EditorialGut Inflammatory Diseases, Infection, and Nutrition

Helieh S. Oz ,1 Sung-Ling Yeh ,2 and Amedeo Amedei 3

1University of Kentucky Medical Center, Lexington, USA2Taipei Medical University, Taipei, Taiwan3University of Florence, Florence, Italy

Correspondence should be addressed to Helieh S. Oz; hoz2@email.uky.edu

Received 24 June 2018; Accepted 24 June 2018; Published 26 July 2018

Copyright © 2018 Helieh S. Oz et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

There is a strong link between inflammation, infectiousagents, and nutritional status. Millions of people suffer fromchronic inflammatory diseases, and the incidence has signif-icantly increased in recent years. Inflammation is a multifac-torial biological and immunological response to differentinjuries. Inflammation is initiated by several stimuli such aspathogens, chemical irritants, nutritional imbalance, anddifferent cell injures. Inflammation is required in the bodyprocess of healing. But, chronic inflammation can causesevere and irreversible complications. Different chronicinflammatory diseases include hepatic, colitis, gastrointesti-nal, and neurodegenerative. Divers microbial (e.g., Helico-bacter, Campylobacter, Clostridium, and Mycobacterium),parasitic (e.g., protozoa, helminthes, and flatworms), andviral (HPV, norovirus, and hepatitis B and C) are linked withchronic inflammatory responses. Additionally, nutritionimbalance and specific nutrients may influence immuneresponse,modulating infections, and inflammatory responses.

Crohn’s and ulcerative colitis are chronic inflammatorybowel disease (IBD) and progressive complication with adysregulated gastrointestinal mucosal immune response inpatient toward intestinal microbiota. Pediatrics often mani-fest with more severe Crohn’s complication than adults.Crohn’s patients may eventually develop strictures andmalignancies. IL-17-A-producing T helper cells (Th17) havea key role in provoking progression of disease by productionof proinflammatory cytokines which in turn required forregeneration and protection of epithelial cells. Crohn’spatients have increased production of IL-17 by T helper cellsand higher IL-17 mRNA expression at the mucosal leveland increased numbers of Th17 cells are associated with

endoscopic definition of disease activity. Unlike previousstudies, A. Dige et al. concluded that anti-TNFα antibodytherapy has no effect on the mucosal levels of IL-17A,IL-21, and IL-22 or LP T cell production during early treat-ment (first 4 weeks) in Crohn’s disease.

Composition of commensal microbiota can influenceautoimmune disease progress and persistence. The intestinalmicrobiota is involved in triggering the immune system andleading to intestinal inflammation. IBD patients suffer froma dysbiosis, with decrease in diversity and abundance of somebeneficial commensal bacteria. For instance, significantreductions have been reported in Bifidobacteria and Lactoba-cillus in the IBD patients’ fecal content suggesting a therapeu-tic application to normalize the gut flora in autoimmunepatients using probiotics. Recent study report that gut micro-bial can translocate from gut into the organs as gut barriercompromises and pathogenic T helper cells are evident inthe gut, liver, and lymphoid organs. Similarly, microbial arealso found in hepatic biopsies of autoimmune patients andnot in healthy counterparts. Bifico is a probiotic mixture ofLactobacillus, Bifidobacterium, and Enterococcus. Previousstudies have demonstrated Bifico to improve colitis andcolitis-associated malignancy, pouchitis, diarrhea, and gastri-tis in models. In addition, clinical trials have revealed thera-peutic application for Bifico in Crohn’s and ulcerativecolitis patients. Bifico has been shown to elevate theexpression of colonic TJs and promote intestinal epithelialbarrier function in IL-10-deficient mice. In vitro experi-ments also showed that Bifico, or single probiotic strains(Bifidobacterium, Lactobacillus, or Enterococcus), increasestransepithelial electrical resistance and the expression of

HindawiMediators of InflammationVolume 2018, Article ID 7160859, 4 pageshttps://doi.org/10.1155/2018/7160859

