Oxygen - the missing link in IBS, IBD + SIBO?

Written By Julie Forrester

Research into the microbiome is booming, so it’s vital to keep abreast of new insights that replace/refine older understandings to adapt new treatment strategies. It’s often people with chronic digestive symptoms (and their consequences) who’ve tried everything without resolution, that benefit the most.

In the past 10-15 years, functional and naturopathic treatments have focussed on improving the integrity of the tight junctions - proteins connecting cells of the digestive tract. However, if this was the only issue for people with intestinal hyperpermeability (aka leaky gut), then why are some still suffering? New evidence highlights the importance of other factors involved in the gut barrier that drive disruption of tight junctions. If you didn’t realise that the digestive system is incredibly complex, you’re in for a treat.

Oxygenation may be the new focal point for treating digestive symptoms of intestinal hyperpermeability (also known as intestinal permeability or leaky gut). Learn what the new evidence is and what can be done to optimise the health of the digestive tract. Is this your missing link?

Is oxygen the missing link in IBS, IBD and SIBO?

In this article, we cover - 

  • The terrain - what makes up our gut lining

  • Anaerobic vs aerobic bacteria

  • Butyrate and oxygenation

  • What are hypoxia-inducible factors (HIFs)?

  • Current treatments

  • What new treatments improve hypoxia


The terrain - what makes up our gut lining

The digestive system is a dynamic environment that protects the body from anything we ingest that may cause harm whilst allowing ‘in’ what we need to survive. The role of the single-celled lining of the gut is to absorb and process nutrients + water, remove waste and ensure detection and destruction of any dangerous molecules (microbial, pathogens, parasites, viruses, chemicals, toxins). 

Tight junctions, the proteins that join those cells together in the digestive lining, have been a focus of attention for the last 10-15 years in treating many digestive disorders, allergies and food intolerances. When tight junction proteins sense toxins or pathogens or become damaged, the lining becomes temporarily permeable, meaning gaps between the cells open to rid the body of the danger.

In a healthy gut, it’s a defence mechanism triggered when we consume a pathogen like Salmonella, the response quickly rids the body of the harmful bacterium by allowing it to cross over the barrier, stimulating an immune reaction. The immune system is mostly located over the other side of the digestive lining with various mechanisms to respond, sample, and destroy pathogens, and then the system recovers and resets, and the barrier is restored.

If allowed to continue, however, chronic insults to the tight junctions can cause a faulty reaction of the system, causing a hyper-permeability (more/larger gaps) of the intestinal lining, then triggering more inflammation, allergy, and intolerances, which then drives more gut microbiome disruption and then more allergies/intolerances in a cyclical fashion.

As newborns, this layer is mostly open, allowing important immune molecules from breastmilk across the digestive barrier, priming and teaching the immune system. At this time, we have only a few species of microbes, predominantly aerobic and mostly from our mum, if we were born vaginally. Interestingly, if born by a caesarian section, we are more likely to carry microbes found on the skin of others present in the delivery room at the time than from mum (unless ‘swabbed’, now the common practice). Antibiotics given to mum at/near the time of birth or to bub in early life can disrupt some of those microbes. They are, of course, necessary sometimes but disruptive nevertheless. As baby matures, the species increase, and the gut barrier closes, becoming less and less permeable.

The one-cell thick lining of the digestive tract and its tight junctions are protected from coming into easy contact with the potentially damaging contents of the gut, and these layers include:

  • The mucosal layer/s- a single thin layer of mucus in the small intestines and 2 layers, one thin and one thick in the colon. Mucus assists food to slide down the gut easily and protects the lining from acidity, chemical insults and direct contact with the contents passing through the gut. The mucus layer is home to microbes and a food source for some, thus regulating the amount and production of the mucus made by goblet cells of the gut lining. 

  • The microbiome layer - living in and on the thin mucus layers, these microbes may be anaerobic (oxygen resistant), facultative anaerobes (primarily anaerobic, but can adapt to oxygenated environments) or aerobic (requiring oxygen for survival). In addition, microbes also regulate each other, the atmospheric layer and highly influence the chemical layer. In the small intestines, there are relatively few species, and the large intestines hold the greatest number of microbes of all the biomes of the body - made up of predominantly bacteria but also fungi, viruses, archaea and protozoa.

