A Place for Everything …

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 

References

1. Sherid M, Samo S, Sulaiman S, Husein H, Sifuentes H, Sridhar S. Liver abscess and bacteremia caused by lactobacillus: role of probiotics? Case report and review of the literature. BMC Gastroenterol. 2016 Nov 18;16(1):138.
2. Mikucka A, Deptuła A, Bogiel T, Chmielarczyk A, Nurczyńska E, Gospodarek-Komkowska E. Bacteraemia Caused by Probiotic Strains of Lacticaseibacillus rhamnosus-Case Studies Highlighting the Need for Careful Thought before Using Microbes for Health Benefits. Pathogens. 2022 Aug 26;11(9):977.
3. https://www.medscape.com/viewarticle/984456?src=WNL_trdalrt_pos1_ous_221128&uac=90527HT&impID=4920157
4. Issacs PE, Kim YS. Blind loop syndrome and small bowel bacterial contamination. Clin Gastroenterol. 1983;12:395–414.
5. Gibson B, Wilson DJ, Feil E, Eyre-Walker A. The distribution of bacterial doubling times in the wild. Proc Biol Sci. 2018 Jun 13;285(1880):20180789.
6. Artis D. Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis in the gut. Nat Rev Immunol. 2008;8:411–20.
7. Sharma R, Young C, Neu J. Molecular modulation of intestinal epithelial barrier: contribution of microbiota. J Biomed Biotechnol. 2010;2010:305879.
8. Kumar M, Nagpal R, Verma V, Kumar A, Kaur N, Hemalatha R, Gautam SK, Singh B. Probiotic metabolites as epigenetic targets in the prevention of colon cancer. Nutr Rev. 2013;71:23–34.
9. Takakura W, Pimentel M. Small Intestinal Bacterial Overgrowth and Irritable Bowel Syndrome – An Update. Front Psychiatry. 2020 Jul 10;11:664.
10. Riordan SM, McIver CJ, Wakefield D, Duncombe VM, Thomas MC, Bolin TD. Small intestinal mucosal immunity and morphometry in luminal overgrowth of indigenous gut flora. Am J Gastroenterol. 2001;96:494–500.
11. Ghoshal UC, Shukla R, Ghoshal U. Small Intestinal Bacterial Overgrowth and Irritable Bowel Syndrome: A Bridge between Functional Organic Dichotomy. Gut Liver. 2017 Mar 15;11(2):196-208. 
12. Black CJ, Ford AC. Global burden of irritable bowel syndrome: trends, predictions and risk factors. Nat Rev Gastroenterol Hepatol. 2020 Aug;17(8):473-486.
13. Corsetti M, Whorwell P. The global impact of IBS: time to think about IBS-specific models of care? Therap Adv Gastroenterol. 2017 Sep;10(9):727-736. 
14. JHA RK, Zou Y, Xia B. Irritable Bowel Syndrome (IBS) At a Glance. BJMP 2010;3(4):a342
15. Aziz I, Tornblom H, Simren M. Small intestinal bacterial overgrowth as a cause for irritable bowel syndrome: guilty or not guilty? Current Op Gastroenterology. 2017;33(3):196-202.
16. Lo WK, Chan WW. Proton pump inhibitor use and the risk of small intestinal bacterial overgrowth: a meta-analysis. Clin Gastroenterol Hepatol. 2013; 11: 483-490
17. Rana SV, Kaur J, Gupta R, Gupta V, Sharma S, Malik A, Sinha SK. Effect of Post-Cholecystectomy on Small Intestinal Bacterial Overgrowth and Orocecal Transit Time in Gallstone Patients. Int J Dig Dis. 2016, 2:1. 
18. https://www.expertmarketresearch.com/reports/proton-pump-inhibitors-market
19. Khan ZA, Khan MU, Brand M. Increases in cholecystectomy for gallstone related disease in South Africa. Sci Rep. 2020 Aug 11;10(1):13516.
20. Chong PP, Chin VK, Looi CY, Wong WF, Madhavan P, Yong VC. The Microbiome and Irritable Bowel Syndrome – A Review on the Pathophysiology, Current Research and Future Therapy. Front Microbiol. 2019 Jun 10;10:1136.
21. Savage J, Johns CB. Food allergy: epidemiology and natural history Immunol. Allergy Clin. N. Am., 35 (2015), pp. 45-59
22. Miller LS, Vegesna AK, Sampath AM, Prabhu S, Kotapati SK, Makipour K. Ileocecal valve dysfunction in small intestinal bacterial overgrowth: a pilot study. World J Gastroenterol. 2012 Dec 14;18(46):6801-8. 
