Global analyses underscore that diarrheal mortality remains substantial and unevenly distributed. The pandemic era underscored both the responsiveness of transmission to public health measures and the persistence of structural inequities; one GBD 2021 analysis reported adults older than 70 years as the highest-risk age group globally during 1990–2021 trend analyses, surpassing under−five children in deaths per population in 2021 (1). In parallel, etiologies vary sharply by socio-demographic context: rotavirus and cryptosporidiosis remain dominant contributors in lower−resource settings, while CDI is disproportionately important in high−SDI regions (1, 2).

In high-income settings, the challenge is often less about incidence and more about complexity: immunomodulators and oncology therapies, advanced endoscopy and surgery, and prolonged post-acute care create new opportunities for enteric pathogens to cause severe disease, spread within healthcare networks, and interact with the host microbiome. In low-resource settings, the challenge remains the persistent convergence of enteric pathogens with undernutrition, limited access to diagnostics, delayed care, and Water, Sanitation, and Hygiene (WASH) deficits, which magnify both incidence and severity (2).

Culture−independent diagnostic tests (CIDTs) and multiplex gastrointestinal panels have reshaped surveillance and perceived incidence for several pathogens. The increasing use of syndromic GI panels has, for example, changed understanding of yersiniosis epidemiology in the United States, with more diagnoses in adults and different seasonality than previously appreciated (9). It has also increased the proportion of falsely abnormal tests.

However, CIDT adoption can paradoxically weaken public health response when reflex culture is incomplete. Public health laboratories report lower recovery of enteric bacteria from CIDT-positive specimens than from culture-derived isolates, increasing costs and limiting the isolates needed for outbreak detection, molecular subtyping, and antimicrobial susceptibility testing (10). This creates a surveillance gap precisely when pathogen evolution is accelerating.

International travel, globalized food systems and population displacement can amplify transmission and introduce resistant lineages into new settings (11, 12). Meanwhile, vulnerable host populations are expanding: older adults, transplant recipients, patients receiving immunosuppression, biologics or chemotherapy, and people with chronic liver disease or inflammatory bowel disease. These trends mean that epidemiology must be studied not only in populations, but within interconnected “ecosystems” of community, hospital, long-term care, and the environment.

A grand challenge for the field is to build surveillance that is faster, more granular, and more equitable integrating clinical data, laboratory analytics, genomics, and environmental signals while also protecting privacy and enabling rapid, practical public health action.

Multiplex PCR panels can identify pathogens rapidly and may support earlier optimization or de−escalation of antibiotics and infection control measures. Implementation of the BioFire FilmArray GI panel, for instance, has been associated with reductions in antibiotic use and earlier transition to optimal therapy in some hospital settings (13). Yet syndromic panels introduce new interpretation problems. Co-detections are common, and panels may detect colonization, low-level carriage, or prolonged shedding, particularly in children and immunocompromised hosts (12). Without quantitative outputs, clinicians often lack a principled way to distinguish causation from coincidence. The resulting uncertainty can drive both over-treatment (unnecessary antibiotics) and under-treatment (discounting actionable findings).

CDI is a diagnostic “stress test” for modern laboratory medicine. Highly sensitive nucleic acid amplification tests like PCR assays can over-diagnose CDI if used without appropriate clinical criteria or confirmatory toxin testing. Both gastroenterology and infectious diseases guidelines emphasize diagnostic algorithms that incorporate a sensitive and a specific test (or careful clinical pretest probability) to distinguish colonization from toxin-mediated disease (7, 8).

Diagnostic misclassification has downstream consequences: inappropriate isolation and antibiotics, inflated hospital metrics, increased costs, and missed alternative diagnoses (e.g., medication-related diarrhea, IBD flare, ischemic colitis). CDI diagnostics therefore exemplify the broader need for diagnostic stewardship: testing only in appropriate clinical contexts, using algorithms aligned with the local laboratory’s strengths, and reporting results with interpretive guidance.

As CIDTs replace culture, the field risks losing routine access to phenotypic antimicrobial susceptibility and the isolates needed for outbreak detection. Lower recovery of pathogens from CIDT-positive specimens undermines surveillance and drives up public health laboratory costs (10). A practical path forward will involve tiered diagnostics: syndromic panels for rapid clinical decisions; selective reflex culture for specific targets, severe disease, outbreak signals, or when susceptibility is clinically important; and integration of genomic or metagenomic approaches to recapture typing and resistance information.

Shotgun metagenomics is increasingly feasible for enteric pathogen detection. Studies demonstrate high sensitivity and specificity for common bacterial pathogens in stool, and emphasize the potential to unify diagnosis with surveillance by enabling detection plus genomic characterization in a single workflow (14). More recent work suggests metagenomics may be applied as a routine pathology test for GI infections, potentially expanding the range of detectable agents without target bias (15).

