nemoci-sympt/GASTROENTEROLOGIE/ulcerozni-kolitida/zhorseni
Genetika
ABCB1, ABCC2, and ABCG2 transporters
- Exert barrier functions influencing
- Absorption,
- Distribution,
- Excretion,
- Toxicology (ADME-Tox) of exogenous substrates
- With potential impact on inflammation and carcinogenesis
- Translocate various phospholipid membrane components
- cholesterol
- Sphingomyelin
- Other glycosphingolipids
- Important for regulating the budding of the membrane function [17]
- Significantly lower concentration of IL-2, IL-4, INF-?, and TNF-?, and unchanged concentration of IL-6 and IL-10 in cultured cells from individuals with ABCB1 C3435T TT genotypes compared to CC genotypes[115]. Also, ABCB1 blockade by the antagonist PSC833 resulted in impaired IL-12 secretion by antigen presenting cells from peripheral blood from healthy human volunteers suggesting that functional ABCB1 is required for IL-12 secretion in these cells[116]. As previously mentioned, cytokines and chemokines are important modulators of intestinal inflammation and carcinogenesis[108,117]. Additionally, ABCB1, ABCC2, and ABCG2 also transport bioactive lipids[15,16,105]. The levels of the ABCB1 substrate platelet-activating factor[117-119] have been found to be high in intestinal mucosa from CD patients[120]. PAF has been reported to regulate the function of tight junctions[121] and to activate human neutrophils to extrusion of neutrophil extracellular traps (NETs) mediating extracellular capture and killing of bacteria[122,123]. Also, ABCB1 has been reported to transport steroids, mineralocorticoids, androgens and oestrogens[106]. Interestingly, the ABC substrate testosterone was found to be a key mediator of autoimmune responses in the non-obese diabetic mouse model of type 1 diabetes[124]. Whether a similar phenomenon contributes to the observed male preponderance in Mdr1a KO IBD mouse model has not been studied as far as we know[94]. ABCG2 transport the anti-inflammatory butyrate, a product of bacterial digestion of dietary fibres, and phytoestrogen from vegetables[125,126]. ABCC2 has been reported to transport the pro-inflammatory signalling molecules leukotriene (LT) B4 and LTC4 involved in dendritic cell migration and CRC, and, furthermore, various diet- and smoke-derived carcinogens[127-131]. Sulfasalazine and 5-aminosalicylic acid (5-ASA, mesalazine) are used for treatment and prevention of UC flares[132]. ABCG2 is regarded as being the main transporter of sulfasalazine[133,134] and ABCG2 activity has been suggested as having impact on sulfasalazine treatment efficacy in patients with rheumatoid arthritis (RA)[135,136]. [17]
A link between ABCB1, diet and the gut microbes in relation to colitis is suggested by the animal studies. High fat diet increases the frequency and severity of colitis in specific pathogen-free Abcb1 KO mice[100]. Undigested dietary items reaching the colon are digested by commensal bacteria thereby providing the host with valuable energy, essential vitamins, fatty acids etc. Dietary fibre from grains, fruit and vegetables is converted into short-chain fatty acids (SCFA) which represent important key regulators of the immune system[12]. The gut microbiome in active IBD is characterised by decreased microbial diversity with a decreased number of Firmicutes[162]. Low abundance of the Clostridium and Bacteroides species which preferentially produce butyrate and other SCFA may result in low production of SCFA[163]. High intake of meat which is a rich source of sulphur may lead to the formation of hydrogen sulphide by bacterial fermentation[12] which, at least theoretically, may be aggravated by high intake of milk fat which was found to favour the presence of the sulphate-reducing bacteria Bilophila wadsworthia in mice[157]. Also, intake of animal fat may give rise to arachidonic acid which is converted into e.g., prostaglandins and leukotrienes[12]. Some of these molecules are ABC transporter substrates including dietary pro- and anti-inflammatory molecules, bioactive lipids, and bacterial derived molecules[125,126]. Figure ?Figure22 shows potential mechanisms of the involvement of ABC transporters in inflammation. In addition, diet and other environmental factors may impact the transcriptional regulation of ABC transporters through effects on nuclear receptors and transcription factors leading to changes of the ABC transporter activity thereby affecting IBD and CRC. The ABC transporters may impact IBD and CRC through their transport of various substrates thereby affecting underlying biological mechanisms involved in intestinal inflammation (Figures ?(Figures11 and ?and22). [17]NFKB1 polymorphism was associated with risk of CRC in a Swedish cohort but not in a Chinese cohort[167]. Meat intake are higher in Denmark and Sweden compared to China[168]. Therefore, NFKB1 was identified as a risk gene in the Danish and Swedish high meat intake cohorts but not in the Chinese low meat intake cohort. A detailed assessment of the diet seems to be important for assessing the roles of ABC polymorphisms. Thus, future studies should focus on studying large cohorts with well-defined and relevant prospectively sampled environmental exposures in order to identify underlying IBD and CRC disease mechanisms.
The finding that presence of ABCB1 on immune cells could be used to identify pro-inflammatory Th17 cells may have important clinical implications as glucocorticoids are a mainstay in the treatment of serious flares of IBD[181] and since a large proportion (20%-30%) of patients are resistant to glucocorticoid treatment[182]. Thus, high ABCB1 mediated drug efflux may lead to decreased intracellular drug concentrations in target cells [183,184] and thereby confer glucocorticoid treatment resistance. Likewise, ABCG2 activity may affect efficacy of treatment with sulfasalazine. Further evaluation of the roles of ABC transporters in treatment response in IBD is warranted.
