Inhibition of colorectal cancer in Alzheimer’s disease is mediated by gut microbiota via induction of inflammatory tolerance

Sep 21, 2026

Uploaded by Miles

Epidemiological evidence links Alzheimer’s disease (AD) with an inverse relationship to cancers, including colorectal cancer (CRC). This study tested AD-like mice for CRC susceptibility and assessed whether gut microbiota protects against tumorigenesis by inducing inflammatory tolerance. AD-like mice showed markedly reduced CRC tumorigenesis, supported by suppressed intestinal inflammation, while fecal microbiota transplantation reversed this protection. Prevotella-associated changes increased in AD-like mice and aMCI patients, and low-dose Prevotella-derived LPS induced inflammatory tolerance in vivo and in vitro, inhibiting CRC. Gut dysbiosis increased barrier permeability, promoting LPS entry into circulation and cognitive decline in AD models. Overall results support a Prevotella-LPS mediated mechanism underlying the AD–CRC inverse association.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages11

Reading Time28 min

AccessFree to download

Research Article

Medical Sciences

Background and Rationale

Gut Microbiota and LPS Mechanisms

Significance

Author Affiliations and Contributions

RESEARCH ARTICLE MEDICAL SCIENCES Inhibition of colorectal cancer in Alzheimer’s disease is mediated by gut microbiota via induction of inflammatory tolerance Nan Zhanga, b,c,1 , Rui Zhanga, b,c,1, Lei Jianga, b,c , Zhaoyu Gaoa, b,c , Wenzhen Xiaa, b,c, Xiaoying Maa, b,c, Yushi Qina, b,c, Di Zhanga, b,c, Jiazheng Lia, b,c, Pei Tiana, b,c, Qi Zhanga, b,c, Wanchang Wanga, b,c, Kaixia Zhanga, b,c, Shan Xua, b,c, Na Zhaoa, b,c, and Shunjiang Xua, b,c,d,2 Edited by Irene Salinas, The University of New Mexico, Albuquerque, NM; received August 29, 2023; accepted July 24, 2024 by Editorial Board Member Tadatsugu Taniguchi Epidemiological studies have revealed an inverse relationship between the incidence of Alzheimer’s disease (AD) and various cancers, including colorectal cancer (CRC) . We aimed to determine whether the incidence of CRC is reduced in AD-like mice and whether gut microbiota confers resistance to tumorigenesis through inducing inflammatory tolerance using 16S ribosomal RNA gene sequencing and fecal microbiota transplantation (FMT) . AD-like mice experienced a significantly decreased incidence ofCRC tumorigenesis induced by azoxymethane–dextran sodium sulfate as evidenced by suppressed intestinal inflammation compared with control mice. However, FMT from age-matched control mice reversed the inhibitory effects on the tumorigenesis of CRC and inflammatory response in AD-like mice. The key bacterial genera in gut microbiota, including Prevotella, were increased in both theAD-like mice and in patients with amnestic mild cognitive impairment (aMCI) but were decreased in patients with CRC. Pretreatment with low-dose Prevotella-derived lipopolysaccharides (LPS) induced inflammatory tolerance both in vivo and in vitro and inhibited CRC tumorigenesis in mice. Imbalanced gut microbiota increased intestinal barrier permeability, which facilitated LPS absorption from the gut into the blood, causing cognitive decline in AD-like mice and patients with aMCI. These data reveal that intestinal Prevotella-derived LPS exerts a resistant effect to CRC tumorigenesis via inducing inflammatory tolerance in the presence of AD. These findings provide biological evidence demonstrating the inverse relationship between the incidence of AD and CRC. Alzheimer’s disease (AD) | colorectal cancer (CRC) | gut microbiota | LPS | inflammatory tolerance Alzheimer’s disease (AD) is a common neurodegenerative disease characterized by progressive cognitive dysfunction, the leading cause of dementia (1) . Cancer is a group of diseases involving the abnormal growth of cells caused by a complex mix of environmental exposure, inherited risk, and random chance (2) . Both AD and cancer are age-related diseases. Recently, epidemiological investigations have identified an inverse relationship between the incidence of AD and cancers (3–7) . A Mendelian random analysis showed that as the incidence of cancer increased, the risk of dementia significantly decreased (8) . Another retrospective study showed that the risk of cancer in patients with AD was reduced by half, and the risk of AD in patients with cancer was reduced by 35% . The incidence of more than 20 common cancer types displays a significantly inverse relationship with AD, including colorectal cancer (CRC) (3, 9). Although this interesting clinical phenomenon has received increasing attention, the experimental evidence to support the inverse relationship between AD and cancer remains lacking, and the molecular mechanisms underlying this relationship remain unclear. The gut microbiota participates in a variety of physiological functions and has been shown to be involved in the pathogenesis of many diseases, including AD and CRC (10) . Derived from the outer membrane of gram-negative bacteria, lipopolysaccharides (LPS) are some of the most abundant and potent immunomodulatory substances present in the intestinal lumen (11). The intestinal inflammation induced by an imbalance of the gut microbiot

FAQs

What was the main goal of this research article?

To determine whether CRC incidence is reduced in AD-like mice and whether gut microbiota can confer resistance to CRC tumorigenesis by inducing inflammatory tolerance.

How did fecal microbiota transplantation (FMT) affect the inhibitory effect on CRC in AD-like mice?

FMT from age-matched control mice reversed the inhibitory effects on CRC tumorigenesis and inflammatory responses in AD-like mice.

What role did Prevotella-derived LPS play in the study?

Low-dose Prevotella-derived LPS induced inflammatory tolerance both in vivo and in vitro, and it inhibited CRC tumorigenesis in mice, supporting a mechanism for the AD–CRC inverse relationship.

Sep 21, 2026

Uploaded by Miles