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The study of human microbiomes has yielded insights into basic science, and applied therapeutics are emerging. However, conflicting definitions of what microbiomes are and how they affect the health of the “host” are less understood. A major impediment towards systematic design, discovery, and implementation of targeted microbiome therapeutics is the continued reliance on taxonomic indicators to define microbiomes in health and disease. Such reliance often confounds analyses, potentially suggesting associations where there are none, and conversely failing to identify significant, causal relationships. This review article discusses recent discoveries pointing towards a molecular understanding of microbiome “dysbiosis” and away from a purely taxonomic approach. We highlight the growing role of systems biological principles in the complex interrelationships between the gut microbiome and host cells, and review current approaches commonly used in targeted microbiome therapeutics, including fecal microbial transplant, bacteriophage therapies, and the use of metabolic toxins to selectively eliminate specific taxa from dysbiotic microbiomes. These approaches, however, remain wholly or partially dependent on the bacterial taxa involved in dysbiosis, and therefore may not capitalize fully on many therapeutic opportunities presented at the bioactive molecular level. New technologies capable of addressing microbiome-associated diseases as molecular problems, if solved, will open possibilities of new classes and categories of targeted microbiome therapeutics aimed, in principle, at all dysbiosis-driven disorders.

Background: Human norovirus (HuNoV) is the leading viral cause of diarrhea, with GII.4 as the predominant genotype of HuNoV outbreaks globally. However, new genogroup variants emerge periodically, complicating the development of anti-HuNoV vaccines; other prophylactic or therapeutic medications specifically for HuNoV disease are lacking. Passive immunization using oral anti-HuNoV antibodies may be a rational alternative. Here, we explore the feasibility of using avian immunoglobulins (IgY) for preventing HuNoV infection in vitro in a human intestinal enteroid (HIE) model. Methods: Hens were immunized with virus-like particles (VLP) of a GII.4 HuNoV strain (GII.4/CHDC2094/1974/US) by intramuscular injection. The resulting IgY was evaluated for inhibition of binding to histo-blood group antigens (HBGA) and viral neutralization against representative GII.4 and GII.6 clinical isolates, using an HIE model. Results: IgY titers were detected by three weeks following initial immunization, persisting at levels of 1:221 (1:2,097,152) from 9 weeks to 23 weeks. Anti-HuNoV IgY significantly (p < 0.05) blocked VLP adhesion to HBGA up to 1:12,048 dilution (0.005 mg/mL), and significantly (p < 0.05) inhibited replication of HuNoV GII.4[P16] Sydney 2012 in HIEs up to 1:128 dilution (0.08 mg/mL). Neutralization was not detected against genotype GII.6. Conclusions: We demonstrate the feasibility of IgY for preventing infection of HIE by HuNoV GII.4. Clinical preparations should cover multiple circulating HuNoV genotypes for comprehensive effects. Plans for animal studies are underway.

Climate variables influence the occurrence, growth, and distribution of Vibrio cholerae in the aquatic environment. Together with socio-economic factors, these variables affect the incidence and intensity of cholera outbreaks. The current pandemic of cholera began in the 1960s, and millions of cholera cases are reported each year globally. Hence, cholera remains a significant health challenge, notably where human vulnerability intersects with changes in hydrological and environmental processes. Cholera outbreaks may be epidemic or endemic, the mode of which is governed by trigger and transmission components that control the outbreak and spread of the disease, respectively. Traditional cholera risk assessment models, namely compartmental susceptible-exposed-infected-recovered (SEIR) type models, have been used to determine the predictive spread of cholera through the fecal–oral route in human populations. However, these models often fail to capture modes of infection via indirect routes, such as pathogen movement in the environment and heterogeneities relevant to disease transmission. Conversely, other models that rely solely on variability of selected environmental factors (i.e., examine only triggers) have accomplished real-time outbreak prediction but fail to capture the transmission of cholera within impacted populations. Since the mode of cholera outbreaks can transition from epidemic to endemic, a comprehensive transmission model is needed to achieve timely and reliable prediction with respect to quantitative environmental risk. Here, we discuss progression of the trigger module associated with both epidemic and endemic cholera, in the context of the autochthonous aquatic nature of the causative agent of cholera, V. cholerae, as well as disease prediction.