Microbial-derived metabolites are important mediators of host-microbial interactions. In recent years, the role of intestinal microbial metabolites in colorectal cancer has attracted considerable attention. These metabolites, which can be derived from bacterial metabolism of dietary substrates, modification of host molecules such as bile acids, or directly from bacteria, strongly influence the progression of colitis-associated cancer (CAC) by regulating inflammation and immune response. Here, we review how microbiome metabolites short-chain fatty acids (SCFAs), secondary bile acids, polyamines, microbial tryptophan metabolites, and polyphenols are involved in the tumorigenesis and development of CAC through inflammation and immunity. Given the heated debate on the metabolites of microbiota in maintaining gut homeostasis, serving as tumor molecular markers, and affecting the efficacy of immune checkpoint inhibitors in recent years, strategies for the prevention and treatment of CAC by targeting intestinal microbial metabolites are also discussed in this review.
Humans ; Gastrointestinal Microbiome/physiology* ; Animals ; Carcinogenesis/metabolism* ; Colitis-Associated Neoplasms/microbiology* ; Fatty Acids, Volatile/metabolism* ; Bile Acids and Salts/metabolism* ; Colitis/microbiology*

Ulcerative Colitis (UC) has been reported to be related to Porphyromonas gingivalis (P. gingivalis). Porphyromonas gingivalis peptidylarginine deiminase (PPAD), a virulence factor released by P. gingivalis, is known to induce inflammatory responses. To explore the pathological relationships between PPAD and UC, we used homologous recombination technology to construct a P. gingivalis strain in which the PPAD gene was deleted (Δppad) and a Δppad strain in which the PPAD gene was restored (comΔppad). C57BL/6 mice were orally gavaged with saline, P. gingivalis, Δppad, or comΔppad twice a week for the entire 40 days (days 0-40), and then, UC was induced by dextran sodium sulfate (DSS) solution for 10 days (days 31-40). P. gingivalis and comΔppad exacerbated DDS-induced colitis, which was determined by assessing the parameters of colon length, disease activity index, and histological activity index, but Δppad failed to exacerbate DDS-induced colitis. Flow cytometry and ELISA revealed that compared with Δppad, P. gingivalis, and comΔppad increased T helper 17 (Th17) cell numbers and interleukin (IL)-17 production but decreased regulatory T cells (Tregs) numbers and IL-10 production in the spleens of mice with UC. We also cocultured P. gingivalis, Δppad, or comΔppad with T lymphocytes in vitro and found that P. gingivalis and comΔppad significantly increased Th17 cell numbers and decreased Treg cell numbers. Immunofluorescence staining of colon tissue paraffin sections also confirmed these results. The results suggested that P. gingivalis exacerbated the severity of UC in part via PPAD.
Animals ; Colitis, Ulcerative/microbiology* ; Mice ; Mice, Inbred C57BL ; Porphyromonas gingivalis/pathogenicity* ; Protein-Arginine Deiminases ; Virulence Factors

Red ginseng is a well-known alternative medicine with anti-inflammatory activity. It exerts pharmacological effects through the transformation of saponin into metabolites by intestinal microbiota. Given that intestinal microflora vary among individuals, the pharmacological effects of red ginseng likely vary among individuals. In order to produce homogeneously effective red ginseng, we prepared probiotic-fermented red ginseng and evaluated its activity using a dextran sulfate sodium (DSS)-induced colitis model in mice. Initial analysis of intestinal damage indicated that the administration of probiotic-fermented red ginseng significantly decreased the severity of colitis, compared with the control and the activity was higher than that induced by oral administration of ginseng powder or probiotics only. Subsequent analysis of the levels of serum IL-6 and TNF-α, inflammatory biomarkers that are increased at the initiation stage of colitis, were significantly decreased in probiotic-fermented red ginseng-treated groups in comparison to the control group. The levels of inflammatory cytokines and mRNAs for inflammatory factors in colorectal tissues were also significantly decreased in probiotic-fermented red ginseng-treated groups. Collectively, oral administration of probiotic-fermented red ginseng reduced the severity of colitis in a mouse model, suggesting that it can be used as a uniformly effective red ginseng product.
Administration, Oral ; Animals ; Colitis ; chemically induced ; drug therapy ; immunology ; Colon ; drug effects ; immunology ; Dextran Sulfate ; adverse effects ; Disease Models, Animal ; Female ; Fermentation ; Humans ; Interleukin-6 ; immunology ; Lactobacillus plantarum ; metabolism ; Mice ; Mice, Inbred BALB C ; Panax ; chemistry ; metabolism ; microbiology ; Plant Extracts ; administration & dosage ; chemistry ; metabolism ; Powders ; administration & dosage ; metabolism ; Probiotics ; metabolism ; Tumor Necrosis Factor-alpha ; immunology

