The Hidden Drivers of Treatment Resistance

From periodontal pocket to tumor bed, hormone recycling and what happens when you miss trash day

Imagine trash day at your house. The liver sorts and bags the waste. Bile is the garbage truck that hauls it to the curb. The gut carries it out. When the system runs on schedule, waste leaves. When it does not, bags sit at the curb. Bacteria overgrow. Mold residue forms. Bags split open, and some of what was meant to leave finds its way back inside.

Most of oncology is built around what goes in: the drug, the surgery, the radiation. I spend an equal amount of time on what comes out.

Elimination is a rate-limiting step in cancer biology. It shapes inflammation, hormone signaling, microbial balance, and treatment tolerance. It matters in prevention, during active treatment, and in survivorship.

Bile flow and the estrogen loop

Bile is the primary exit route for fat-soluble toxins, conjugated estrogen metabolites, and the byproducts of hepatic phase I and phase II detoxification. When the liver conjugates a compound, the plan is for it to ride bile into the intestine and leave the body in stool. If bile is sluggish, from low dietary fat, sedentary lifestyle, poor gallbladder motility, or prior cholecystectomy, those conjugated compounds sit in the gut longer than they should.

This is where the microbiome enters the equation. Dysbiotic bacteria express beta-glucuronidase, an enzyme that cleaves the conjugate and liberates the parent compound, including estrogen metabolites. That estrogen re-enters circulation through enterohepatic recirculation. In symptom management and hormone-sensitive cancers, this is a clinically meaningful place to intervene. In prevention, constipation, high-glucuronidase gut flora, and stagnant bile may be modifiable risk factors for breast and endometrial cancers.

I tell patients this plainly. If you are not pooping at least once per day, you are recycling what your liver is trying to get rid of.

Gut barrier integrity and systemic inflammation

The microbiome gets a lot of attention, but if the gut barrier is not intact, even a “healthy” microbiome cannot function the way it should. Tight junction proteins are what keep the intestinal lumen separate from systemic circulation. When those junctions are disrupted, by chemotherapy, radiation, NSAIDs, PPIs, alcohol, or chronic dysbiosis, lipopolysaccharide from gram-negative bacteria translocates into the bloodstream. LPS activates TLR4 and drives NF-kB, one of the most potent inflammatory signaling cascades in the body.

Image from Bhat et al., Frontiers in Physiology, 2019

In active treatment, this is what underlies chemo-induced mucositis and poor treatment tolerance. In prevention and survivorship, it is subtler and more insidious. A compromised barrier can exist without GI symptoms or a slew of other systemic symptoms, at first glance unrelated to GI system. Or the patient might feel fine, but their baseline inflammatory tone is elevated, cytokine signaling is dysregulated, and the tumor microenvironment is primed for progression. Chronic LPS exposure is associated with hepatocellular carcinoma, colorectal cancer, and immune exhaustion that matters in any oncology context.

I believe barrier support belongs in standard supportive care during cytotoxic therapy, and in risk modification for anyone else.

The oral-gut-immune axis

This is the part the field has caught up on in the last five years. The bacteria in your mouth show up inside your tumors. Fusobacterium nucleatum, a periodontal pathogen, has been identified inside colorectal, pancreatic, and esophageal tumors, where it is not a passive contaminant. It actively promotes tumor progression and chemoresistance.

Fig. 1: The role of Fusobacterium within the tumor microenvironment from: Fusobacterium in the microbiome: from health to disease across the oral–gut axis and beyond

Porphyromonas gingivalis is associated with elevated pancreatic cancer risk. The clinical separation of dentistry and oncology is no longer an option.

In the gut, microbiome diversity and specific commensal species predict whether a patient responds to checkpoint inhibitor immunotherapy. Akkermansia muciniphila and Faecalibacterium prausnitzii are two of the best-studied. Routy et al. in Science showed that patients whose microbiomes were disrupted by broad-spectrum antibiotics before starting a checkpoint inhibitor had significantly worse outcomes. Fecal microbiota transplant trials are now underway to convert non-responders into responders. The microbiome is a treatment variable, not a wellness add-on.

For prevention, the implication is the same. A diverse, short-chain-fatty-acid-producing microbiome is associated with lower risk across multiple cancer types. Diet shapes it, stress shapes it, antibiotics disrupt it, and most people do very little to actively maintain it.

