Worms and gut microbes-Best of frenemies.

Abstract

Over millions of years, helminths have shared their host habitat with a myriad of other microorganisms, collectively known as the ‘microbiota’. Of the microbial communities that inhabit host organs and tissues, those residing in the gastrointestinal tract are known to play active roles in several key biological processes, including but not limited to, nutrient processing and absorption, defence against pathogens and, crucially, development and maintenance of innate and adaptive immunity. Over the past decade, the tight association between parasitic worms and the gut microbiota has attracted significant interest, as the concept of ‘host–parasite interactions’ has progressively shifted towards acknowledging the former as ‘holobiont’, that is, the host in association with its associated mutualistic symbionts. Thus, a deep knowledge of worm–holobiont interactions is essential to better understand worm biology and mechanisms of helminth disease, and ultimately to identify parasite ‘Achille's heels’ that may represent useful targets of helminth control. This timely collection of articles provides insights into the intricate network of interactions between helminths and the host gut microbiota. Given the substantial diversity of host–parasite pairs, and the several factors that have been proven to influence worm– microbiota crosstalk, covering all nuances of this relationship is undoubtedly challenging. Nevertheless, in this special issue, we aimed to include key aspects of worm–microbiota interplay, spanning the increasingly documented relative contribution of worm-associated changes in gut microbiota composition and function to health and disease, the role of gut microbes in regulating effective anti-helminth immunity, as well as the effect that diet exerts in shaping immune responses over the course of helminth infection. Building on the latter, future areas of research focusing on the development of new and sustainable strategies to counteract the negative effects of helminth infections in both humans and animals based on the manipulation of the vertebrate gut microbiota are also discussed. The issue starts with a review article by Piazzesi and Putignani, who provide an in-depth overview of the fine balance between gut microbiota establishment and maturation in early life, helminth infections, and the onset of an array of severe childhood diseases and disorders, including undernutrition, stunting and cognitive impairment. In parallel, this article discusses the likely contribution of wormmediated alterations in gut microbiota composition to the antiinflammatory properties of helminths, and argues that mimicking such alterations in absence of live infections may represent the key to translating the ‘hygiene hypothesis’ into new and effective therapeutics for chronic intestinal inflammatory diseases, obesity and metabolic disorders. Following on from this, Stark et al. discuss mounting evidence that Schistosoma infections may induce profound alterations in the composition and function of the host gut microbiota that, while mainly associated with the passage of schistosome eggs through the intestinal wall, may also result from the systemic host immune response mounted against the invading parasites. Building on recent experimental evidence derived from murine models of hepatointestinal schistosomiasis mansoni, as well as from observational studies in communities of people from schistosome-endemic areas, Stark et al. highlight the likely role(s) that the vertebrate gut microbiota plays in the cascade of events that lead to the formation of tissue granulomas. Given this evidence, the authors propose that a better understanding of the mechanisms that underpin such events may lead to the discovery of microbiome-targeting methods to minimize schistosomeassociated histopathology. If successful, these therapeutics may complement current treatment and control strategies based on mass administration of anthelmintics, hopefully leading to a significant reduction in disease burden. While likely implicated in the pathophysiology of helminth disease, the vertebrate gut microbiota exerts key functions in regulating host immune responses against non-microbial targets such as parasitic worms. In this special issue, Elizalde-Velázquez et al. elegantly explore the effects of long-term antibiotic treatment of mice on the dynamics of effector, memory and recall Th2 immune responses against the small intestinal nematode, Heligmosomoides polygyrus. The authors show that removal of gut bacteria leads to only slightly increased worm burdens in secondary infections, and hypothesize that the microbiota associated with helminth larvae administered to antibiotic-treated mice may be sufficient to modulate Th2-type immune responses during primary infection. Elizalde-Velázquez et al. conclude that temporary removal of the gut microbiota does not impair the onset, maintenance and function of memory Th2 cell responses during primary H. polygyrus infection, or the activation of host recall Th2 responses during secondary infection. The composition and thus immune-modulatory functions of the vertebrate gut microbiota are highly dependent on diet and metabolism of dietary components. In their highly pertinent review article, Myhill and Williams provide an overview of the mechanisms that underpin the ability of diet to dramatically influence the effectiveness of immune responses to helminth infections; nevertheless, the authors present a series of examples that demonstrate that the effect of diet manipulation (e.g., via the administration of prebiotics and/or probiotics) on anti-helminth immunity may be contingent to several factors (e.g., host and parasite species, and location of the latter in the Received: 25 January 2023 Accepted: 25 January 2023