TJs in Escherichia coli-treated Caco-2 monolayers. Bificosignificantly inhibited the secretion of proinflammatorycytokines and reduced bacterial invasion and combinationof probiotics were more pronounced than single-strain pro-biotics. Bifico was shown to have anti-inflammatory effectto expand Tregs in mesenteric lymph nodes and disturbanceof Th1/Th2 cytokines in the colonic mucosa of TNBS-induced colitis mice. However, the effect of Bifico on theTregs in intestinal tissue and peripheral blood has not beenreported. These experimental studies were performed inactive colitis induced with dextran sulfate sodium (DSS) toexplore the therapeutic effects of Bifico. Here, Y. Zhanget al. used DSS-active colitis model to investigate Bifico effectassociated with local and systemic immune responses. Thisstudy explored the protective effect of Bifico pretreating onsubsequent intestinal inflammation.

Acute pancreatitis (AP) is an acute and life-threateninginflammatory disease that commonly damages peripancrea-tic tissues and other distant organs. A consistent percentage(about the 25%) of patients with severe acute pancreatitis(SAP) develops into infected pancreatic necrosis and persis-tent organ failure, contributing the most to AP mortality.In fact the SAP, due to excessive release of inflammatoryfactors and increased oxidative stress response, can causedistant organ damage, especially acute lung injury. In addi-tion, currently, there is no effective therapeutic strategy forAP. For this purpose, Y. Li et al. used Cae-induced mild AP(MAP) model and L-arginine-induced SAP model, toinvestigate the role of naringenin (Nar) in AP and theaccompanying organ dysfunctions in mice as well as theunderlying mechanisms. Nar is a type of flavonoid, withanti-inflammatory properties, organ-protective effects, andantioxidative functions. They observed that the serum levelsof amylase, lipase, and cytokines and the malondialdehyde(MDA) levels of pancreatic tissue were significantly decreasedin both MAP and SAP models after Nar treatment. Incontrast, glutathione peroxidase, glutathione reductase,glutathione-S-transferase, total sulfhydryl, and nonproteinsulfhydryl were markedly increased both in MAP and SAPafter Nar treatment. In addition, the injury in pancreaticand pulmonary tissues was markedly improved as evidencedby the inhibited expression of myeloperoxidase, nod-likereceptor protein 3, and interleukin-1β as well as the enhancedexpression of nuclear factor erythroid 2-related factor2/hemeoxygenase-1 in pancreatic tissues. So, they concluded thatNar exerted protective effects on Cae-induced MAP andL-arginine-induced SAP in mice, suggesting that Nar maybe a potential therapeutic intervention for AP.

Gut microbiota (GM) plays several crucial roles in hostphysiology, influencing different relevant functions. GMdiversity is affected by diet and influences metabolic andimmune functions of the host’s physiology. Consequently, adysbiosis may be the cause or at least may lead to the progres-sion of various pathologies such as infectious diseases, gas-trointestinal cancers, IBD, and even obesity and diabetes.Therefore, GM is an appropriate target for nutritionalintervention to improve health and phytochemicals (thatcan influence GM) have recently been studied as adjuvantsfor the treatment of obesity and inflammatory diseases.

L. Carrera-Quintanar et al. discussed the most recent evi-dence indicating a relationship between the effects of differentphytochemicals and gut microbiota, affecting obesity and/orinflammation. Authors focused on the effect of approximately40 different phytochemical compounds, candidates for thetreatment of obesity and inflammatory diseases. They con-cluded that several issues need to be resolved before naturalproducts can be effectively translated into the clinic. Withregard to the best source of bioactive molecules, the follow-ing aspects should be considered: (a) whether it is better toacquire them directly from diet food or from pharmacolog-ical sources and (b) whether they should be used alone oras a cotreatment in combination with approved drugs.Therefore, it is urgent to develop specific clinical trials. Inaddition, disadvantages of commercial nutraceutics’ prepa-rations include the high variability in formulations, as wellas the dosage quantification and the different means ofadministration. Finally, critical investigations are requiredto optimize these phytochemical formulation and dosagesfor possible future administration.

