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Oral mucositis remains one of the most dominant, serious, disrupThe mucositis puzzle is complicated and consists of multiple pieces tive, and symptomatic complications of radiation therapy used for the treatment of cancers of the head and neck (Villa and Sonis, 2015). Progressive mucosal injury accompanies increasing daily radiation fractions until confluent, deep, ulceration develops in the majority of patients, and the lack of an effective intervention is one of the biggest clinical frustrations for healthcare professionals charged with caring for them. Given the breadth of microbial colonization in the oral cavity, a role for the oral microbiome in altering the risk or course of mucositis has been suspected for years. Andwhile the literature is repletewith reports demonstrating a change in the composition of the oral flora following cancer therapy (Hu et al., 2013), anti-bacterial treatment strategies for mucositis have been largely unsuccessful (Trotti et al., 2004). A consistent and clinically meaningful link between the oral microbiome and mucositis has been elusive. The historical paradigm for radiation-induced tissue injury, which was predicated on indiscriminate clonogenic cell death of rapidly dividingnormal cells, has been overturned in favor of amore complex biological cascade (Sonis, 2009). How, if, and where the oral microbiome contributes to this scheme was the subject of a study reported in this issue of EBioMedicine by Zhu et al. (2017) who prospectively evaluated the relationship between the trajectory of changes in the oral microbiome and oral mucositis in nineteen patients being treated with radiation or concomitant chemoradiation for nasopharyngeal carcinoma (NPC). Thirteen of the studied subjects developed severe mucositis. Differences in the baseline (pre-radiation) oral microbiota were noted between control and NPC subjects: not only was there more similarity in the bacterial communities among healthy patients, but the healthy controls also had a more diverse microflora. Speciation of the oral flora among patients with no or mild mucositis differed from those developing more severe forms of the condition. This observation leads to key questions of its clinical significance: does it represent a means for facilitation of mucositis and is it specific enough to predict the course of mucositis, or do changing bacteria simply reflect the microflora's response to other, non-mucositis, but parallel factors?

The Chicken or the Egg? Changes in Oral Microbiota as Cause or Consequence of Mucositis During Radiation Therapy