increases barrier protective genes, elicits protective innate immune responses, and activates an antimicrobial response through the increase in β -defensins. HIF-2 α is essential in maintaining an epithelial-elicited inflammatory response and the regenerative and proliferative capacity of the intestine following an acute injury. HIF-1 α activation in colitis leads to a protective response, whereas chronic activation of HIF-2 α increases the pro-inflammatory response, intestinal injury, and cancer. In this mini-review, we detail the role of HIF-1 α and HIF-2 α in intestinal inflammation and injury and therapeutic implications of targeting HIF signaling in IBD.
Theory on the evolution of life history traits has suggested that living in a ‘ risky ’ environment, where individual longevity is potentially impaired, should select for higher investment into life history traits that are expressed in early life, promoting faster development and earlier age at reproduction (Stearns, 1992). It is therefore possible that worms facing intestinal inflammation adopted a faster pace of life, with accelerated development, enhanced early survival but increased late mortality. Such shifts in life history strategies have been documented in several species in response to threatening environmental conditions (Agnew et al., 2000). For instance, recent work has provided very convincing evidence for life history shifts in filarial nematodes infecting either immunocompetent mouse hosts or hosts lacking the appropriate immune response (Babayan et al., 2010). In the presence of IL-5- driven eosinophilia, which reduces parasite life expectancy, filarial worms have accelerated development and reproduce earlier (Babayan et al., 2010). Our results also fit into this general scenario, as DSS-exposed worms emerged earlier into the intestinal lumen (a proxy of age at first reproduction) and had higher survival
In this model, up-regulation of MMP-9 and MMP-2 has been also shown (Tarlton et al., 2000). Interestingly, in this study, mucosal and epithelial matrix degradation was clearly asso- ciated with infiltrating leukocytes. In addition, serine pro- teases were also up-regulated, but studies with MMP inhib- itors showed that proteolytic activity on the injured tissue was due more to the action of MMPs than serine proteases. There is increasing evidence that bacteria may also be implicated in the pathophysiology of IBD. Evidence from human and animal studies supports the idea that patients suffering from IBD have a nonphysiological immune re- sponse to intestinal flora. For instance, it has been found that bacteria from common rat flora may invade the colonic wall immediately after colonic instillation of TNBS, suggesting a significant role for enteric microorganisms in colonic tissue damage (Garcia-Lafuente et al., 1997). In addition, wide- spectrum antibiotic treatment may decrease the bacterial load and alleviate intestinal inflammation in this experimen- tal model of colitis (Garcia-Lafuente et al., 1997) and also in human IBD (Casellas et al., 1998). We have recently eluci- dated the role of bacterial MMPs in colonic tissue damage in rats (Medina et al., 2005). When studying mechanisms im- plicated in transmural inflammation induced by Bacteroides fragilis, we found that suspensions of this bacterium, but not Escherichia coli, showed significant MMP activity. Pharma- cologic inhibition of MMPs with phenanthroline reduced both the activity of MMPs in B. fragilis and the ability of these bacteria to induce colitis, suggesting that bacterial MMPs may play an important role in the induction of chronic trans- mural colonic inflammation (Medina et al., 2005). These data provide evidence that MMPs are implicated in the patho- physiology of intestinal inflammation in diverse experimen- tal models of colitis and, therefore, MMP inhibitors could be considered as potential candidates for the treatment of IBD.
Pulmonary function tests were available for 44 patients. Patients with lower FEV1 were more likely to have higher FC levels; however this was not statistically significant. Lower FEV1 indicates worse pulmonary status, and hence probably more sputum production which if swallowed could contribute to increased intestinal inflammation. Ex- cluding the sputum from the GI tract is impossible since the muco-ciliary escalator cannot be turned off in vivo [2,12]. Bacteria and other contents of swallowed sputum might be involved in direct stimulation of the intestinal mucosa. Calprotectin in the sputum itself might also in- crease the fecal levels. Golden et al. studied plasma calpro- tectin levels as a marker of pulmonary inflammation in CF. They found that plasma calprotectin was significantly higher in CF patients compared to matched controls . Both sputum and serum calprotectin significantly de- creased following treatment of a pulmonary exacerbation in a study by Gray et al. . In our study, there was no significant difference in FC levels between patients who had a pulmonary exacerbation within one month prior to sample collection and those who had no recent exacerba- tions. The patients who were receiving inhaled antibiotics had significantly lower FC levels. But this was not true for oral or intravenous antibiotic usage (within one month prior to sample collection).
