Low Abundance of Lactococcus lactis in Human Colorectal Cancer Is Associated with Decreased Natural Killer Cells.

A limited number of studies have demonstrated the role of Lactococcus lactis (L. lactis) in human colorectal cancers (CRCs). The association of L. lactis abundance with the density of natural killer (NK) cells has not been investigated before. In this study, the L. lactis abundance in 60 CRC specimens, 20 adenoma (AD) specimens, and 29 normal colorectal tissues (NCs) specimens was investigated using the fluorescence in situ hybridization of 16S ribosomal RNA. The density of NK cells was detected using immunofluorescence in 28 CRC specimens, 12 AD specimens, and 22 NC specimens. The presence of L. lactis in NCs (48.28%) was detected significantly higher than that in the AD (20.00%, P = .044) and CRC (23.33%, P = .018) specimens. The abundance of L. lactis in NCs (32.73 ± 7.24) was also found to be significantly higher than that in AD (8.91 ± 5.89, P = .029) and CRC (5.63 ± 1.67, P = .003) specimens. In addition, the density of NKp30+ NK cells in NCs (51.14 ± 4.84) was significantly higher than that in the AD (6.10 ± 1.31) and CRC (1.72 ± 0.40) specimens (P < .001). Moreover, a positive association of L. lactis abundance with NKp30+ NK cells density in the colorectal samples (P < .001) was observed. The low abundance of L. lactis in the CRC tissues was associated with the decreased NK cells, which suggested that this might contribute to the progression of CRC by decreasing the number of NK cells.Supplemental data for this article is available online at https://doi.org/10.1080/01635581.2021.1944649.

The Norepinephrine-QseC Axis Aggravates F. nucleatum-associated Colitis Through Interkingdom Signaling.

AIMS: Inflammatory bowel disease (IBD) is associated with F. nucleatum, and chronic stress can increase the risk of aggravation. However, whether norepinephrine (NE) can enhance the pathogenicity of F. nucleatum to aggravate dextran sulfate sodium salt (DSS)-induced colitis is unclear. METHODS: Transcriptome sequencing was used to identify differentially expressed genes in bacteria treated with NE. Affinity testing and molecular docking were applied to calculate and predict the binding of NE and Quorum sensing  regulators C (QseC). The pathogenicity of Fusobacterium nucleatum treated with NE and QseC inhibitors was examined in vitro and further verified using the IBD mouse model induced by DSS. RESULTS: Norepinephrine could bind to QseC directly to upregulate the quorum sensing pathway of F. nucleatum and enhance its virulence gene expression (FadA, FomA, Fap2) and invasiveness in vitro. Meanwhile, it promoted the invasion of F. nucleatum into the intestine and increased the expression of host inflammatory cytokines (IL-6, IL-1ß) to aggravate colonic inflammation in IBD mice. The QseC inhibitor LED209 inhibited the effect of NE on F. nucleatum and partially restored short-chain fatty acid (SCFA)-producing bacteria (Prevotellaceae, Lactobacillaceae) to attenuate colonic inflammation in IBD mice. CONCLUSIONS: Generally, the NE-QseC axis enhanced the pathogenicity of F. nucleatum through interkingdom signaling to aggravate colonic inflammation in IBD mice. We see that QseC may be a potential target for microbiota management of IBD under chronic pressure.

Norepinephrine could bind to QseC directly to enhance the pathogenicity of F. nucleatum to aggravate colonic inflammation. The QseC inhibitor inhibited the effect of NE on F. nucleatum and partially restored short-chain fatty acid­producing bacteria to attenuate colonic inflammation.

Gut microbiota-derived autoinducer-2 regulates lung inflammation through the gut-lung axis.

OBJECTIVE: This study aimed to determine whether autoinducer-2 (AI-2), a crucial bacterial metabolite and quorum sensing molecule, is involved in lung immunity through the gut-lung axis. METHODS: The level of AI-2 and the gut microbiome composition were analysed in the stools from pneumonic patients and the mouse model of acute lung injury. The effect of AI-2 on lung inflammation was further investigated in the mouse model. RESULTS: The diversity of the faecal microbiota was reduced in pneumonic patients treated with antibiotics compared with healthy volunteers. The AI-2 level in the stool was positively correlated with inflammatory molecules in the serum of pneumonic patients. Intraperitoneal injection of AI-2 reinforced lung inflammation in the acute lung injury mouse model, characterized by increased secretion of inflammatory molecules, including IL-6, IL-1ß, C-C chemokines, and CXCL chemokines, which were alleviated by the AI-2 inhibitor D-ribose. CONCLUSIONS: Our results suggested that gut microbiota-derived AI-2 could modulate lung inflammation through the gut-lung axis.

Alterations of the Gut Microbiome and Fecal Metabolome in Colorectal Cancer: Implication of Intestinal Metabolism for Tumorigenesis.

Objective: The gut microbiota and its metabolites are important for host physiological homeostasis, while dysbiosis is related to diseases including the development of cancers such as colorectal cancer (CRC). In this study, we characterized the relationship of an altered gut microbiome with the fecal metabolome in CRC patients in comparison with volunteers having a normal colorectal mucous membrane (NC). Methods: The richness and composition of the microbiota in fecal samples of 30 CRC patients and 36 NC controls were analyzed through 16S rRNA gene sequencing, and the metabolome was determined by ultra-performance liquid chromatography coupled to tandem mass spectrometry. Spearman correlation analysis was to determine the correlation between the gut microbiome and fecal metabolome in CRC patients. Results: There were significant alterations in the gut microbiome and fecal metabolome in CRC patients compared with NC controls. Bacteroidetes, Firmicutes, Actinobacteriota, and Proteobacteria dominated the gut microbial communities at the phylum level in both groups. Compared with NC controls, CRC patients had a lower frequency of Blautia and Lachnospiracaea but a higher abundance of Bacteroides fragilis and Prevotella. Regarding the fecal metabolome, twenty-nine metabolites were identified as having significantly changed, showing increased levels of adrenic acid, decanoic acid, arachidonic acid, and tryptophan but a reduction in various monosaccharides in the fecal samples of CRC patients. Moreover, increased abundance of Bacteroides fragilis was strongly associated with decreased levels of monosaccharides, while Blautia was positively associated with the production of monosaccharides in the fecal samples. Conclusion: These results highlight alterations of gut microbiota in association with certain metabolites in CRC progression, implying potential diagnostic and intervention potential for CRC.