Toll-like receptors (TLRs) family may play important roles in inflammatory bowel disease. This study examined the expression of TLR2, TLR4 and TLR9 in the colonic tissues of patients with ulcerative colitis (UC) and explored their roles in the pathogenesis of UC. Colonic biopsies were taken from the colon of 30 patients with mild or moderate UC (at active phase) and 10 healthy controls during colonoscopy. TLR2, TLR4 and TLR9 protein expression levels were immunohistochemically detected. The mRNA expression levels of TLR2, TLR4 and TLR9 were assessed by reverse transcription polymerase chain reaction (RT-PCR). The disease activity index (DAI), colonoscopic and histologic grades and fecal microbial flora were determined. Histological examination showed that the intestinal mucous membrane of UC patients underwent acute inflammation changes. Immunohistochemistry exhibited that the expression levels of TLR2, TLR4 and TLR9 in colon epithelia and inflammatory cells were higher in UC patients than in control group (P<0.01). The mRNA expression levels of TLR2, TLR4 and TLR9 were increased in UC patients but were not detected in the normal controls. Expression levels of TLR2, TLR4 and TLR9 were positively correlated, and bore close correlation with DAI, colonoscopic and histologic grades and fecal microbial flora. An important mechanism of UC might be that abnormal activation of mucosal immunity by intestinal dysbacteriosis caused dysregulation of TLRS that mediates innate immunity.
Colitis, Ulcerative ; genetics ; metabolism ; pathology ; Colon ; metabolism ; microbiology ; Colonoscopy ; Feces ; microbiology ; Female ; Gene Expression ; Humans ; Immunohistochemistry ; Intestinal Mucosa ; metabolism ; microbiology ; Male ; Reverse Transcriptase Polymerase Chain Reaction ; Severity of Illness Index ; Toll-Like Receptor 2 ; biosynthesis ; genetics ; Toll-Like Receptor 4 ; biosynthesis ; genetics ; Toll-Like Receptor 9 ; biosynthesis ; genetics

BACKGROUND/AIMS: Diversion colitis is the inflammation of the excluded segment of the colon in patients undergoing ostomy. It has been suggested that a change in colonic flora may lead to colitis; however, direct evidence for this disease progression is lacking. The aim of this study was to evaluate the relationship between the severity of diversion colitis and the composition of colonic bacteria. METHODS: We used culture methods and polymerase chain reaction to analyze the colonic microflora of patients who underwent rectal cancer resection with or without diversion ileostomy. In the diversion group, we also evaluated the severity of colonoscopic and pathologic colitis before reversal. RESULTS: This study enrolled 48 patients: 26 in the diversion group and 22 in the control group. Significant differences were observed between the two groups in the levels of Staphylococcus (p=0.038), Enterococcus (p<0.001), Klebsiella (p<0.001), Pseudomonas (p=0.015), Lactobacillus (p=0.038), presence of anaerobes (p=0.019), and Bifidobacterium (p<0.001). A significant correlation between the severity of colitis and bacterial composition was only observed for Bifidobacterium (p=0.005, correlation coefficient=-0.531). CONCLUSIONS: The colonic microflora differed significantly between the diversion and control groups. Bifidobacterium was negatively correlated with the severity of diversion colitis.
Aged ; Aged, 80 and over ; Case-Control Studies ; Colitis/*microbiology ; Colon/*microbiology ; Female ; Gram-Negative Bacteria/isolation & purification ; Gram-Positive Bacteria/isolation & purification ; Humans ; Ileostomy ; Male ; Middle Aged ; Polymerase Chain Reaction ; Pouchitis/*microbiology ; Prospective Studies ; Rectal Neoplasms/microbiology/surgery

OBJECTIVETo investigate the changes in fecal flora and its correlation with the occurrence and progression of inflammatory bowel disease (IBD).