The digestive system plays an important part in patho-genesis of infection by the human immunodeficiency virus(HIV), which can infect hepatocytes, Kupffer cells, andhepatic stellate cells, inducing the production of inflamma-tory cytokines and favoring hepatic steatosis. Circulatinglevels of different hepatic proteins (e.g., albumin, prealbumin,and transferrin) decrease, increasing the mortality risk inAIDS patients. L. Xu et al. evaluated whether the level ofbutyrylcholinesterase (BchE) could be associated with theprogression/prognosis of AIDS patients. Evaluating a cohortof 505 patients, the associations between BChE level and CD4count, WHO stage, body mass index, and C-reactive proteinlevel, the authors concluded that BChE level is associatedwith HIV/AIDS severity and is an independent risk factorfor increased mortality in AIDS patients.

Surgery is elective treatment for colorectal malignancy,yet the morbidity rate following colorectal resection remainsas high as 24%–43%. Some of these postsurgical complica-tions include tissue adhesions at the site of surgery, infec-tions, anastomotic leakage, impaired bowel movement, andmalfunction as transient or prolonged postsurgical ileus ifnot resolved after 5 days or recurrent after recovery. Thesecomplications can delay recovery and increase the lengthof hospitalization and acquired infections and medicalexpenses. An effective biomarker to predict postsurgical ileusand other complications can be useful for recovery in thesepatients. G.S.A. Boersema et al. investigated a prospectivecohort trail for the association between the inflammatorycytokines and the postoperative complications. The authorsstudied 47 patients from which 34 (72%) recovered. From13 patients (28%) who developed postsurgical ileus, 8 (20%)recovered after 5 days and 5 patients (10%) developedrecurrent disease. The authors discuss the association ofdifferent inflammatory cytokines involvement with postsur-gical complications and reason IL-6 changes to predict theinfectious complications but not postsurgical ileus aftercolorectal surgery. They concluded that IL-6 may be prom-ising candidate to assist an early detection of the infectionsfollowing surgeries.

2 Mediators of Inflammation

Maresins, a group of lipid mediators, are biosynthe-sized from docosahexaenoic acid which displays stronganti-inflammatory and proresolving activity. Resolution ofinflammation is an active and highly regulated cellular andbiochemical process required to protect against inflamma-tory complications. S. Tang et al. review the biologicalactions, pathways, and mechanisms of maresins and theirroles in the resolution of inflammation in various diseaseconditions including lung disease, vascular disease, obesity,diabetes, and IBD. Authors concluded that maresins mayprevent neutrophil infiltration, enhance macrophage phago-cytosis, inhibit nuclear factor-κB activation, and stimulatetissue regeneration. Similar studies may provide new direc-tions to discover maresin-related stable analogues to controlinflammation in the future.

IBD is a multifactorial inflammatory disease of the intes-tine. Diet has long been suspected to contribute to the IBDdevelopment and the Western dietary pattern, which is highfat, high n-6 polyunsaturated fatty acids (PUFA), is associ-ated with an increased IBD risk. N-3 PUFAs contain mostlyfish oil andhave anti-inflammatory properties. C.Charpentieret al. investigated the dietary influence of fatty acid composi-tion on 2,4,6-trinitrobenzen sulfonic acid- (TNBS-) inducedcolitis. Rats were fed with diets varying in n-3/n-6/n-9 ratioto reproduce dietary pattern from a pragmatic to a Westerndiet. There were 4 groups with n-3/n-6/n-9 ratio 1 : 4 : 16,1 : 1 : 4, 1 : 16 : 16, and 1 : 4 : 24, respectively. n-3/n-6/n-9 ratio1 : 4 : 16 is recommended as a well-balanced control diet, and1 : 1 : 4 was a target by dietary advice in a Japanese clinicaltrial for IBD patients. 1 : 16 : 16 is considered comparableto Western diet, and ratio 1 : 4 : 24 is comparable to theMediterranean diet. The results showed that compared tothe control diet, n-3 polyunsaturated fatty acids-rich dietsignificantly decreased colon-inducible nitric oxide syn-thase, cycloxygenase-2 expression, IL-6, and leukotrieneB4 production. The authors concluded that n-3 diet groupwhich showed n-3/n-6 ratio equals to 1 attenuated inflam-matory markers in the colon that may contribute to par-tially limit colitis genesis.