Challenges that remain include cost, turnaround time, sample preparation, contamination control, bioinformatic standardization, and most importantly clinical interpretation. Parallel progress in host-response diagnostics (e.g., multi-omics signatures of invasive bacterial infection) could help assign causality and guide therapy, but will require rigorous validation across age groups, geographies, and immunologic states.

For most acute infectious diarrhea, optimal management hinges on hydration and electrolyte replacement. The IDSA guidelines underscore the centrality of supportive care and careful risk stratification, especially for infants, older adults, and immunocompromised patients (12). However, implementation remains uneven, particularly where access to oral rehydration solution, diagnostics, and timely referral is limited.

When antibiotics are indicated, choices are increasingly constrained by resistance and by collateral harms: selection for multidrug-resistant organisms, microbiome disruption, and increased CDI risk. In travel-associated diarrhea, CDC guidance discourages prophylactic antibiotics for most travelers and highlights that antibiotic exposure increases the risk of acquiring resistant Enterobacterales; when treatment is needed, therapy should be matched to syndrome severity and likely pathogens.

A continuing grand challenge is building evidence that supports targeted therapy: who benefits from antibiotics, which agents remain effective in a given region, and what duration minimizes harms while preserving outcomes. This requires harmonized, practical endpoints (including patient-reported outcomes and post-infectious sequelae), and better integration of resistance surveillance with clinical guidance.

CDI illustrates the dilemma of treating a dysbiosis-driven infection with antibiotics that further perturb the microbiome. The 2021 focused update from IDSA/SHEA prioritizes fidaxomicin when feasible (7). Microbiota-based approaches have matured from traditional fecal microbiota transplantation (FMT) to standardized, regulated products supported by randomized trials. Fecal microbiota spores, live-brpk (an oral microbiome therapy) reduced recurrence in a randomized trial (16), and fecal microbiota, live-jslm demonstrated superiority over placebo in a phase III trial using a Bayesian primary analysis (17). In the United States, the FDA has approved these two microbiota-based products for prevention of recurrent CDI after antibacterial treatment (18, 19).

Eradication of Helicobacter pylori remains central to ulcer disease management and gastric cancer prevention, but rising resistance has eroded traditional clarithromycin- and fluoroquinolone-based regimens. The Maastricht VI/Florence consensus and the 2024 ACG guideline both emphasize empiric bismuth quadruple therapy when susceptibility is unknown, the importance of test-of-cure, and limiting clarithromycin- or levofloxacin-containing salvage regimens to cases with documented susceptibility (20, 21).

The therapeutic challenge is implementing susceptibility-guided care at scale. That includes expanding access to molecular resistance testing, validating point-of-care and noninvasive sampling approaches, and ensuring that new acid-suppressing strategies and novel antibiotics are evaluated with outcomes that matter (eradication, adverse events, cost, and long-term cancer prevention).

For norovirus and many viral gastroenteritides, specific antivirals remain limited, making prevention and outbreak control paramount (5). For protozoa such as Cryptosporidium, treatment options are limited in immunocompromised hosts, and drug development has lagged. Novel anti-infectives, monoclonal antibodies, bacteriophages, and anti-virulence strategies are promising, but translation requires better trial infrastructure, harmonized endpoints, and integration with stewardship to avoid repeating the cycle of resistance.

The most durable reductions in GI infection burden come from prevention: clean water, sanitation, hygiene, safe food systems, and vaccination. Rotavirus vaccination has reduced mortality and morbidity, with global analyses estimating tens of thousands of deaths averted each year and many more preventable with full coverage (4).

Norovirus prevention is an active frontier. The WHO highlights the large global burden and supports vaccine research that could reduce both sporadic disease and outbreaks in healthcare and congregate settings (5). For enteric fever, cholera, and other vaccine-preventable enteric infections, the challenge is implementing vaccines alongside WASH and food safety interventions to achieve durable, equitable impact.

CDI prevention depends on environmental decontamination, hand hygiene, contact precautions, judicious antibiotic and acid-suppressing medication use, and surveillance across care transitions. National estimates highlight the substantial U.S. burden of CDI despite prevention efforts (6). Because healthcare is increasingly distributed across hospitals, long-term care, outpatient infusion, and home health, infection prevention must be network-aware: interventions should target transmission pathways across facilities, not just within a single ward.

Microbiota-based strategies carry unique safety considerations. FDA safety communications have highlighted the risk of transmitting multidrug-resistant organisms and other pathogens via FMT and have outlined donor screening and testing requirements, including during the COVID−19 pandemic (22).

The grand challenge is to preserve the therapeutic promise of microbiome repair while making safety systematic and scalable. Standardized manufacturing, validated pathogen screening, robust pharmacovigilance, and long-term follow-up are essential, particularly as microbiota-based products expand beyond recurrent CDI into broader indications.