response . The process of autophagy counteracts a spontaneous IFN-I response to gut microbiota that is bene- ficial in the presence of infectious and non-infectious intes- tinal hazards and injury. In autophagy deficient mice, the gut microbiota contributes to spontaneous IFN-I signaling resulting in enhanced resistance to C. rodentium infection. Conversely, inflammatory cytokines also influence autoph- agy. It has been reported that the Th1 type cytokines, such as IFN-γ, produced during bacterial infection activates autophagy as opposed to the inhibitory Th2 response . Autophagy has crucial roles in the transcription, degra- dation and secretion of pro-inflammatory cytokines highlighting its importance in cytokine signaling. Macro- phages from Atg16L1 deficient mice have been documented to produce increased amounts of LPS induced IL-1β, IL-18 and TNF-α [63–65]. Fetal liver cell chimeric mice with Atg16L1 deficient hematopoietic cells have increased sus- ceptibility to DSS colitis as demonstrated by acute weight loss and severe distal colon inflammation suggesting a protective role of autophagy in the suppression of colitis . In addition, these chimeric mice have increased levels of pro-inflammatory cytokines IL-1β and IL-18 in the sera after DSS treatment. Treatment with neutralizing anti- bodies for these cytokines reduce the susceptibility of Atg16L1 deficient mice to DSS induced colitis, indicating the importance of Atg16L1 in the suppression of intestinal inflammation . Cd11b + DCs and macrophages isolated from Atg16L1 T300A knock in mice also express increased levels of LPS induced IL-1β and decreased anti-bacterial autophagy . Similarly, human macrophages isolated from patients with CD Atg16L1 T300A variant are reported to produce higher levels of interferon β (IFN-β) and IL-1β . Both Atg16L1 deficient chimeric and Atg16L1 T300A knock in mice are autophagy deficient.
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Abstract: Pegylated liposomal doxorubicin (PLD) has been widely used to treat cancer. The adverse effects of PLD noted in clinical practice, especially hand-foot syndrome (HFS), are regarded as unique, and the management methods for them remain limited. This study was aimed at developing a feasible experimental model for translational medicine to solve this clinical issue by using skin fluorescent transgenic zebrafish. We established an optimal protocol for the administration of Lipo-Dox™, a PLD in current clinical use, to the Tg(k18:dsred) zebrafish line expressing red fluorescence in keratinocytes. We made use of bodyweight, survival rate, gross observation, flssuorescent microscopic assessment, and pathological examination of the zebrafish to assess this model. The consecutive administration protocol of PLD resulted in growth retardation of the zebrafish embryo and survival impairment, indicating establishment of a significant toxicity. We observed fin necrosis and keratinocyte dissociation phenotypes in the PLD-treated fish after consecutive administration. The skin toxicity induced by the Lipo- Dox injection was subsequently reversible, which might be compatible with a clinical course of skin recovery after discontinuation of Lipo-Dox administration. Furthermore, we found that the number of intestinal goblet cells, an important marker of intestinal inflammation, in the Lipo- Dox-injected zebrafish was markedly increased, accompanied by impaired mucosal integrity. The intestinal inflammation induced by Lipo-Dox resembled the intestinal mucositis the clinical patients suffered from after the administration of PLD. In conclusion, we established a zebrafish model for PLD-induced HFS. The intestinal mucositis simultaneously noted in the PLD-treated zebrafish validated the similarity of clinical courses after administration of PLD. This model is easily assessable, efficient, and worthy for use in developing a new therapeutic protocol for prevention or treatment of HFS as well as intestinal mucositis. Further clinical investigations to validate the correlation between human and zebrafish data are warranted.
living in Sweden in 1987 and later: 17 959 with CD, 7455 with small- intestinal inflammation, and 2307 women with normal small-intestinal mucosa, but positive CD serology. Through the government agency Statistics Sweden, each individual undergoing biopsy was matched by sex, age, calendar period of birth, and county of residence with up to 5 controls from the general population (n = 137 818) (Fig 1). Our main analyses were restricted to women to eliminate wrongful AN diagnoses in men.