A word on antibacterial mouthwash

For the love of your health, stop using antibacterial mouthwash unless you have a specific clinical reason. Chlorhexidine, cetylpyridinium chloride, and high-alcohol formulations wipe out the oral microbiome indiscriminately, including the nitrate-reducing bacteria on the tongue that are essential for nitric oxide production. Disruption of that pathway raises blood pressure within days of regular use and has emerging links to glucose dysregulation and cardiovascular risk. These rinses also leave a scorched-earth oral environment that pathogens recolonize faster than commensals, which means the long-term effect is often more dysbiosis, not less. Post-surgical use, active periodontal treatment, and specific circumstances in immunocompromised patients are reasonable indications for short-term use. Daily cosmetic use for fresh breath does more harm than good.

Mold and biofilms

Two additional layers the standard workup misses. Biofilms are structured bacterial and fungal communities that adhere to mucosal surfaces, produce a protective polysaccharide matrix, and resist both the immune system and antimicrobial treatment. In the oral cavity they drive periodontal disease. In the gut they house the dysbiotic species that keep recurring after you treat them. Fusobacterium forms biofilms inside colorectal tumors, which is part of why it is so difficult to clear. If a patient has been treated for SIBO or dysbiosis three times and it keeps returning, you are dealing with biofilm.

Mold is the other blind spot. Environmental mold exposure and mycotoxin load drive chronic immune activation, disrupt the gut barrier, and feed intestinal fungal overgrowth. Aflatoxin is a class 1 carcinogen with direct hepatocarcinogenic activity. Ochratoxin A is associated with renal and urothelial malignancies. In patients with unexplained inflammation, treatment-resistant dysbiosis, or a history of water-damaged building exposure, a urinary mycotoxin panel and a careful environmental history belong in the workup.

Fasting and the fed-fasted cycle

One of the simplest tools is fasting. It is also one of the oldest. Hippocrates advocated it. Every major religious tradition has built a fast into its calendar, from Ramadan to Lent to Yom Kippur to the Hindu Ekadashi cycle. Ayurveda has prescribed it as langhana for thousands of years. Fasting is a conserved biological rhythm.

The body cleans in the fasted state. The migrating motor complex sweeps debris and bacteria out of the small intestine every 90 to 120 minutes between meals, which is a primary defense against SIBO and small bowel dysbiosis. Autophagy, the cellular recycling system, ramps up during prolonged fasts and is part of how the body clears damaged proteins, organelles, and malignant cells. Constant grazing shuts both of these off.

For prevention, a 12 to 14 hour overnight fast is associated with reduced breast cancer recurrence in the Marinac et al. data. During active treatment, Valter Longo's fasting-mimicking diet carries the strongest evidence base, with data suggesting it can protect healthy cells during chemotherapy and improve treatment response. Work with a clinician who can tailor it to your plan. Prolonged fasting carries real risk in patients with active weight loss, sarcopenia, or nutritional compromise. The clinical picture matters.

Daily intermittent fasting suits some people poorly, particularly those with already dysregulated endocrine systems. A longer fast (either water or vegetable broth) of 24 to 72 hours every couple of months often works better, and for otherwise healthy individuals it is one of the most effective tools for primary prevention. It keeps the house clean and the trash going out on schedule.

My nutrient dense broth for the next few days

How to assess it all

If you want to know whether these pathways are functioning, test them. A comprehensive stool panel with beta-glucuronidase, calprotectin, short-chain fatty acid production, and microbial diversity gives a functional read on the gut. Zonulin and LPS antibodies, while imperfect, can support a barrier assessment. A urinary mycotoxin panel is worth adding in anyone with unexplained inflammation, chronic dysbiosis, or known mold exposure. An oral microbiome panel is worth considering in patients with a GI or pancreatic cancer workup, chronic periodontal disease, or a strong family history. Cost varies. Individual tests like zonulin or an oral panel run $150 to $300. A full stool panel runs $300 to $500 cash pay, though private insurances and even Medicare will cover the pathogen PCR portion of GI-MAP when clinically indicated.

Targeted support

For bile flow: dietary fat at each meal, bitters before eating, taurine, and ox bile when motility is sluggish or the gallbladder has been removed. Build meals around bitter greens like arugula, dandelion, radicchio, and endive. Beets and artichokes directly support bile production. Lemon water or apple cider vinegar before meals primes gastric and bile acid release. Extra-virgin olive oil stimulates CCK and gallbladder contraction. Castor oil packs and adequate hydration are underused. Address constipation aggressively. Daily transit is non-negotiable.

