A Place for Everything …On
Multicellular organisms like you and me have a complex and shifting relationship with microbes. We need the right amounts of the right ones in the right places if we are to have a chance of good health. If we acquire too few or too many of the right ones, or if the right ones get into the wrong place, and of course when we acquire the wrong ones in any place, we are either sick or heading into sickness.
For example. Endogenous probiotic species such as lactobacilli can (rarely) cause serious problems including liver abscess, peritonitis and meningitis, if they get into the circulation (1, 2). Probiotic supplements have recently been linked to a slight but significant increased risk of death in ICU’s (3), mostly involving powder (air-dispersible) products able to contaminate iv lines.
A more familiar example. Up to 2/3 of the population carry Staph aureus in their nose and on the skin where it can cause problems, but generally not serious ones. During surgery or immunosuppression, those microbes can invade deeper tissues and cause potentially life-threatening infections.
Another well-known example: SIBO. The small intestine isn’t sterile – no tissue is – and under normal circumstances it contains mostly gram-positive microorganisms at around 1000 microbes / ml (4). If the factors controlling these numbers malfunction, a hundred-fold increase in microbial counts, which could theoretically occur within a few days (5), will cause problems. Today’s lifestyles – see below – are making these problems more and more likely.
If the bacteria are gram-positive saccharolytic (broadly, probiotic) species, ie the ones that normally live there, it won’t be too bad. There might be bloating and pain due to excessive hydrogen production but probiotic metabolites, including short chain fatty acids and secreted proteins, are fundamentally anti-inflammatory and support intestinal epithelial function (6-8).
Having the ‘wrong’ bacteria in the small intestine is more common, and more serious. Overgrowth of gram-negative species causes inflammatory stress and more intense symptoms (9, 10), due in part to the highly pro-inflammatory lipopolysaccharides in their cell membranes.
It’s hard to locate robust data on the prevalence of SIBO, but as 30 to 80% of IBS patients are reckoned to have SIBO (11) and IBS is increasing (12-14), it is fairly certain that SIBO cases are increasing too; although the direction of causality is unclear (15). And there are other reasons to think that SIBO is on the up-swing.
In health, bacterial counts in the small intestine are kept in check by gastric acid, bile, peristalsis and the one-way ileocecal valve into the large intestine.
Proton Pump Inhibitors and cholecystectomy both increase the risk of developing SIBO (16, 17). PPI sales (18) and cholecystectomy surgeries (ie 19) are both on the rise, due to our desperately unhealthy diet and lifestyles. The modern diet and lifestyle also increase the risk of IBS (12-14), which dysregulates peristalsis (20), and the incidence of food allergy (21), now considered to be a contributor to ileocecal valve failure (22, 23).
Ultra-processed foods may also damage the ileocecal valve more directly.
The mix of microbes in a healthy colonic microbiome promotes low-level (physiological) inflammation. The removal of prebiotic fibers from today’s ultra-processed foods reduces the numbers of saccharolytic gram-positive bacteria in the gut (24). This enables the overgrowth of gram-negative proteolytic species such as Proteobacteria, leading to LPS-mediated pathological levels of chronic inflammation in the large bowel (24-26), up to and including IBD (27).
The ileocecal area is known to be vulnerable to inflammatory damage (28). Inflammatory bowel disease (Crohn’s, UC) is an important cause of ileocecal valve damage, and appears to be a substantial risk factor for SIBO (29). IBD is increasing (30), providing another reason to believe there will be more SIBO in our collective future. The type of chronic inflammation triggered by prebiotic depletion is not always as severe as in IBD, but likely also affects ileocecal valve competence.
Inflammation in the colon wall also degrades the gut epithelial barrier. This allows translocation of bacterial metabolites such as LPS, implicated in causing NAFLD (31-35) and systemic inflammation (36); and the bacteria themselves. Both ‘wrong’ and ‘right’ bacteria can now get into some very wrong places.
The fact that UTI’s often involve gut bacteria has traditionally been attributed to ano-genital transfer, but recent research is beginning to consider the possibility of other routes, including via the circulation (37, 38). This resembles the way in which oral bacteria can transfer to the bloodstream during dental surgery and cause infections on prosthetic joints (ie 39) or heart valves (40).
Gut bacteria that move into the wrong tissues may also cause or contribute to prion disease (41, 42) and autoimmune disease, particularly in genetically susceptible individuals with specific HLA variants (43, 44).
Infections are important environmental triggers of autoimmunity, and it is widely believed that pathogens may cause autoimmunity via immune dysregulation and molecular mimicry either directly, or via biofilm components (45-49, 46). Colonic dysbiosis is a hallmark of autoimmune disease (40, 43); and a beautiful proof of concept study demonstrated that a gut bacterium which accessed tissues outside the gut consistently triggered autoimmunity in mice, and in human tissue (44).
IBD patients have colonic dysbiosis and chronic inflammation, which encourages translocation of gut microbes – and a substantially increased risk of autoimmune diseases (42, 43, 45). Conversely, the risk of autoimmunity in IBD patients is reduced by long-term use of aminosalicylates (45), anti-inflammatory drugs widely used to manage Crohn’s and ulcerative colitis.
Given all the above, the ongoing and substantial increase in autoimmune diseases (47) may well be a consequence of gut dysbiosis caused by the ultra-processed diet, with subsequent colonic inflammation and migration of gut bacteria into sites outside the gastrointestinal tract (48-50).
For these reasons, the molecular mimicry theory of autoimmunity is under revision. Some believe that chronic intracellular infection involving misplaced enteric bacteria may trigger an immune response that is directed at expressed fragments of the pathogen, and is therefore not technically autoimmune at all. Additional support for this idea derives from the successful use of antibiotics to improve established autoimmune diseases including rheumatoid arthritis and uveitis (ie 51 and possibly 52); and, perhaps, the protective effects of aminosalicylates (45).
As aminosalicylates are only given to established IBD cases, this suggests that reducing the translocation of gut microbes can slow or stop the progression of autoimmunity, even after the initial translocation and subsequent immune dysregulation has occurred.
This in turn suggests that continuous or repeated bacterial translocation may be necessary to drive the process that we currently think of as autoimmunity. It implies that when using antibiotics to improve autoimmune problems, restoring eubiosis will be critically important; and this may indeed be the case (53).
Dysbiosis is connected to neurodegenerative disease too.
Translocation of bacterial and/or bacterially modified peptides from gut bacteria is implicated in the pathogenesis of Alzheimer’s (54), Parkinsonism (55, 56) and other neurodegenerative diseases (57). Abnormalities in the oral flora which produce similarly modified peptides (57) are also involved in the pathogenesis of these conditions (ie 58).
There are huge dietary implications.
The drugs used to treat neurodegenerative diseases are ineffective, and the immunosuppressants used to treat autoimmune disease exert serious and frequently lethal adverse effects. Accordingly, as your enterotype is largely determined by what you eat (59), it makes good sense to focus on dietary strategies to maintain healthy gut epithelial function and keep your gut bacteria from straying, if you want to hold on to your brains.
The data strongly support adding a range of prebiotic fibers in your diet (ie 60, 61). I would combine these with an increased intake of polyphenols, which are metabolised by the right microbiome to form neuro-protective metabolites (62), and a healthy dose of fucoidans to reduce biofilm formation in the mouth (623
These are all characteristic of a pre-transitional diet, and are all included in the extended Health Protocol.
Finally, today’s inappropriate theme music (64).
Next week: I Was a Teenage Werewolf
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