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T helper (Th) 2 cell polarization is induced. The switch from type 1 to type 2 is elicited by the eggs released by adult female worms. Indeed, whole S. mansoni eggs or their soluble egg antigens (SEA) potently induce type 2 responses when injected into naïve mice (21). Importantly, a defect in switching the type of immune response leads to aberrant intestinal inflammation and fatal disease (22, 23). The protective type 2 immune response is characterized by expansion of Th2 cells, eosinophils, and basophils, increased production of IL-4, IL-5, and IL-13, an isotype switch toward IgG1 and IgE, as well as polarization of macrophages toward the M2 phenotype (24, 25). During the chronic phase of infection ( > 3 months), the magnitude of the Th2 response decreases, coincident with a reduction in granulomatous inflammation around eggs, and regulatory T and B cells emerge leading to a state of immune hyporesponsiveness. Granuloma formation around eggs trapped within hepatic and intestinal tissue is a hallmark of schistosome infection and the major cause of pathology in infected hosts. However, the egg granuloma functions for both the host and parasite (26): (a) intestinal granulomatous inflammation facilitates the translocation process for the egg into the gastrointestinal lumen, (b) it ameliorates bacterial translocation from the intestine into the circulation of the host, (c) it protects host tissues from exaggerated immune responses against the antigenic eggs, and (d) it ultimately benefits the adult parasites to keep the host intact.
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Such diseases include Inflammatory Bowel Diseases (IBD) and diseases characterized by low- grade inflammation, such as metabolic syndrome. Perturbations in the microbiota do not merely mark disease. Rather, that microbiota transplantation from IBD patients or colitic animals to germfree recipient mice results in intestinal inflammation argues altered microbiota plays a key role in driving inflammatory disease 81, 82, 99, 151, 152 . While the specific alterations in microbiota composition associated with inflammation vary across study cohorts, common features of dysbiosis frequently include reduced species diversity and increase relative abundance of Proteobacteria 98, 153 . Moreover, we previously reported that, whether induced by transient presence of a pathobiont, an innate immune deficiency, or the consumption of dietary emulsifiers (commonly used food additive with detergent-like properties), one common feature of inflammation-associated microbiotas is increased levels of flagellin, which can occur due to changes in species composition and/or microbial gene expression 57, 81, 82, 147, 148 . The link between elevated microbiota flagellin levels and intestinal inflammation is thought to involve flagellin’s ability to activate pro-inflammatory gene expression via TLR5 and the NLRC4 inflammasome. Additionally, as the structural component of flagella, elevated levels of flagellin might reflect enriched levels of motile bacteria that have high ability to penetrate the mucus layer that serves to protect the host against microbial onslaught.
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disaccharidase activity in newly weaned pigs . Moreover, our recent work also demonstrated that dietary supplemen- tation with 0.1 % tributyrin alleviated intestinal injury by inhibiting apoptosis, promoting tight-junction formation and activating epidermal growth factor receptor signaling in a piglet colitis model induced by intrarectal administra- tion of acetic acid . Using a porcine IPEC J2 cell model, Ma et al.  also found that butyrate promoted the recov- ering of intestinal wound healing through enhanced mRNA expression of the intestinal mucosal tight junction proteins. Furthermore, Wen et al.  reported that sodium butyrate (1 g/kg feed) improved intestinal morphology, reduced the total viable counts of proximal colon Clostridium and Escherichia coli , decreased TNF-α and IL-6 levels in the serum and DNA-binding activity of the intestinal nuclear factor-κB in weaned piglets. Le Gall et al.  reported that sodium butyrate (3 g/kg dry matter intake) supplementa- tion before weaning stimulated efficiently body growth and feed intake after weaning, by reducing gastric emptying and intestinal mucosa weight and by increasing feed digestibil- ity. Zeng et al.  showed that short-chain fatty acids and their analogs induced porcine host defense peptide gene expression in IPEC-J2 intestinal epithelial cells. Taken together, dietary supplementation of butyrate to promote pig intestinal health and attenuate intestinal inflammation is a promising means.