In conclusion, results from animal and human studies indicate that ABCB1, diet, and gut microbes mutually interact in colonic inflammation. Diet and microbes may give rise to molecules which are substrates for the ABC transporters and may additionally affect ABC transporter function through e.g., nuclear receptors and transcriptional regulation. The Abcb1 KO mice might provide a model in which these factors can be controlled and investigated. Such strategy may provide insight which can be translated into preventive and treatment strategies to benefit the patients. The evidence for the involvement of ABCC2 and ABCG2 in colitis was weak.
Deletion of Abcb1
- Leads to fundamental changes of host-microbiota interaction
- Changes in the levels of ABC transporters
- Early events in the adenoma-carcinoma sequence leading to CRC
- ABCB1, high fat diet and gut microbes in relation to colitis
- Suggested by the animal studies
- High fat diet
- Increases the frequency and severity of colitis in specific pathogen-free Abcb1 KO mice
- Abcb1 KO mice
- Defective transport of inflammatory mediators and/or
- Phospholipid translocation by ABC transporters
- Affecting inflammatory response and/or
- Function of tight junctions
- Phagocytosis
- Vesicle trafficking [17]
- ABCB1 expression identifies a subpopulation of pro-inflammatory Th17 cells
- Resistant to treatment with glucocorticoids [17]
variation in ABC transporters
Polymorphisms ABCB1 C3435T - rs1045642
- Impaired interaction between the tRNA and the chaperone protein that aids the folding process at the ribosome
- Due to ribosome stalling
- Resulted in altered transporter function
- Associated with risk of UC, but not with CD [17]
- ABCB1 polymorphisms, including the C3435T
- Associated with CRC risk
- Found to interact with meat intake in relation to risk of CRC [17]
ABCC2 and ABCG2 polymorphisms
- No strong indications that genetic variation in ABCC2 or ABCG2 per see is associated with IBD or CRC were found [17]
Rizikové faktory
- Many dietary substances which may encourage inflammation
High intake Vitamin B6 [3]
Fried food
Food additives
High intake of iron
Meat protein and alcoholic beverages
- Association with milk allergy
Breastfeeding
- Conflicting reports
- One Italian study showed a potential protective effect.[3]
Isotretinoin
- Small increased in the rate of ulcerative colitis [3]
Recent cessation of tobacco smoking [3]
Hydrogen peroxide
- In enemas or other procedures [3]
DNBS (2,4 - dinitrobenzene sulfonic acid)
- Induced rat colitis
- Frequently used animal model for inflammatory bowel disease [3]
Non-steroidal anti-inflammatory drugs
- Can trigger exacerbations of UC
- Occasionally, inducede novo disease
- Decreased production of protective mucosal prostanoid
- Increased leukocyte adherence and migration [4]
Psychological stress
- Cca in 40% of patients with UC reported as a potential trigger
- Duration of stress might so be important
Appendicectomy
- At a young age
- The strongest preventive effect on the development of UC [4]
Čemu se vyhnout
- The foods that make ulcerative colitis worse
- Typically depend on the person and the location of inflammation
Aktuní zánět - during flare-ups
- High-fiber foods are harder to digest
- Removing fibrous foods like nuts, seeds, whole grains, and raw fruits and vegetables from the diet = low-residue diet
- This can help to ease pain, cramps and other symptoms
- It does not get rid of inflammation
- If raw fruits and vegetables lead to discomfort
- May help to steam, bake or stew them
- Cabbage family, such as broccoli and cauliflower, easier to digest
Čemu se vyhýbat / co redukovat (pacientské fórum)
- Alcohol
- Zvyšuje střevní propustnost
- Caffeine
- Zvyšuje ztráty minerálů
- Snižuje hlaidny melatoninu
- Působí spíše prozánětlivě
- Carbonated soft drinks
- Chemie
- Prozánětlivé cukry
- Bublinky zvyšují střevní propustnost
- Mohou zhoršovat nadýmání a křeče v břiše
- Laktóza - mléko
- často může být i intolerance
- často i alergie
- Seeds and nuts
- škoda se o ně ošidit
- Lépe rozemleté na jemnou kašičku, aby nedráždila konzistence
- Luštěniny
- Vždy vařené, ideálně před tím ještě stažení slupiček, které jsou nadýmavé
- Dají se i namixovat na kašičku
- Dried fruits
- Spíše nevhodné, obzvláště pokud obsahují siřičitany
- Foods that have sulfur or sulfate
- Mnohé sušené plody
- Některé typy vína aj. alkoholu
- High-fiber foods
- Slupičky některých druhů zeleniny
- Loupat, vařit, ev. mixovat
- Meat
- Snižovat podíl ve stravě
- Dávat pozor na dodanou chemii a braviva
- Především nejíst uzeniny
- tuky
- Omezit tepelně zrpacované tuky, živočišné tuky a tuky bohaté na omega-6 MK
- Preferovat omega-3 MK - lněný olej, konopný, rybí tuk, (řepkový olej)
- Lze ev. užívat i olivový olej - také působí protizánětlivě
- Popcorn
- Nic pufovaného - obshauje to kancerogenní látky
- Products that have sorbitol (like sugar-free gum and candies)
- Nadýmání, osmotické průjmy, další nežádoucí vlivy
- Refined sugar
- Přerůstání bakterií, prozánětlivé vlivy
- Spicy foods
- Některá ostrá dráždivá koření nejsou vhodná
- Kapsacin - zvyšuje dál střevní propustnost
- Ostatní bylinky naopak vhodné jsou - často působí protizánětlivě a desinfekčně