Formononetin is an isoflavone compound that has beenreported to possess anti-inflammatory properties. D. Wuet al. investigated the effects of formononetin on DSS-induced acute colitis in vivo and in vitro on tumor necrosisfactor-α-induced human colonic cell injury models. Micewith colitis were intraperitoneal injected with different dos-ages of formononetin. The main findings showed that formo-nonetin administration relieved clinical symptoms of colitis,mitigated colonic epithelial cell injury, and upregulated thelevels of colonic tight junction proteins ZO-1, claudin-1,and occluding. In the in vitro study, the formononetin pre-vented acute injury of human colonic cells by increasingcolonic tight junction proteins and decreasing inflamma-tory cytokine expression. The mechanism may partly beassociated with NLRP3 inflammasome signaling inhibition,as the NLRP3 pathway protein levels including NLRP3,ASC, and interleukin-1β were downregulated in a dose-dependent manner, in vivo and in vitro, when formononetinwas administered. The authors concluded that formonone-tin could protect colonic epithelial cells from injury to

relieve the disease severity of colitis and may have poten-tial to be used in the clinical prevention and treatment ofIBD in future.

Angiostrongylosis is an important food-borne diseasesand eosinophilic encephalitis in humans, caused by ratgut nematode (rat lungworm). Outbreaks of eosinophilicmeningitis have been reported due to the consumptionof infected raw snails and vegetables’ juice. Angiostrongy-lus invades the central nervous system and causes neurons’demyelination, eosinophilic encephalitis, and meningoen-cephalitis. An inflammatory response and surge of cytokinessuch as IL-17 have been detected in the central nervoussystem. IL-17 can induce Act1-mediated signaling cascadesin CNS resident cells (astrocytes, oligodendrocytes, and neu-rons) might coordinately mediate CNS inflammation, demy-elination, and neurodegeneration. But the mechanisms bywhich IL-17 involves in the demyelination caused by thisnematode is not investigated. F. Ying et al. explore the roleof IL-17A on the demyelination and introduce IL-17A-neutralizing antibody to protect against demyelinationcaused by the parasite as a possible therapeutic option inangiostrongylosis. In addition, iNOS inhibition is the possi-ble mechanism for the therapeutic effect. This study providesa new potential therapeutic alternative for demyelinationcaused by Angiostrongylus cantonensis.

Alcohol consumption in excess causes extensive liverinjuries of fatty liver which progresses to hepatitis, fibrosis,cirrhosis, and hepatocarcinoma. Ethanol increases NADH/NAD+ ratio and promotes fatty acid synthesis and lipidaccumulation in liver cells. Further, it causes excessive oxi-dative stress and increases CYP2E1 activity. In addition,ethanol increases endotoxin bypass from leaky gut whichtriggers Kupffer’s cell activation and inflammatory pro-cesses. There is an emerging theory that chronic ethanolabuse damages the tight junction structure in intestinalepithelial cells results in bacterial translocation from theintestines into the in vivo circulation to induce hepaticinflammation. Indeed, patients with alcoholic liver diseasehave higher levels of endotoxin and intestinal barrier dis-turbances caused by ethanol are the major source of endo-toxemia in these patients. Different source of dietary fatcan effect progression of liver injury as diets rich in satu-rated fatty acids or medium chain triglycerides protectagainst ethanol-induced liver injury in rodents. In contrast,polyunsaturated fatty acids can provoke liver injury. How-ever, there were some limitations of these previous studiessuch as only one type of fat was used in each experimentaldiet, but the effects on other organs or tissues were notexplored. Studies have demonstrated that fish oil, whichis rich in n-3 polyunsaturated fatty acids, eicosapentaenoicacid, and docosahexaenoic acid, can provide immune reg-ulation, vascular protection, and lipid metabolism modula-tion. However, the mechanism by which oil can modifyintestinal integrity in alcoholic liver disease is not wellunderstood. Further, some studies reveal fish oil and oliveoil to improve the fecal microbiota under ethanol expo-sure, but the effects on intestinal pathological changes inethanol-fed rats are still unclear. Y.-W. Chien et al.explored whether fish oil can provoke hepatoprotective