The first global and comprehensive analysis of the colon microflora in the DSS-induced colitis model revealed that acute barrier-damage in the colon is accompanied by accumulation of commensal E. coli. Because intestinal overgrowth occurs in different intestinal injuries , these flora shifts are most possibly caused by a breakdown of the mucosal physiology. Together with the finding that the lack of TLRs 2 and/or 4 per se had no impact on the composition of the intestinal microflora in healthy mice (Figure 3), the lower abundance of E. coli in TLR-deficient mice with less macroscopic disease symptoms indicates that E. coli can serve as a sensitive biomarker for colitis severity. This is in line with the earlier finding that commensal E. coli accumulated drastically during ileitis in our C57BL/10 mice and displayed a strong pro-inflammatory potential to trigger small intestinal inflammation via TLR4 [8,14]. Similarly, abundant numbers of E. coli were associated with inflammation in the colon of IL2 -/- mice
constipation in CKD patients is multifactorial: decreased physical activity, comorbidities affecting bowel movement, such as diabetes mellitus, cerebrovascular disease, and hyperparathyroidism, a restricted dietary intake of plant- based fiber-rich foods, and multiple medications, including phosphate binders and potassium-binding resins, have all been implicated. CKD is associated with alterations in the composition and function of the gut microbiota, so- called gut dysbiosis. Recent studies showed that CKD-related gut dysbiosis decreased intestinal motility via intestinal inflammation or the increased generation of gut-derived uremic toxins, such as indoxyl sulfate and p- cresyl sulfate. Furthermore, the gastrointestinal secretion of mucin was found to be decreased in CKD animal models, which may delay colonic transit by diminished lubrication in the alimentary tract. Thus, CKD-related gut dysbiosis may play a role in constipation, but limited information is currently available. Since constipation is often intractable, particularly in CKD patients, every available means needs to be employed in its treatment. The effects of probiotics, prebiotics, and synbiotics on the composition of the gut microbiota and gut-derived uremic toxins have been increasingly reported. However, their effects on stool consistency or frequency in CKD patients remain unclear. Some laxatives may be beneficial for improving not only bowel habits but also gut dysbiosis. Further studies are required to elucidate the CKD-specific pathogenesis of constipation and develop novel effective treatment options.
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In view of the requirement for luminal bacteria in the gene- sis of intestinal inflammation, the consistent presence of gas- troduodenitis and the relatively infrequent and mild distal ile- itis is somewhat surprising. The stomach and proximal small intestine are mainly colonized by aerobic bacteria, whereas high concentrations of predominantly anaerobic bacteria are in intimate contact with the mucosa of the distal ileum, cecum, and colon (13). But the proximal gastrointestinal tract of rats is exposed to high concentrations of swallowed aerobic and anaerobic bacteria from oropharyngeal secretions, food, and ingested feces. Although gastric acid kills most of these in- gested bacteria, nonviable bacterial components such as PG-PS polymers are capable of inducing and perpetuating intestinal and systemic inflammation (2, 10, 44). Furthermore, a focus of inflammation in the stomach and duodenum with relative sparing of the ileum is a consistent feature of the inflammatory response in IL-10, IL-2, TGF- b, and G protein–deficient mice (38, 39, 45, 46), and histologic evidence of antral gastritis oc- curs in up to 60% of Crohn’s disease patients (47). Although we did not observe consistent gross or histologic evidence of il- eal inflammation in the B27 transgenic rats, Aiko and Grisham (48) showed increased ileal MPO concentrations and dry weights but no increased ileal mucosal permeability in these rats. The profile of cytokines and biochemical markers in B27 transgenic rats exposed to enteric bacteria suggests that mecha- nisms of tissue injury are similar to those described in human IBD (1, 49). Increased expression of the monokines IL-1 a, IL-1b, IL-1RA, TNF-a, and IL-6 in the inflamed colons of transgenic rats exposed to bacteria incriminate activated macrophages, whereas IFN-g is a product of activated T lymphocytes and natural killer cells. Histologic analysis of the inflamed colonic tissues demonstrates infiltrations of macrophages and lympho- cytes. Elevated tissue MPO concentrations could be a conse- quence of infiltration by either neutrophils or eosinophils (29), although the latter cell type was seen far more frequently on histologic assessment than the former. Similar profiles of cy- tokines have been described in human IBD (1, 49) and numer- ous animal models of experimental intestinal inflammation (50).
