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Bacterial biofilms are often defined as communities of surface-attached bacteria and are typically depicted with a classic mushroom-shaped structure characteristic of Pseudomonas aeruginosa. However, it has become evident that this is not how all biofilms develop, especially in vivo, in clinical and industrial settings, and in the environment, where biofilms often are observed as non-surface-attached aggregates. In this Review, we describe the origin of the current five-step biofilm development model and why it fails to capture many aspects of bacterial biofilm physiology. We aim to present a simplistic developmental model for biofilm formation that is flexible enough to include all the diverse scenarios and microenvironments where biofilms are formed. With this new expanded, inclusive model, we hereby introduce a common platform for developing an understanding of biofilms and anti-biofilm strategies that can be tailored to the microenvironment under investigation.In this Review, Bjarnsholt and colleagues propose a revised conceptual model of the biofilm life cycle that encompasses the three major steps of biofilm formation — aggregation, growth and disaggregation — independently of surfaces, and initiation from single-cell planktonic bacteria, and thus represents a broader range of biofilm systems.

The biofilm matrix can be considered to be a shared space for the encased microbial cells, comprising a wide variety of extracellular polymeric substances (EPS), such as polysaccharides, proteins, amyloids, lipids and extracellular DNA (eDNA), as well as membrane vesicles and humic-like microbially derived refractory substances. EPS are dynamic in space and time and their components interact in complex ways, fulfilling various functions: to stabilize the matrix, acquire nutrients, retain and protect eDNA or exoenzymes, or offer sorption sites for ions and hydrophobic substances. The retention of exoenzymes effectively renders the biofilm matrix an external digestion system influencing the global turnover of biopolymers, considering the ubiquitous relevance of biofilms. Physico-chemical and biological interactions and environmental conditions enable biofilm systems to morph into films, microcolonies and macrocolonies, films, ridges, ripples, columns, pellicles, bubbles, mushrooms and suspended aggregates — in response to the very diverse conditions confronting a particular biofilm community. Assembly and dynamics of the matrix are mostly coordinated by secondary messengers, signalling molecules or small RNAs, in both medically relevant and environmental biofilms. Fully deciphering how bacteria provide structure to the matrix, and thus facilitate and benefit from extracellular reactions, remains the challenge for future biofilm research.In this Review, Flemming et al. revisit our understanding of the biofilm matrix, focusing on the diversity of the extracellular polymeric substance components and novel aspects of mechanisms and consequences of their functional interactions.

Chronic infections caused by microbial biofilms represent an important clinical challenge. The recalcitrance of microbial biofilms to antimicrobials and to the immune system is a major cause of persistence and clinical recurrence of these infections. In this Review, we present the extent of the clinical problem, and the mechanisms underlying the tolerance of biofilms to antibiotics and to host responses. We also explore the role of biofilms in the development of antimicrobial resistance mechanisms.Chronic infections caused by microbial biofilms represent an important clinical challenge owing to the recalcitrance of microbial biofilms to antimicrobials and the immune system, causing persistence and clinical recurrence of these infections. In this Review, Ciofu and colleagues discuss our current understanding of the mechanisms of tolerance of such biofilms to the immune system as well as of tolerance and resistance to antimicrobials.

A wide diversity of microorganisms, typically growing as biofilms, has been implicated in corrosion, a multi-trillion dollar a year problem. Aerobic microorganisms establish conditions that promote metal corrosion, but most corrosion has been attributed to anaerobes. Microbially produced organic acids, sulfide and extracellular hydrogenases can accelerate metallic iron (Fe0) oxidation coupled to hydrogen (H2) production, as can respiratory anaerobes consuming H2 as an electron donor. Some bacteria and archaea directly accept electrons from Fe0 to support anaerobic respiration, often with c-type cytochromes as the apparent outer-surface electrical contact with the metal. Functional genetic studies are beginning to define corrosion mechanisms more rigorously. Omics studies are revealing which microorganisms are associated with corrosion, but new strategies for recovering corrosive microorganisms in culture are required to evaluate corrosive capabilities and mechanisms. Interdisciplinary studies of the interactions among microorganisms and between microorganisms and metals in corrosive biofilms show promise for developing new technologies to detect and prevent corrosion. In this Review, we explore the role of microorganisms in metal corrosion and discuss potential ways to mitigate it.In this Review, Xu, Gu and Lovley examine the varied mechanisms by which microorganisms can cause metal corrosion and explore different strategies that could prevent it.

Marine biofilms are ubiquitous in the marine environment. These complex microbial communities rapidly respond to environmental changes and encompass hugely diverse microbial structures, functions and metabolisms. Nevertheless, knowledge is limited on the microbial community structures and functions of natural marine biofilms and their influence on global geochemical cycles. Microbial cues, including secondary metabolites and microbial structures, regulate interactions between microorganisms, with their environment and with other benthic organisms, which affects their community succession and metamorphosis. Furthermore, marine biofilms are key mediators of marine biofouling, which greatly affect marine industries. In this Review, we discuss marine biofilm dynamics, including their diversity, abundance and functions. We also highlight knowledge gaps, areas for future research and potential biotechnological applications of marine biofilms.Marine biofilms grow on diverse marine surfaces, ranging from particles to animals and ships. In this Review, Qian and colleagues discuss the diversity and composition of marine biofilms and their role in the development of marine benthos and biofouling.

