Randomised Clinical Study

Oral Aspirin 325 mg Daily vs Placebo Alters Gut Microbial Composition and Bacterial Taxa Associated With Colorectal Cancer Risk

Anna E. Prizment; Christopher Staley; Guillaume C. Onyeaghala; Sithara Vivek; Bharat Thyagarajan; Robert J. Straka; Ryan T. Demmer; Dan Knights; Katie A. Meyer; Aasma Shaukat; Michael J. Sadowsky; Timothy R. Church

Disclosures

Aliment Pharmacol Ther. 2020;52(6):976-987. 

In This Article

Abstract and Introduction

Abstract

Background: Aspirin is associated with decreased risk of colorectal cancer (CRC), potentially by modulating the gut microbiome.

Aims: To evaluate the effect of aspirin on the gut microbiome in a double-blinded, randomised placebo-controlled pilot trial.

Methods: Healthy volunteers aged 50–75 received a standard dose of aspirin (325 mg, N = 30) or placebo (N = 20) once daily for 6 weeks and provided stool samples every 3 weeks for 12 weeks. Serial measurements of gut microbial community composition and bacterial abundance were derived from 16S rRNA sequences. Linear discriminant analysis of effect size (LEfSe) was tested for between-arm differences in bacterial abundance. Mixed-effect regression with binomial distribution estimated the effect of aspirin use on changes in the relative abundance of individual bacterial taxa via an interaction term (treatment × time).

Results: Over the study period, there were differences in microbial composition in the aspirin vs placebo arm. After treatment, four taxa were differentially abundant across arms: Prevotella, Veillonella, Clostridium XlVa and Clostridium XVIII clusters. Of pre-specified bacteria associated with CRC (n = 8) or aspirin intake (n = 4) in published studies, interactions were significant for four taxa, suggesting relative increases in Akkermansia, Prevotella and Ruminococcaceae and relative decreases in Parabacteroides, Bacteroides and Dorea in the aspirin vs placebo arm.

Conclusion: Compared to placebo, aspirin intake influenced several microbial taxa (Ruminococcaceae, Clostridium XlVa, Parabacteroides and Dorea) in a direction consistent with a priori hypothesis based on their association with CRC. This suggests that aspirin may influence CRC development through an effect on the gut microbiome. The findings need replication in a larger trial.

Introduction

Aspirin, an accessible and affordable drug, is one of the most intriguing prospects for cancer prevention. In 2016, the U.S. Preventive Services Task Force recommended using low-dose aspirin (81 mg) to reduce cardiovascular disease (CVD) and colorectal cancer (CRC) risk among adults aged 50–59 with a 10% increased CVD risk.[1] Currently, more than 30% of adults over the age of 40 reported taking low-dose aspirin for primary or secondary CVD prevention; this translates into almost 39 million aspirin users in the U.S.[2] In addition to preventing CVD, aspirin use may protect against CRC development. In randomised clinical trials, aspirin use was associated with a reduction in CRC risk by 24%-38%.[3] However, aspirin has not been recommended for population-based prevention in healthy people because of aspirin's side effects (eg gastrointestinal bleeding and cerebral haemorrhage) in some individuals and lack of understanding about population subgroups in which aspirin decreases CRC risk but does not cause adverse reactions.[4,5] Tailoring aspirin to individuals who will especially benefit from using this drug for CRC prevention is one of the current priorities in cancer research in the U.S.[6]

Aspirin modulates inflammation and immune response via cyclooxygenase (COX)-dependent and -independent mechanisms.[7–9] However, the exact mechanisms through which aspirin reduces risk of colorectal neoplasia and the molecular targets of aspirin in the context of CRC prevention have not been established. Data from animal studies have revealed that aspirin influences the gut microbiome either indirectly via an immune mechanism or directly via a local effect.[10–14] Moreover, it was shown in humans that aspirin and other salicylate may inhibit the growth of pro-inflammatory bacteria in a dose-dependent manner.[15] Despite these findings, surprisingly little research has been conducted in humans. An observational study in Finland suggested that aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) may alter the composition of the intestinal microbiome and partially counteract an increase in unfavourable bacterial taxa inhabiting the gut at older age.[16] In addition, in a cross-sectional study of 150 individuals taking NSAIDs, four taxa (Prevotella species, Bacteroides species, Barnesiella species and Ruminococcaceae family) discriminated aspirin users from non-users (AUC = 0.96; 95% CI 0.84–1.00).[17] These studies provide compelling evidence for aspirin's role in modulating gut bacteria, but have been limited by their cross-sectional design.

In the present study, we addressed these gaps using a randomised placebo-controlled design to test the extent to which aspirin changes gut microbial composition. Given aspirin's anti-inflammatory effect and its protective role in CRC, we hypothesised that aspirin alters the composition of gut microbiome in a way consistent with decreased inflammation and reduced CRC risk. Specifically, aspirin intake may lead to lower relative abundance of pro-inflammatory gut bacteria associated with CRC (e.g., Streptococcus) and higher abundance of anti-inflammatory/anti-CRC bacteria (eg butyrate-producing bacteria). Thus, we conducted a double-blinded, placebo-controlled, randomised trial of 50 healthy volunteers who took aspirin or placebo for 6 weeks and collected stool samples before, during and after the intervention. The objective of this pilot trial was to compare the between-arm changes in microbiome composition and pre-specified bacterial taxa associated with CRC and with inflammation in previous studies.[17,18]

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