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Intestinal barrier permeability is defined as the facil- ity with which intestinal epithelium allows molecules to pass through by non-mediated passive diffusion . The passive diffusion of potentially harmful small mol- ecules from the intestinal lumen into the epithelial cells is counteracted by a family of plasma-membrane bound efflux pumps, called ATP-binding cassette transporters or multi-drug resistance (MDR) pumps . These MDR pumps seem to be expressed in the intestinal tract of all animal species including poultry . A defect in the MDR pumps leads to intestinal inflammation . Con- versely, inflammation is associated with decreased MDR1 expression in the human intestinal epithelium . Intes- tinal barrier permeability also depends on the stabil- ity of intercellular junctions (tight junctions, adherens junctions and desmosomes) that control the paracellular transport pathway passing in between neighboring intes- tinal epithelial cells. Intestinal barrier permeability can be altered by a wide range of diet-derived compounds  and by many enteric pathogen-derived toxins, as recently reviewed in the chicken by Awad et al. . Changes in the molecular structure of the junctional complexes or reduced expression of junctional structural proteins will result in decreased absorption of nutrients, increased secretory passage of ions and water causing leak flux diar- rhea (gut leakage), and increased passage of macromol- ecules from the lumen which may induce inflammation . A direct link between intestinal inflammation and loss of intercellular junction integrity has been repeat- edly observed [12, 13]. In line with these observations, the presence of pro-inflammatory cytokines as such can increase epithelial permeability in vitro . As dys- biosis has been associated also with destabilization of tight junctions , it appears that there is an intimate link between dysbiosis, intestinal barrier disruption and inflammation. Although an exhaustive review of the dif- ferent host, environmental and nutritional factors that may act as primary triggers of these disturbances of the intestinal ecosystem is outside the scope of this paper,
Abstract: Autism spectrum disorder (ASD) is a genetically determined neurodevelopmental brain disorder presenting with restricted, repetitive patterns of behaviors, interests, and activi- ties, or persistent deficits in social communication and social interaction. ASD is characterized by many different clinical endophenotypes and is potentially linked with certain comorbidities. According to current recommendations, children with ASD are at risk of having alimentary tract disorders – mainly, they are at a greater risk of general gastrointestinal (GI) concerns, con- stipation, diarrhea, and abdominal pain. GI symptoms may overlap with ASD core symptoms through different mechanisms. These mechanisms include multilevel pathways in the gut–brain axis contributing to alterations in behavior and cognition. Shared pathogenetic factors and pathophysiological mechanisms possibly linking ASD and GI disturbances, as shown by most recent studies, include intestinal inflammation with or without autoimmunity, immunoglobulin E-mediated and/or cell-mediated GI food allergies as well as gluten-related disorders (celiac disease, wheat allergy, non-celiac gluten sensitivity), visceral hypersensitivity linked with functional abdominal pain, and dysautonomia linked with GI dysmotility and gastroesophageal reflux. Dysregulation of the gut microbiome has also been shown to be involved in modulating GI functions with the ability to affect intestinal permeability, mucosal immune function, and intestinal motility and sensitivity. Metabolic activity of the microbiome and dietary components are currently suspected to be associated with alterations in behavior and cognition also in patients with other neurodegenerative diseases. All the above-listed GI factors may contribute to brain dysfunction and neuroinflammation depending upon an individual patient’s genetic vulnerability. Due to a possible clinical endophenotype presenting as comorbidity of ASD and GI disorders, we propose treating this situation as an “overlap syndrome”. Practical use of the concept of an overlap syndrome of ASD and GI disorders may help in identifying those children with ASD who suffer from an alimentary tract disease. Unexplained worsening of nonverbal behaviors (agitation, anxiety, aggression, self-injury, sleep deprivation) should alert professionals about this possibility. This may shorten the time to diagnosis and treatment commencement, and thereby alleviate both GI and ASD symptoms through reducing pain, stress, or discomfort. Furthermore, this may also protect children against unnecessary dietary experiments and restrictions that have no medical indications. A personalized approach to each patient is necessary. Our understanding of ASDs has come a long way, but further studies and more systematic research are warranted.
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Rhizome is astringent, anthelmintic and is useful in diarrhoea and for the treatment of inflammation in the gastric and intestinal mucous membranes. Decoction of rhizomes and fronds is given for chronic disorders of viscera and spleen. Rhizome boiled in oil and made into an ointment is used for healing wounds. Fronds are reported to be poisonous and sometimes fatal to the grazing animals. The dried fronds are employed as packing material. Tender fronds are used as vegetable and for soup; whole plant is used as insect repellent. This plant is also used as a fire indicator.
TNF-alpha, a marker of low-grade inflammation, was not different between groups but increased towards the end of the study in both groups. This is similar to CP and GPx3 and we already observed a correlation be- tween CP and TNF-alpha in the past , but related this to common cold pathophysiology. We do not have an explanation for this increase other than this change might also be related to a reduced intake of food high in micronutrients and antioxidants over winter time. Nevertheless, although TNF-alpha concentrations in- creased, all values observed were within the reference range and thus, we think that the changes might be due to biological variability.
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In conclusion, this study showed a different expression patterns of P1-HNF4α and P2- HNF4α in chronic gastritis. An increased expression of P1-HNF4α was associated with the severity of inflammation in chronic gastritis, and the expression come to a head in gastric IM, while P2-HNF4α expression was wide- spread and there was no difference in all chron- ic gastritis. These results suggest that the expression of P1-HNF4α but not P2-HNF4α may be a useful diagnostic marker for chronic gastritis.