  • The chemical layer - made up of short-chain fatty acids such as acetate, propionate and butyrate, the breakdown products of the beneficial microbes (think of it like fertiliser for the gut), as well as damaging endotoxins of pathogenic microbes, a host of other chemical signalling molecules, and protective molecules keeping some microbes from taking hold.

  • The atmospheric layer - is possibly the most important. There is a decreasing amount of oxygen as you travel down the digestive tract from the mouth to the anus. This oxygen to hypoxia (meaning ‘without oxygen’)  gradient is integral to the health of all of the other layers, as it supports different microbiota in different zones, e.g. in the upper parts of the mouth to the stomach, there is greater oxygen supporting more aerobic species, and facultative anaerobes. In contrast, anaerobic microbes largely dominate the colon because there is substantially less oxygen. 

Think about how well you would survive on the moon without oxygen. When this atmospheric layer is out of balance, the species, usually living there and maintaining the important protective layers cannot survive, and other microbes that should not be there might thrive. This imbalance becomes self-perpetuating, causing greater impermeability, inflammation, food allergies/intolerances and digestive discomfort.

On the other side of the barrier, other layers also impact the functioning of the digestive lining and the amount of oxygen, including;

  • Vascular & lymphatic networks - crucial for delivering nutrients, oxygen and other gases to and removing waste from the lining cells. 

  • Immune system - a vast system of innate and adaptive cells interacting with molecules crossing the barrier lining, testing and tagging, and presenting parts of these molecules for attack or memory. Essentially, like border control, they check everything that comes in and decide if it’s safe or not.

These layers work in conjunction with one another to keep the gut lining healthy while still allowing nutrients to pass across into circulation. It is also important to understand that there is an oxygen gradient between the inside and outside of the gut layers, as the vascular system delivers oxygen to the cells. Then, progressively different mechanisms in the layers reduce that oxygen, e.g. the cells may consume some, the microbes may consume some and aspects of the chemical layer may also use that oxygen, decreasing the amount inside the gut. Giving both horizontal and vertical changes in oxygenation throughout the gut. 

Anaerobes, facultative anaerobes versus aerobes

The location of microbiota in various parts of the digestive system is determined by their tolerance to oxygen and other gases. Alterations to these gases can then alter the species that thrive there.

Anaerobes use fermentation of different food sources and can only survive in hypoxic (no oxygen) environments. Anaerobes comprise the greatest number of microbes in the gut and have differing tolerances to oxygen. Interestingly, anaerobes cause almost all dental cavities and infections of the mouth and gums living in oxygen-free pockets, e.g. the gums. Anaerobes outnumber other types of bacteria by nearly 10:1 in the colon. They include Actinomyces, Bacteroides, Clostridioides (previously known as Clostridium), Fusobacterium, Peptostreptococcus, Porphyromonas, Prevotella, Propionibacterium, and Veillonella. 

Facultative anaerobes - use either fermentation in hypoxic environments or change to produce ATP (the same as our body’s main energy source) in oxygenated environments. Mostly, bacterial facultative anaerobes include Lactobacillus, Salmonella, Listeria, Corynebacterium Staphylococci spp., Streptococci spp., Enterococci and Shewnella oneidensis, and fungi such as Saccharomyces cerevisiae

Aerobes can only survive in an oxygenated environment. They include E. Coli, Citrobacter, Mycobacterium tuberculosis, Pseudomonas aeruginosa, Bacillus, Klebsiella, Proteus, Salmonella, and Achromobacter. Almost all fungal species are aerobes. 

Microaerophilic Anaerobes can only thrive in low oxygen concentration or high carbon dioxide environments. A bacterium associated with Lyme disease, Borrelia burgdorferi, and Helicobacter pylori, a proteobacterium associated with stomach ulcers (and more recently considered to be a commensal opportunistic species) are both examples of microaerophilic anaerobes.

Butyrate and oxygenation

Beneficial species of bacteria produce short-chain fatty acids (SCFAs) acetate, propionate and butyrate. Of those, butyrate has a multitude of benefits to ‘the host’ (us), including:

  • Gut benefits

    • Nurtures the cells of the small and large colon linings

    • Promotes healthy intestinal linings (i.e. reduces intestinal hyperpermeability)

    • Reduces absorption of endotoxins produced by pathogenic species

    • Decreases abdominal pain

    • Decreases the sensation of urgency in patients with visceral hypersensitivity (a consequence of IBS)

    • Enhances (pooping) the movement of fecal matter through the colon

    • Inhibits tumour cells and reduces the incidence of colon cancers

  • The rest of the body

    • Improves insulin sensitivity

    • Protects brain/nerve cell death

    • Improves mitochondrial (energy cells) function

    • Reduces the impact of endotoxins to all cells of the body

    • Anti-inflammatory to the brain

    • Increases Brain-Derived Neurotrophic Factor (BDNF), which is like a super-tonic for brain cells.

