The occurrence of colorectal cancer (CRC) shows a large disparity among recognized races and ethnicities in the U.S., with Black Americans demonstrating the highest incidence and mortality from this ...disease. Contributors for the observed CRC disparity appear to be multifactorial and consequential that may be initiated by structured societal issues (e.g., low socioeconomic status and lack of adequate health insurance) that facilitate abnormal environmental factors (through use of tobacco and alcohol, and poor diet composition that modifies one's metabolism, microbiome and local immune microenvironment) and trigger cancer-specific immune and genetic changes (e.g., localized inflammation and somatic driver gene mutations). Mitigating the disparity by prevention through CRC screening has been demonstrated; this has not been adequately shown once CRC has developed. Acquiring additional knowledge into the science behind the observed disparity will inform approaches towards abating both the incidence and mortality of CRC between U.S. racial and ethnic groups.
The aryl hydrocarbon receptor (AHR) recognizes xenobiotics as well as natural compounds such as tryptophan metabolites, dietary components and microbiota-derived factors, and it is important for ...maintenance of homeostasis at mucosal surfaces. AHR activation induces cytochrome P4501 (CYP1) enzymes, which oxygenate AHR ligands, leading to their metabolic clearance and detoxification. Thus, CYP1 enzymes have an important feedback role that curtails the duration of AHR signalling, but it remains unclear whether they also regulate AHR ligand availability in vivo. Here we show that dysregulated expression of Cyp1a1 in mice depletes the reservoir of natural AHR ligands, generating a quasi AHR-deficient state. Constitutive expression of Cyp1a1 throughout the body or restricted specifically to intestinal epithelial cells resulted in loss of AHR-dependent type 3 innate lymphoid cells and T helper 17 cells and increased susceptibility to enteric infection. The deleterious effects of excessive AHR ligand degradation on intestinal immune functions could be counter-balanced by increasing the intake of AHR ligands in the diet. Thus, our data indicate that intestinal epithelial cells serve as gatekeepers for the supply of AHR ligands to the host and emphasize the importance of feedback control in modulating AHR pathway activation.
Full text
Available for:
IJS, KISLJ, NUK, SBMB, UL, UM, UPUK
With a worldwide prevalence of 15%, chronic constipation is one of the most frequent gastrointestinal diagnoses made in ambulatory medicine clinics, and is a common source cause for referrals to ...gastroenterologists and colorectal surgeons in the United States. Symptoms vary among patients; straining, incomplete evacuation, and a sense of anorectal blockage are just as important as decreased stool frequency. Chronic constipation is either a primary disorder (such as normal transit, slow transit, or defecatory disorders) or a secondary one (due to medications or, in rare cases, anatomic alterations). Colonic sensorimotor disturbances and pelvic floor dysfunction (such as defecatory disorders) are the most widely recognized pathogenic mechanisms. Guided by efficacy and cost, management of constipation should begin with dietary fiber supplementation and stimulant and/or osmotic laxatives, as appropriate, followed, if necessary, by intestinal secretagogues and/or prokinetic agents. Peripherally acting μ-opiate antagonists are another option for opioid-induced constipation. Anorectal tests to evaluate for defecatory disorders should be performed in patients who do not respond to over-the-counter agents. Colonic transit, followed if necessary with assessment of colonic motility with manometry and/or a barostat, can identify colonic dysmotility. Defecatory disorders often respond to biofeedback therapy. For specific patients, slow-transit constipation may necessitate a colectomy. No studies have compared inexpensive laxatives with newer drugs with different mechanisms. We review the mechanisms, evaluation, and management of chronic constipation. We discuss the importance of meticulous analyses of patient history and physical examination, advantages and disadvantages of diagnostic testing, guidance for individualized treatment, and management of medically refractory patients.
Screening colonoscopy's effectiveness in reducing colorectal cancer mortality risk in community populations is unclear, particularly for right-colon cancers, leading to recommendations against its ...use for screening in some countries. This study aimed to determine whether, among average-risk people, receipt of screening colonoscopy reduces the risk of dying from both right-colon and left-colon/rectal cancers.
We conducted a nested case-control study with incidence-density matching in screening-eligible Kaiser Permanente members. Patients who were 55-90 years old on their colorectal cancer death date during 2006-2012 were matched on diagnosis (reference) date to controls on age, sex, health plan enrolment duration and geographical region. We excluded patients at increased colorectal cancer risk, or with prior colorectal cancer diagnosis or colectomy. The association between screening colonoscopy receipt in the 10-year period before the reference date and colorectal cancer death risk was evaluated while accounting for other screening exposures.
We analysed 1747 patients who died from colorectal cancer and 3460 colorectal cancer-free controls. Compared with no endoscopic screening, receipt of a screening colonoscopy was associated with a 67% reduction in the risk of death from any colorectal cancer (adjusted OR (aOR)=0.33, 95% CI 0.21 to 0.52). By cancer location, screening colonoscopy was associated with a 65% reduction in risk of death for right-colon cancers (aOR=0.35, CI 0.18 to 0.65) and a 75% reduction for left-colon/rectal cancers (aOR=0.25, CI 0.12 to 0.53).