3Mediators of Inflammation

effects in ethanol-fed rats by means of maintaining theepithelial barrier function in the intestines and further inhi-biting endotoxin in circulation. Authors concluded thatthe chronic ethanol can elevate plasma endotoxin concen-trations and trigger inflammatory responses which canresult in liver injury. Substitution of fish oil for olive oilinhibited the appearance of endotoxin in the circulationunder ethanol exposure; thus, it decreased inflammatoryresponses and exerted a hepatoprotective potential in ratsunder chronic ethanol feeding. However, the mechanismof decreased plasma endotoxin levels by fish oil supple-mentation alone might not be enough to improve intesti-nal structural integrity.

About 30–40% of chronic inflammatory disease patientsuse some form of complementary and alternative medicine,including Chinese traditional herbal therapies. It is esti-mated that 12 million tons of herbal wastes is produced eachyear by about 1,500 Chinese traditional herbal medicineenterprises in China. During process, the active ingredientsare extracted from plants, and the waste which still containsabout 30%–50% of the medicinal active ingredient is buriedor burned which becomes major source of environmentalpollutant in water and in air. Fermentation by digestiveenzymatic reaction utilizing cellulase, protease, pectinase,and lipase can degrade plant cell wall and expose intercellu-lar organelles to assist in extraction of active ingredients. Inaddition, certain probiotics can improve digestive processand protect against malabsorption, malnutrition, and diar-rhea. Antibiotic-associated diarrhea is a frequent side effectcaused by altered gut microbiota which supports pathogengrowth. F. Meng et al. used probiotics to ferment theherbal residues in Jianweixiaoshi, a mixture of herbal rem-edy used for diarrhea, and the reason for this compoundmay become as therapeutic potential against antibiotic-associated diarrhea, as well as to reduce the waste productsfrom herbal residues produced by traditional herbal medi-cine enterprises.

Flowers of Osmanthus fragrans (O. fragrans) and Chry-santhemum morifolium (C. morifolium) are commonly usedas folk medicine and additives for tea and beverages. Theactive components isolated from these flowers contain manyphenolic compounds that have been shown to have anti-inflammatory and antioxidant properties. Lipotoxicity occurswhen excessive harmful lipid accumulates in cells leadingto cellular dysfunction and disruption of tissue function.Lipotoxicity plays a critical role in the pathogenesis ofnonalcoholic fatty liver disease and renal diseases. P.-J.Tsai et al. investigated the effects of methanolic flowerextracts of O. fragrans and C. morifolium against free fattyacid-induced lipotoxicity in hepatocytes and renal glomer-ular mesangial cells. The results showed that both extractsinhibited free fatty acid-induced hepatocyte triglycerideaccumulation and suppressed mRNA expression of inflam-matory cytokines when hepatocytes were stimulated withlipopolysaccharide-treated monocytes. Also, flowers extractsof O. fragrans and C. morifolium effectively inhibited oleate-induced cellular lipid accumulation and overexpression offibronectin in mesangial cells. The authors concluded thatthese flower extracts possess hepato- and renal-protective

activity by inhibiting hepatic fat load and inflammationand mesangial extracellular matrix formation. These find-ings imply that flowers of O. fragrans and C. morifoliummay have potential to protect against nonalcoholic steato-hepatitis and renal fibrosis.

Helieh S. OzSung-Ling Yeh

Amedeo Amedei

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