For beta-glucuronidase and estrogen recirculation: calcium-D-glucarate, cruciferous vegetables or concentrated DIM, insoluble fiber to bind and move conjugated estrogens out, and treating the underlying dysbiosis at the source. Eat cruciferous vegetables daily, including broccoli, cauliflower, Brussels sprouts, cabbage, kale, bok choy, and arugula. Ground flaxseed, two to three tablespoons daily, provides lignans that bind circulating estrogen and shift metabolism toward safer estrogen fractions. Pomegranate, green tea, and shiitake or white button mushrooms offer aromatase inhibition. Adequate protein and choline from eggs, liver, and legumes fuel the methylation pathways that clear estrogen metabolites.

For barrier repair during or after cytotoxic therapy: L-glutamine, zinc carnosine, and deglycyrrhizinated licorice. Bone broth, wild salmon and other omega-3 rich fish, and collagen peptides. Cooked and stewed vegetables sit more easily on inflamed mucosa than raw. Ginger and turmeric support inflammatory resolution. Fermented foods once tolerance is established. Aloe inner leaf where tolerated. Removing the ongoing insult, whether NSAIDs, alcohol, chronic PPI use, or industrial seed oils, matters more than any supplement.

For microbiome diversity: fiber variety first, ideally 30 different plants per week. Fermented foods daily. Targeted prebiotics like partially hydrolyzed guar gum, resistant starch, or larch arabinogalactan. Specific probiotic strains when there is a clinical reason, including Bifidobacterium longum, Lactobacillus rhamnosus GG, and Saccharomyces boulardii for antibiotic-associated dysbiosis. Akkermansia muciniphila is now available as a direct-feed strain and worth considering in metabolic and immunotherapy contexts, but best outcomes are achieved through feeding your own Akkermansia through prebiotics:

• Polyphenols: pomegranate, green tea, cranberry, dark chocolate

• Inulin/FOS: garlic, onions, leeks, chicory root

• Resistant starch: green bananas, cooled potatoes or rice, legumes

• PHGG (supplement)

For biofilm disruption, often the reason microbiome interventions finally hold: bismuth, NAC, lactoferrin, EDTA, proteolytic enzymes like serrapeptase, nattokinase, and lumbrokinase, and botanicals such as berberine, oregano oil, and garlic. Pharmaceutical options include rifaximin and tinidazole for gut and SIBO-associated biofilm, nitazoxanide for broader spectrum coverage including protozoal involvement, and sub-antimicrobial dose doxycycline for periodontal biofilm.

The interventions shift based on testing, treatment phase, and what the patient is actively managing. A patient on active chemo has different priorities than someone in year three of survivorship.

What this means clinically

For clinicians, this means asking about bowel frequency and stool character at every oncology intake, screening for periodontal disease in any GI, pancreatic, or esophageal workup, and treating bile flow and constipation as first-line interventions in hormone-sensitive cancers. Barrier support belongs in the supportive care plan during and after cytotoxic therapy. A urinary mycotoxin panel belongs in the workup of any patient with unexplained inflammation, treatment-resistant dysbiosis, or a history of water-damaged building exposure. If a patient has been treated for SIBO or dysbiosis three times and it keeps returning, biofilm is the next layer. Be thoughtful about PPIs and broad-spectrum antibiotics around immunotherapy initiation whenever the clinical picture allows.

For patients, focus on building healthier habits over time. Aim for a daily bowel movement. When transit slows, the body reabsorbs what it was trying to eliminate. Oral health is systemic health, so reconsider the antibacterial mouthwash if you are using it daily. Build meals around fiber variety, working toward 30 different plants per week. Cruciferous vegetables belong on the plate most days. Fermented foods can come in once your gut is ready for them, and ground flaxseed offers gentle support for estrogen clearance. Bitter greens, beets, and olive oil help bile move. Reducing NSAIDs, alcohol, chronic PPIs, and industrial seed oils gives a compromised gut lining the space to heal. If you are on immunotherapy, anything that disrupts your gut flora without a strong clinical reason is worth a conversation with your oncology team.

Elimination is part of treatment. The barrier is part of treatment. The microbiome is part of treatment. In prevention, they are the protection.

Ksenia Malarkey, ND is a naturopathic physician specializing in integrative oncology, hormones, and metabolic health.

She provides medical care for Washington residents and offers global health coaching.

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To schedule a free 15-minute consult, visit drkseniamalarkey.com