    • Can reduce fatty liver

    • Improves the integrity of ducts, linings of organs and vessels of the cardiovascular system

    • Suppresses pro-inflammatory mediators (such as TNF-a, NFkB, IFy, IL-6 & IL-12) in the liver, fat cells and white blood cells, reducin systemic inflammation throughout the body. This has enormous benefits for all people with chronic disease and is preventative against many chronic diseases.

However, butyrate as a supplement has shown little, or conflicting benefits as a treatment strategy in human studies. More research in this area is required. Some studies show that butyrate needs to be in the same ratio to acetate and propionate found in a healthy gut to be beneficial. Others have used enema infusions or have proposed that any supplement needs to be coated to ensure its safe passage to the colon. The dosage and ideal form of butyrate supplements require further investigation.

When butyrate levels are healthy, the oxygenation levels to the gut are better regulated, improving intestinal hyperpermeability and the proper distribution and location of microbiota.

What are hypoxia-inducible factors (HIFs)?

Hypoxia-inducible factors (HIFs) are signalling molecules that affect the oxygenation of the digestive tract by regulating the tight junctions. Two main HIFs have been studied, HIF-1a and HIF-2a, and are required in a balanced ratio to one another to perform this function. When out of balance, it can cause the failure of tight junctions, altering the oxygen levels of the gut. Imbalances in HIF-1a and HIF-2a are associated with chronic disease states such as inflammatory bowel diseases (IBD) and colonic cancers.

In a healthy gut, aerobic species consume oxygen and reduce the oxygen levels to support anaerobic species and facultative anaerobes. Microbes live in the locations where they should be. The beneficial and less beneficial species are in appropriate ratios (though, we really can’t think of them as good and bad so much as ‘in the right proportions’), and producing the appropriate ratios of short-chain fatty acids, supporting the gut layers, the body, and resolving any inflammation. The tight junctions that join the gut cells remain permeable, and the immune system is on standby, not hypervigilant.

Current treatments

The tight junctions have been the focus of treatments because they are responsible for managing the ins and outs of molecules that can cause some gut symptoms. This is justified where inflammation is causing damage to the lining and in some other circumstances. However, some people don’t recover from their digestive symptoms, applying the same successful treatments for others - why is this?

  • Old thinking - Firstly, treating only the tight junctions while not addressing the other layers of protection may be addressing only part of the picture. Perhaps a newer approach is required for those not finding relief from their symptoms, including ensuring all layers function optimally, starting with the atmospheric layer..

  • Microbiome + mucus interaction  In intestinal hyperpermeability, damage to the gut lining may be due to an alteration of microbiome species. The mucosal layer is, in part, regulated by the microbes and mucus produced by the goblet cells of the gut lining. Conversely, goblet cells may not function optimally or, at all if the lining is damaged, regardless of the microbial balance. 

  • Terrain or pathogen? - Much of the difference in thinking between conventional medicine and holistic practices like naturopathy is around the fundamental question of ‘Is the terrain (environment/host/human) somehow dysfunctional, allowing harmful pathogens from taking hold?’ or ‘Is the pathogen overwhelming and damaging the terrain?’ In other words, are you sick because something in the body is damaged/missing/weakened, allowing the pathogens to take hold (holistic thinking)? Or, are the bugs making you sick and causing the damage (conventional medicine thinking)? 

  • Oxygenation versus hypoxia - There is growing evidence that damage to the atmospheric layer of the gut can be more difficult to reverse, as this is determined by a delicate balance of microbes, their by-products, mucus, pH and HIFs. Until recently, the importance of this delicate gas balance has been underestimated or poorly understood. With research focussing on pharmaceutical treatments, we now understand the factors involved in regulating the oxygen in the gut.

  • Chain reaction - In the case of the gut lining and tight junctions, if you don’t have the right environment for the microbes to thrive, they aren’t present to regulate the amount of mucus. When the mucus isn’t present, the lining is more vulnerable to contact with the chemical layers and the contents of the intestines and, therefore, prone to damage. Where this process continues over a long period and becomes chronic, the added complication of newly acquired food intolerances due to immune overactivation can mean more potential insults, triggering even more food and other allergens/intolerances. 

