Demystifying the manipulation of host immunity, metabolism, and extraintestinal tumors by the gut microbiome

Abstract

The trillions of microorganisms in the gut microbiome have attracted much attention recently owing to their sophisticated and widespread impacts on numerous aspects of host pathophysiology. Remarkable progress in large-scale sequencing and mass spectrometry has increased our understanding of the influence of the microbiome and/or its metabolites on the onset and progression of extraintestinal cancers and the efficacy of cancer immunotherapy. Given the plasticity in microbial composition and function, microbial-based therapeutic interventions, including dietary modulation, prebiotics, and probiotics, as well as fecal microbial transplantation, potentially permit the development of novel strategies for cancer therapy to improve clinical outcomes. Herein, we summarize the latest evidence on the involvement of the gut microbiome in host immunity and metabolism, the effects of the microbiome on extraintestinal cancers and the immune response, and strategies to modulate the gut microbiome, and we discuss ongoing studies and future areas of research that deserve focused research efforts.

Keywords: Cancer; Cancer metabolism; Cancer therapy.

Fig. 1

Mechanisms of signaling from microbial-derived SCFAs to multiple immune cells in the gut. SCFAs participate in a sophisticated and dynamic host–microbiome network to orchestrate intestinal immune responses (such as Treg development, macrophage and DC activity, and the release of anti-inflammatory cytokines or AMP, plasma B cell proliferation, and antibody production) by suppressing HDAC or by stimulating GPRs (such as GPR109A and GPR43), ultimately exerting anti-inflammatory effects and conferring resistance against pathogens

Fig. 2

Gut microbiome-associated SCFAs shape the homeostatic host–microbiome interface. SCFAs foster a hypoxic microenvironment by activating PPAR-γ and undermining the pH homeostasis of pathogens to inhibit pathogen growth. SCFAs also signal through GPRs (such as GPR43) to secrete IL-18 and AMP, contributing to enhanced intestinal barrier function

Fig. 3

Bacterial catabolism of TRP impacts the host–microbiome interface and immune and metabolic functions. Indoles and their derivatives facilitate the release of AMP and mucin by Paneth cells and goblet cells, respectively, which helps to fortify intestinal barrier integrity. Tryptamine accelerates gastrointestinal motion by acting on the serotonin receptor on IECs. Indole also stimulates enteroendocrine L cells to produce GLP-1, thus maintaining glycometabolism homeostasis. Lactobacillus reuteri-derived ILA drives the development of CD4⁺CD8αα⁺ IELs to prevent colitis

Fig. 4

Effects of gut microbiome-derived TRP metabolites on distant organs. Microbially derived metabolites can systemically influence remote tissues, such as the brain, pancreas, and liver. Microbial tryptophan TRP metabolites suppress the proinflammatory activity of astrocytes to inhibit CNS inflammation. TRP metabolites also increase Treg cells while decreasing effector T cells to prevent autoimmunity diabetes. I3A elicits overall instrumental immune effects to inhibit hepatic inflammation via diminishing the generation of proinflammatory cytokines (such as TGF-α, IL-1β, and MCP-1)

Fig. 5

Additional gut microbial metabolites regulate host immunity and metabolism. Microbiome-derived succinate can facilitate IGN and upgrade type 2 immunity against parasitic infection. Lactate participates in intestinal wound repair by triggering ISCs in a GPR81-dependent manner. DAT confers resistance against virus infection by amplifying IFN-I signaling. A mixture of 11 rare, commensal-derived bacteria facilitates the development and accumulation of IFNγ⁺CD8⁺ T cells to enhance anti-tumor immunity and anti-intracellular pathogen infection. UroA can modulate junction proteins, which directly regulate epithelial permeability. Imidazole propionate obstructs the insulin receptor signaling pathway and results in the onset of insulin resistance following the inhibition of IRS function

Fig. 6

The crosstalk between the gut microbiome and CD4⁺ T cells as well as ILC3s. The specific gut microbiome is sufficient to induce the development of Treg, Th17, and Th1 cells, as well as IgA secretion by plasma B cells. ILC3s play a central role in such an immune network to maintain gut homeostasis through the exclusion of pathogens, maintenance of the intestinal mucosal barrier, and anti-inflammatory effects

Fig. 7

The underlying mechanisms by which the gut microbiome and its metabolites influence hepatocarcinogenesis and progression. Dysbiosis and a leaky gut facilitate hepatocarcinogenesis and progression through distinct mechanisms. Microbial-derived LPS can worsen liver inflammation and fibrosis and favor hepatocyte proliferation in a TLR4-dependent manner. DCA induces DNA damage and the SASP in HSCs and synergizes with LTA to weaken the anti-tumor activity of CD8⁺ T cells. Moreover, DCA downregulates the accumulation of CXCR6⁺ NKT cells in the hepatic tumor microenvironment, which is conducive to hepatic tumor growth