METHODSWe collected fresh fecal specimens from 167 IBD patients (including 113 with ulcerative colitis and 54 with Crohn's disease) and 54 healthy volunteers. The fecal flora was analyzed by gradient dilution method and the data of inflammatory markers including WBC, PLT, CRP and ESR were collected to assess the association between the fecal flora and the inflammatory markers.

RESULTSThe species Enterrococcus (6.60∓0.23, P<0.01), Saccharomyces (2.22∓0.27, P<0.05), Bacteriodes (5.57∓0.28, P<0.001), Bifidobacterium (5.08∓0.30, P<0.01), Peptococcus (6.22∓0.25, P<0.001), Lactobacillus (6.00∓0.26, P<0.001), and Clostridium (3.57∓0.30, P<0.05) all increased significantly, while Eubacterium (1.56∓0.24, P<0.01) reduced markedly in patients with ulcerative colitis compared with those in the control subjects. Enterrococcus (6.93∓0.28, P<0.01), Saccharomyces (2.73∓0.37, P<0.01), Bacteriodes (4.32∓0.52, P<0.05), Bifidobacterium (4.88∓0.42, P<0.05), Peptococcus (6.19∓0.32, P<0.01) and Lactobacillus (4.73∓0.47, P<0.001) all increased significantly and Eubacterium (1.01∓0.29, P<0.01) and Clostridium (0.87∓0.31, P<0.01) decreased in patients with Crohn's disease. The positivity rates of bacterial culture were consistent with the results of quantitative analysis of the fecal flora. The changes in fecal flora did not show a significant correlation with these inflammatory markers.

CONCLUSIONIBD patients have fecal flora imbalance compared with the healthy controls, and this imbalance may contribute to the occurrence and progression of IBD. The decline of Eubacterium contributes to the occurrence and development of IBD.

Adult ; Bacteria ; isolation & purification ; Bacteroides ; isolation & purification ; Bifidobacterium ; isolation & purification ; Biomarkers ; analysis ; Clostridium ; isolation & purification ; Colitis, Ulcerative ; microbiology ; Crohn Disease ; microbiology ; Enterococcus ; isolation & purification ; Eubacterium ; isolation & purification ; Feces ; microbiology ; Female ; Humans ; Inflammatory Bowel Diseases ; etiology ; microbiology ; Lactobacillus ; isolation & purification ; Male ; Peptococcus ; isolation & purification ; Saccharomyces ; isolation & purification

Toll-like receptors (TLRs) are key components of the innate immune system which trigger antimicrobial host defense responses. This study aimed to investigate the impact of probiotics (Lactobacillus, Bifidobacterium) on the expression of TLR4 and tumor necrosis factor-alpha (TNF-α) in the colon mucosa of rat experimental ulcerative colitis model induced by trinitrobenzene sulfonic acid (TNBS)/ethanol and immune complexes. The gross and histological changes of the colonic mucosa were observed and assessed by the means-standard deviation and independent samples t-test. The protein expression levels of TLR4 and TNF-α were detected by using immunohistochemistry and Western blotting, respectively. It was revealed that there was visible infiltration of inflammatory cells, formation of crypt abscess, and the reduction of goblet cells in the colon tissue of experimental models. As compared with the control group, the levels of TLR4 and TNF-α protein were significantly increased in the model group (P<0.01 for both). No significant difference was found in the expression of TLR4 and TNF-α between the two-week probiotics treatment group and the model group (P>0.05), whereas significant reductions were shown in rats which were treated with probiotics for four weeks as compared with the model group (P<0.01). There was no significant difference between two probiotics-treated groups. Our results implied that probiotics were likely to play a key role in protecting ulcerative colitis by reducing the inflammatory factor TNF-α expression through inhibiting the TLR4 expression in the colon tissue of experimental models.
Animals ; Bifidobacterium ; physiology ; Blotting, Western ; Colitis, Ulcerative ; chemically induced ; metabolism ; Colon ; drug effects ; metabolism ; microbiology ; Immunohistochemistry ; Intestinal Mucosa ; drug effects ; metabolism ; microbiology ; Lactobacillus ; physiology ; Male ; Probiotics ; pharmacology ; Rabbits ; Rats ; Rats, Sprague-Dawley ; Time Factors ; Toll-Like Receptor 4 ; biosynthesis ; Trinitrobenzenesulfonic Acid ; Tumor Necrosis Factor-alpha ; metabolism