There is a strong association in the research between intestinal hyperpermeability and the development of autoimmune diseases, particularly IBDs such as ulcerative colitis and Crohn’s disease, but also includes the development of other autoimmune diseases. The evidence is continually growing in this area. Still, in the case of IBDs, IBS and SIBO, there is sufficient evidence to show that a holistic approach, treating both the microbiome and its home, is necessary to optimise all aspects of health. 

Therefore, the oxygen status must be considered to address intestinal hyperpermeability, perhaps before addressing all other layers and factors known to maintain healthy gut linings, microbial abundance, and diversity.

What new treatments improve hypoxia

Improving butyrate is a treatment objective, however, achieving this, if the butyrate-producing species are not located where they should be or thriving, then this will be difficult to address. Supplementing butyrate seems an obvious choice, but the product needs to be selected to ensure delivery to the lower portions of the small intestines or the colon and in the right form to ensure efficacy. 

Another home remedy, which can sometimes be helpful, is taking apple cider vinegar - 1 tbsp 3 times daily, as the acetic acid may improve both HCl acid production in the stomach and oxygenation of the gut. Other naturopathic strategies to improve hydrochloric acid production prior to meals would also address this aim. 

In patients who have histamine intolerance, seasonal allergies, or other allergic conditions, apple cider vinegar may be an allergic trigger and needs to be used cautiously, as vinegar is a product that can contribute to a histamine load. 

This is why a carefully tailored strategy by a holistic healthcare practitioner familiar with the oxygenation of the digestive tract would be appropriate. This would ensure that the treatment is staged to reduce the incidence of flare-ups. 

If you are experiencing bloating, reflux, diarrhoea, constipation, allergies and food intolerances, then make a booking for a FREE 15-minute discovery call, and we can discuss how I may help you. There is no obligation, and if you feel I’m the right practitioner for you, I would love to help.

  • A FODMAP diet can be really helpful for some people, to reduce the symptoms of a leaky gut. Sometimes, it is a short-term intervention while the root cause of the issue is being treated. However, the FODMAP diet excludes a whole range of nutritious foods essential to a healthy microbiome, so it’s not a long-term solution and staying on the FODMAP diet can cause further problems.. Having said that, if you haven’t been eating these foods and the root cause has not been addressed, then eating them again could cause you a flare-up of symptoms that would be very uncomfortable. Reintroducing these foods needs to be done in a staged and careful fashion with the support of a practitioner who understands what is going on with your health.

    If you’ve been on a FODMAP diet long term and you’d like some assistance introducing these foods back into your diet to improve your overall health, then give me a call, and we can start a plan back to eating the foods your body needs.

  • Long term improvement doesn’t come until the root cause that led to the IBS in the first place is addressed. That can be different for each person. Several things may be the underlying cause, such as another hidden/delayed food intolerance, stress/anxiety, extreme exercise, nutritional deficiencies, chemical exposures, medications, low stomach acid, or a combination of factors. An experienced naturopathic gut health specialist practitioner can help you navigate this sometimes confusing maze of cause and effect.

    Book a free 15-minute discovery call to discuss your specific issues and how I can help give you a roadmap to recovery.

  • Yes! I work via Zoom telehealth, and so as long as you have a device with a camera and a microphone and internet, then we can work together - wherever you are!

    I’d love to help you find answers to your particular issues. In our first consultation which is 90 minutes, I will take a detailed case history including:

    • Your symptom history

    • Other conditions, illnesses, and viruses

    • Personal medical history from birth

    • Family genetic history

    • Diet, lifestyle, exercise, work and social factors

    • Trauma, stress, anxiety or mental health issues

    • Medications

    What you have tried before and the results

    And more

    Once I have a comprehensive understanding of your symptoms and about factors affecting all of you, then I go to work putting the pieces together of the jigsaw puzzle that is your health. Like a detective, I’m looking for clues that connect your body systems to identify the root cause or causes and other contributing factors. Then, I build a treatment strategy around that.

    Treatments may include lifestyle and diet recommendations, clinical nutrition supplements, and herbal medicines in liquid, powder, tea, or capsule form. I may prescribe probiotics, prebiotics, and other supplements to restore balance to your body. I’m essentially looking to find where I can support your body to heal itself. Better than treating the symptoms, this can bring about optimal health and well-being…not just symptom relief.

Julie Forrester
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