The Influence of Seasonal Variations in Clinical Trials Based on Gut Microbiota Studies

Abstract

Seasonality is a key determinant in shaping the composition and function of the human gut microbiota, exerting its influence through multiple interconnected factors. These include seasonal variations in diet, environmental conditions (such as temperature, humidity, and sunlight exposure), behavioral patterns (physical activity, time spent outdoors), and the incidence of seasonal infections. These changes are most visible in certain populations where food availability follows a seasonal pattern. Increasing evidence suggests that gut microbiota composition undergoes seasonal variations, which may have significant implications for human health. In patients with non-communicable chronic diseases (NCDs), where microbiota dysbiosis plays a crucial role in disease progression, understanding the seasonal effects on gut microbiota is essential. These dynamic changes impact the gut microbiota immune system interaction and may contribute to the onset or exacerbation of various diseases, including chronic inflammatory, metabolic, and autoimmune disorders. Most clinical trials on probiotics do not consider seasonality as a confounding variable, which could impact the interpretation of results and therapeutic efficacy, potentially biasing estimates of intervention efficacy or associations with disease. This review examines the current evidence on gut microbiota seasonality, discusses its potential bias, and outlines methodological considerations for future clinical trials.

Keywords: dietary; gut microbiota; non-communicable chronic diseases; seasonality.

Figure 1

The Influence of Seasonality on the Gut Microbiota. Schematic representation of the main seasonal environmental and behavioral factors that influence gut microbiota composition and function. Environmental factors include temperature variation, sunlight exposure, and seasonal infections, while behavioral factors encompass changes in physical activity and dietary intake. These elements interact with the host immune system, circadian rhythm, and metabolic pathways, collectively shaping microbial diversity and function across seasons.

Figure 2

Methodological strategies for Clinical Trials to minimize bias. Diagram summarizing methodological strategies to minimize the confounding effect of seasonality in microbiota-targeted clinical trials. Approaches include longitudinal study design spanning multiple seasons, seasonal stratification during randomization, detailed tracking of seasonal covariates (diet, activity, vitamin D), post hoc statistical corrections such as Inverse Probability Weighting, and use of adaptive clinical trial designs. These methods enhance internal validity by reducing biases introduced by seasonal fluctuations in microbial composition and host physiology.