Screening colonoscopy was associated with a substantial and comparably decreased mortality risk for both right-sided and left-sided cancers within a large community-based population.
The optimal surgical approach for distal transverse colon cancer has not been well established. This study aimed to evaluate the oncologic safety of left colectomy with a modified complete mesocolic ...excision for distal transverse colon cancer as compared with descending colon cancer.
This study involved 383 patients who underwent left colectomy with modified complete mesocolic excision for non-metastatic distal transverse and splenic flexure colon (transverse group, N = 110) and descending colon cancer (descending group, N = 237) from 3 institutions. Recurrence-free survival (RFS) and overall survival (OS) were compared between the two groups.
Baseline characteristics between the two groups were similar except for the length of the distal margin (transverse group = 11.0 cm vs descending group = 9.0 cm, p = 0.004). During a median follow-up of 47.0 months, RFS and OS were not different between the transverse and descending groups (5-year RFS: 82% vs 71%, p = 0.139; 5-year OS: 83% vs 79%, p = 0.416, respectively). In multivariable analysis, RFS and OS were not different between the two groups (transverse group vs. descending group: adjusted hazard ratio aHR = 1.557, 95% CI = 0.786–3.084, p = 0.204; aHR = 1.251, 95% CI = 0.530–2.952, p = 0.609).
The oncologic outcomes of left colectomy with a modified complete mesocolic excision of distal transverse colon cancer were comparable to those of descending colon cancer. Left colectomy with a modified complete mesocolic excision can be an acceptable surgical treatment for distal transverse colon cancer.
●Optimal surgical approach for distal transverse colon cancer has not been well established●Left colectomy for descending colon cancer was demonstrated oncological safety●The oncologic outcomes of left colectomy for the distal transverse colon were comparable●Left colectomy can be an acceptable surgical treatment for distal transverse colon cancer.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Giant colonic diverticula (GCD), defined as a diverticulum larger than 4 cm in diameter, have been rarely reported as a complication of diverticular disease.1 They maintain all layers of the bowel ...wall and should be differentiated from colonic pseudodiverticula, in which only the mucosa and submucosa are present.2 Because they enlarge over time, GCD may cause a variety of symptoms, including fullness, discomfort, and obstruction or bleeding.3 Surgical resection, with open or laparoscopic dissection, is the only option for cure.3 No publication to date has focused on possible prevention for a previously unrecognized cause of GCD, which may be iatrogenic in origin: a colonic anastomosis. Type III is the only true giant diverticulum, containing all layers of the bowel wall (about 10% of all cases).2 In true GCD, the pathogenesis is thought to be secondary to progressive distention, and gradual enlargement caused by intestinal gas and stool excluded from colonic transit.1' 2 The clinical manifestation and symptoms of GCD range from none to gradual change in bowel habits, bleeding, abdominal distention, and discomfort. Acute complications requiring emergency surgical intervention, such as perforation, abscess, volvulus, or infarction, have been reported as well.4 Diagnostic tests may begin with an abdominal X-ray, but CT scan is the test of choice to define the size and location of the GCD.
Full text
Available for:
NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
37.
Colonic macrophage polarization in homeostasis, inflammation, and cancer Isidro, Raymond A; Appleyard, Caroline B
American journal of physiology. Gastrointestinal and liver physiology/American journal of physiology: Gastrointestinal and liver physiology,
07/2016, Volume:
311, Issue:
1
Journal Article
Peer reviewed
Open access
Our review focuses on the colonic macrophage, a monocyte-derived, tissue-resident macrophage, and the role it plays in health and disease, specifically in inflammatory conditions such as inflammatory ...bowel disease and cancer of the colon and rectum. We give special emphasis to macrophage polarization, or phenotype, in these different states. We focus on macrophages because they are one of the most numerous leukocytes in the colon, and because they normally contribute to homeostasis through an anti-inflammatory phenotype. However, in conditions such as inflammatory bowel disease, proinflammatory macrophages are increased in the colon and have been linked to disease severity and progression. In colorectal cancer, tumor cells may employ anti-inflammatory macrophages to promote tumor growth and dissemination, whereas proinflammatory macrophages may antagonize tumor growth. Given the key roles that this cell type plays in homeostasis, inflammation, and cancer, the colonic macrophage is an intriguing therapeutic target. As such, potential macrophage-targeting strategies are discussed.
Ursodeoxycholic acid and lithocholic acid exert anti-inflammatory actions in the colon Ward, Joseph B J; Lajczak, Natalia K; Kelly, Orlaith B ...
American journal of physiology. Gastrointestinal and liver physiology/American journal of physiology: Gastrointestinal and liver physiology,
2017-Jun-01, 2017-06-01, 20170601, Volume:
312, Issue:
6
Journal Article
Peer reviewed
Open access
Ursodeoxycholic acid and lithocholic acid exert anti-inflammatory actions in the colon.