Historically, appreciation for the roles of resource gradients in biology has fluctuated inversely to the popularity of genetic mechanisms. Nevertheless, in microbiology specifically, widespread recognition of the multicellular lifestyle has recently brought new emphasis to the importance of resource gradients. Most microorganisms grow in assemblages such as biofilms or spatially constrained communities with gradients that influence, and are influenced by, metabolism. In this Review, we discuss examples of gradient formation and physiological differentiation in microbial assemblages growing in diverse settings. We highlight consequences of physiological heterogeneity in microbial assemblages, including division of labour and increased resistance to stress. Our impressions of microbial behaviour in various ecosystems are not complete without complementary maps of the chemical and physical geographies that influence cellular activities. A holistic view, incorporating these geographies and the genetically encoded functions that operate within them, will be essential for understanding microbial assemblages in their many roles and potential applications.Differential availability of oxygen, nutrients and other resources leads to metabolic and structural heterogeneity in multicellular systems, including in biofilms. In this Review, Jo et al. discuss how chemical and physical gradients can affect the physiology of microbial biofilms.

Biofilms are a form of collective life with emergent properties that confer many advantages on their inhabitants, and they represent a much higher level of organization than single cells do. However, to date, no global analysis on biofilm abundance exists. We offer a critical discussion of the definition of biofilms and compile current estimates of global cell numbers in major microbial habitats, mindful of the associated uncertainty. Most bacteria and archaea on Earth (1.2 × 1030 cells) exist in the ‘big five’ habitats: deep oceanic subsurface (4 × 1029), upper oceanic sediment (5 × 1028), deep continental subsurface (3 × 1029), soil (3 × 1029) and oceans (1 × 1029). The remaining habitats, including groundwater, the atmosphere, the ocean surface microlayer, humans, animals and the phyllosphere, account for fewer cells by orders of magnitude. Biofilms dominate in all habitats on the surface of the Earth, except in the oceans, accounting for ~80% of bacterial and archaeal cells. In the deep subsurface, however, they cannot always be distinguished from single sessile cells; we estimate that 20–80% of cells in the subsurface exist as biofilms. Hence, overall, 40–80% of cells on Earth reside in biofilms. We conclude that biofilms drive all biogeochemical processes and represent the main way of active bacterial and archaeal life.In this Analysis article, Flemming and Wuertz calculate the total number of bacteria and archaea on Earth and estimate the fraction that lives in biofilms. They propose that biofilms are the most prominent and influential type of microbial life.

Key Points Biofilms harbour complex structural and biological attributes, such as the presence of an extracellular polymeric matrix, physical and chemical heterogeneity and drug tolerance, which provide remarkable therapeutic challenges. Biofilm drug tolerance is a consequence of complex physicochemical and biological properties with multiple microbial genetic and molecular factors, often involving polymicrobial interactions. The challenges to existing antimicrobial or monotherapeutic approaches by the multifactorial nature of biofilm development, combined with drug tolerance, requires robust effective multitargeted or combinatorial therapies. Combinatorial strategies are needed to eliminate existing biofilms by targeting vital structural and functional traits of biofilms, such as the EPS matrix and dormant cells, as well as approaches exploiting host–pathogen interactions. Promising technologies based on 'smart release' or 'on-demand activation' of bioactive agents when triggered by biofilm-derived cues can degrade the matrix and kill resident bacteria, and have the potential to eradicate the pathogenic niche with precision and minimal cytotoxicity to surrounding tissues. Validation of proof-of-concept studies using clinically relevant animal models, as well as clinical trials, are needed for rigorous evaluation. In this Review, Stoodley and colleagues discuss current therapeutic strategies and those under development for the treatment of pathogenic biofilms. They explore novel technologies that promise to enhance the efficacy of current therapeutics or provide novel effects and argue that treating biofilm infections requires combination therapies. Biofilm formation is a key virulence factor for a wide range of microorganisms that cause chronic infections. The multifactorial nature of biofilm development and drug tolerance imposes great challenges for the use of conventional antimicrobials and indicates the need for multi-targeted or combinatorial therapies. In this Review, we focus on current therapeutic strategies and those under development that target vital structural and functional traits of microbial biofilms and drug tolerance mechanisms, including the extracellular matrix and dormant cells. We emphasize strategies that are supported by in vivo or ex vivo studies, highlight emerging biofilm-targeting technologies and provide a rationale for multi-targeted therapies aimed at disrupting the complex biofilm microenvironment.

The dynamic and polymicrobial oral microbiome is a direct precursor of diseases such as dental caries and periodontitis, two of the most prevalent microbially induced disorders worldwide. Distinct microenvironments at oral barriers harbour unique microbial communities, which are regulated through sophisticated signalling systems and by host and environmental factors. The collective function of microbial communities is a major driver of homeostasis or dysbiosis and ultimately health or disease. Despite different aetiologies, periodontitis and caries are each driven by a feedforward loop between the microbiota and host factors (inflammation and dietary sugars, respectively) that favours the emergence and persistence of dysbiosis. In this Review, we discuss current knowledge and emerging mechanisms governing oral polymicrobial synergy and dysbiosis that have both enhanced our understanding of pathogenic mechanisms and aided the design of innovative therapeutic approaches for oral diseases.

Biofilm formation is a process in which microbial cells aggregate to form collectives that are embedded in a self-produced extracellular matrix. Bacillus subtilis is a Gram-positive bacterium that is used to dissect the mechanisms controlling matrix production and the subsequent transition from a motile planktonic cell state to a sessile biofilm state. The collective nature of life in a biofilm allows emergent properties to manifest, and B. subtilis biofilms are linked with novel industrial uses as well as probiotic and biocontrol processes. In this Review, we outline the molecular details of the biofilm matrix and the regulatory pathways and external factors that control its production. We explore the beneficial outcomes associated with biofilms. Finally, we highlight major advances in our understanding of concepts of microbial evolution and community behaviour that have resulted from studies of the innate heterogeneity of biofilms.In this Review, Stanley-Wall and colleagues provide an overview of biofilm composition and formation in Bacillus subtilis and how this research is informing microbial evolution and ecology and aiding in the development of beneficial applications for biofilms.