BACKGROUND/AIMS: Clinical manifestations of intestinal yersiniosis include enterocolitis, mesenteric adenitis, and terminal ileitis presenting with fever, right lower quadrant pain, and leukocytosis. According to a previous Korean study in 1997, Yersinia was revealed in two among 15 adult patients with mesenteric adenitis (13%). However, recent reports on the prevalence of Yersinia infection in adult patients are few. The aim of this study was to investigate the prevalence of Yersinia infection in adult patients with acute right lower quadrant pain. METHODS: Adult patients (>18 years) who visited Eulji medical center, due to acute right lower quadrant pain were enrolled prospectively from December 2007 to July 2009. Abdominal CT, stool culture, serologic test for Yersinia, and Widal test were performed. RESULTS: Among 115 patients, 5 patients were excluded due to positive Widal test or salmonella culture. In 110 patients, abdominal CT showed right colitis in 20 (18.2%), terminal ileitis in 16 (14.5%), mesenteric adenitis in 13 (11.8%), acute appendicitis in 10 (9.1%), acute diverticulitis in 7 (6.4%), non specific mucosal edema in 36 (32.7%) and no specific lesion in 8 (7.3%). Two (1.8%) of the 110 patients had antibodies to Yersinia. One patient showed acute enteritis and the other patient was diagnosed with acute appendicitis and underwent appendectomy. No Yersinia species were grown on stool or tissue culture. CONCLUSIONS: Nowadays, among adult Korean patients presenting with acute right lower quadrant pain, there have been few incidences of Yersinia infection.
Abdominal Pain/*microbiology ; Acute Disease ; Adult ; Aged ; Aged, 80 and over ; Antibodies/blood/immunology ; Appendicitis/epidemiology ; Colitis/epidemiology ; Diverticulitis/epidemiology ; Edema/epidemiology ; Female ; Humans ; Ileitis/epidemiology ; Lymphadenitis/epidemiology ; Male ; Middle Aged ; Prevalence ; Prospective Studies ; Tomography, X-Ray Computed ; Yersinia/*isolation & purification ; Yersinia Infections/*diagnosis/*epidemiology

Shiga toxin producing E. coli (STEC) may cause severe hemorrhagic colitis followed by hemolytic uremic syndrome (HUS). In Korea, there had been a few case reports of HUS by STEC, mostly due to O157 serotype. The reports of HUS caused by STEC non-O157 serotype were rare. We report a sporadic case of HUS associated with hemorrhagic colitis. A 51-year-old woman was admitted to our hospital due to intractable abdominal pain and bloody diarrhea. Three days after admission, azotemia and microangiopathic hemolysis developed. E. coli, serotype O111 was identified. Conservative management with plasmapheresis resulted in a complete recovery.
Colitis/complications/*microbiology ; Escherichia coli/*classification ; Escherichia coli Infections/complications/*microbiology ; Female ; Gastrointestinal Hemorrhage/*etiology ; Hemolytic-Uremic Syndrome/complications/*microbiology ; Humans ; Middle Aged ; Serotyping

Tuberculous colitis, an important extra-pulmonary tuberculosis, is still prevalent in the developing countries and has been resurging in the Western world. The duration and dose of anti-tuberculous therapy have not yet been clarified in the tuberculous colitis. We experienced a case of tuberculous colitis, which relapsed after 9 months of therapy. A 28-year-old man presented with hematochezia and was diagnosed as tuberculous colitis on the basis of colonoscopic findings. He was treated with anti-tuberculous agents for 9 months successfully. Three months later, however, he complained of hematochezia again, suggesting the relapse of tuberculous colitis. He had taken anti-tuberculous therapy for another 15 months and showed no evidence of relapse. Although anti-tuberculous therapy is efficient for tuberculous colitis, rare cases of reactivation should be reminded.
Adult ; Colitis/*drug therapy/microbiology ; English Abstract ; Humans ; Male ; Recurrence ; Tuberculosis, Gastrointestinal/*drug therapy