312: G550-G558, 2017. First published March 30, 2017; doi:10.1152/ajpgi.00256.2016.-Inflammatory bowel diseases ...(IBD) comprise a group of common and debilitating chronic intestinal disorders for which currently available therapies are often unsatisfactory. The naturally occurring secondary bile acid, ursodeoxycholic acid (UDCA), has well-established anti-inflammatory and cytoprotective actions and may therefore be effective in treating IBD. We aimed to investigate regulation of colonic inflammatory responses by UDCA and to determine the potential impact of bacterial metabolism on its therapeutic actions. The anti-inflammatory efficacy of UDCA, a nonmetabolizable analog, 6α-methyl-UDCA (6-MUDCA), and its primary colonic metabolite lithocholic acid (LCA) was assessed in the murine dextran sodium sulfate (DSS) model of mucosal injury. The effects of bile acids on cytokine (TNF-α, IL-6, Il-1β, and IFN-γ) release from cultured colonic epithelial cells and mouse colonic tissue in vivo were investigated. Luminal bile acids were measured by gas chromatography-mass spectrometry. UDCA attenuated release of proinflammatory cytokines from colonic epithelial cells in vitro and was protective against the development of colonic inflammation in vivo. In contrast, although 6-MUDCA mimicked the effects of UDCA on epithelial cytokine release in vitro, it was ineffective in preventing inflammation in the DSS model. In UDCA-treated mice, LCA became the most common colonic bile acid. Finally, LCA treatment more potently inhibited epithelial cytokine release and protected against DSS-induced mucosal inflammation than did UDCA. These studies identify a new role for the primary metabolite of UDCA, LCA, in preventing colonic inflammation and suggest that microbial metabolism of UDCA is necessary for the full expression of its protective actions.
On the basis of its cytoprotective and anti-inflammatory actions, the secondary bile acid ursodeoxycholic acid (UDCA) has well-established uses in both traditional and Western medicine. We identify a new role for the primary metabolite of UDCA, lithocholic acid, as a potent inhibitor of intestinal inflammatory responses, and we present data to suggest that microbial metabolism of UDCA is necessary for the full expression of its protective effects against colonic inflammation.
Individuals with sporadic colorectal cancer (CRC) frequently harbor abnormalities in the composition of the gut microbiome; however, the microbiota associated with precancerous lesions in hereditary ...CRC remains largely unknown. We studied colonic mucosa of patients with familial adenomatous polyposis (FAP), who develop benign precursor lesions (polyps) early in life. We identified patchy bacterial biofilms composed predominately of
and
Genes for colibactin (
) and
toxin (
), encoding secreted oncotoxins, were highly enriched in FAP patients' colonic mucosa compared to healthy individuals. Tumor-prone mice cocolonized with
(expressing colibactin), and enterotoxigenic
showed increased interleukin-17 in the colon and DNA damage in colonic epithelium with faster tumor onset and greater mortality, compared to mice with either bacterial strain alone. These data suggest an unexpected link between early neoplasia of the colon and tumorigenic bacteria.
Full text
Available for:
BFBNIB, NMLJ, NUK, ODKLJ, PNG, SAZU, UL, UM, UPUK
Intestinal immune homeostasis and microbiome structure play a critical role in the pathogenesis and progress of inflammatory bowel disease (IBD), whereas IBD treatment remains a challenge as the ...first‐line drugs show limited therapeutic efficiency and great side effect. In this study, a colon‐targeted adhesive core–shell hydrogel microsphere is designed and fabricated by the ingenious combination of advanced gas‐shearing technology and ionic diffusion method, which can congregate on colon tissue regulating the gut immune‐microbiota microenvironment in IBD treatment. The degradation experiment indicates the anti‐acid and colon‐targeted property of the alginate hydrogel shell, and the in vivo imaging shows the mucoadhesive ability of the thiolated‐hyaluronic acid hydrogel core of the microsphere, which reduces the systematic exposure and prolongs the local drug dwell time. In addition, both in vitro and in vivo study demonstrate that the microsphere significantly reduces the secretion of pro‐inflammatory cytokines, induces specific type 2 macrophage differentiation, and remarkably alleviates colitis in the mice model. Moreover, 16S ribosomal RNA sequencing reveals an optimized gut flora composition, probiotics including Bifidobacterium and Lactobacillus significantly augment, while the detrimental communities are inhibited, which benefits the intestinal homeostasis. This finding provides an ideal clinical candidate for IBD treatment.
A colon‐targeting and mucoadhesive hydrogel core–shell microsphere is fabricated by advanced gas‐shearing technology for treatment of inflammatory bowel disease. The oral‐administrated microsphere targets the colon where the alginate shell collapses and the HA‐SH‐Ag hydrogel core is released, which congregates on the inflamed colon mucosa for regulation of macrophage differentiation and optimization of gut flora.
Full text
Available for:
FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
PDF