23. Valeur J, Lappalainen J, Rita H, Lin AH, Kovanen PT, Berstad A, Eklund KK, Vaali K. Food allergy alters jejunal circular muscle contractility and induces local inflammatory cytokine expression in a mouse model. BMC Gastroenterol. 2009 May 18;9:33. 
24. Leo EEM, Campos MRS. Effect of Ultra-Processed Diet on Gut Microbiota and Thus Its Role in Neurodegenerative Diseases.  Nutrition. 2020 Mar;71:110609.
25. Looijer-van Langen MA, Dieleman LA. Prebiotics in chronic intestinal inflammation. Inflamm Bowel Dis. 2009 Mar;15(3):454-62. 
26. Rizzatti G, Lopetuso LR, Gibiino G, Binda C, Gasbarrini A. Proteobacteria: A Common Factor in Human Diseases. Biomed Res Int. 2017;2017:9351507. 
27. Narula N, Wong ECL, Dehghan M, Mente A, Rangarajan S, Lanas F, Lopez-Jaramillo P, Rohatgi P, Lakshmi PVM, Varma RP, Orlandini A, Avezum A, Wielgosz A, Poirier P, Almadi MA, Altuntas Y, Ng KK, Chifamba J, Yeates K, Puoane T, Khatib R, Yusuf R, Boström KB, Zatonska K, Iqbal R, Weida L, Yibing Z, Sidong L, Dans A, Yusufali A, Mohammadifard N, Marshall JK, Moayyedi P, Reinisch W, Yusuf S. Association of ultra-processed food intake with risk of inflammatory bowel disease: prospective cohort study. BMJ. 2021 Jul 14;374:n1554.
28. Agarwala R, Singh AK, Shah J, Mandavdhare HS, Sharma V. Ileocecal thickening: Clinical approach to a common problem. JGH Open. 2019 Apr 22;3(6):456-463.
29. Shah A, Morrison M, Burger D, Martin N, Rich J, Jones M, Koloski N, Walker MM, Talley NJ, Holtmann GJ. Systematic review with meta-analysis: the prevalence of small intestinal bacterial overgrowth in inflammatory bowel disease. Aliment Pharmacol Ther. 2019 Mar;49(6):624-635.
30. GBD 2017 Inflammatory Bowel Disease Collaborators. The global, regional, and national burden of inflammatory bowel disease in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol. 2020 Jan;5(1):17-30.
31. Oddy WH, Herbison CE, Jacoby P, Ambrosini GL, O’Sullivan TA, Ayonrinde OT, Olynyk JK, Black LJ, Beilin LJ, Mori TA, Hands BP, Adams LA. The Western dietary pattern is prospectively associated with nonalcoholic fatty liver disease in adolescence. Am J Gastroenterol. 2013 May; 108(5):778-85.
32. Simoes ICM, Janikiewicz J, Bauer J, Karkucinska-Wieckowska A, Kalinowski P, Dobrzyń A, Wolski A, Pronicki M, Zieniewicz K, Dobrzyń P, Krawczyk M, Zischka H, Wieckowski MR, Potes Y. Fat and Sugar-A Dangerous Duet. A Comparative Review on Metabolic Remodeling in Rodent Models of Nonalcoholic Fatty Liver Disease. 2019 Nov 24;11(12):2871.
33. Liu X, Peng Y, Chen S, Sun Q. An observational study on the association between major dietary patterns and non-alcoholic fatty liver disease in Chinese adolescents. Medicine (Baltimore). 2018 Apr;97(17):e0576.
34. Kalafati IP, Borsa D, Dimitriou M, Revenas K, Kokkinos A, Dedoussis GV. Dietary patterns and non-alcoholic fatty liver disease in a Greek case-control study. Nutrition. 2019 May;61:105-110.
35. Shim P, Choi D, Park Y. Association of Blood Fatty Acid Composition and Dietary Pattern with the Risk of Non-Alcoholic Fatty Liver Disease in Patients Who Underwent Cholecystectomy. Ann Nutr Metab. 2017; 70(4):303-311.
36. Mohammad S, Thiemermann C. Role of Metabolic Endotoxemia in Systemic Inflammation and Potential Interventions. Front Immunol. 2021 Jan 11;11:594150.
37. Meštrović T, Matijašić M, Perić M, Čipčić Paljetak H, Barešić A, Verbanac D. The Role of Gut, Vaginal, and Urinary Microbiome in Urinary Tract Infections: From Bench to Bedside. Diagnostics (Basel). 2020 Dec 22;11(1):7. 
38. Thänert R., Reske K.A., Hink T., Wallace M.A., Wang B., Schwartz D.J., Seiler S., Cass C., Burnham C.A., Dubberke E.R., et al. Comparative Genomics of Antibiotic-Resistant Uropathogens Implicates Three Routes for Recurrence of Urinary Tract Infections. mBio. 2019;10:e01977-19.
39. Danilkowicz RM, Lachiewicz AM, Lorenzana DJ, Barton KD, Lachiewicz PF. Prosthetic Joint Infection After Dental Work: Is the Correct Prophylaxis Being Prescribed? A Systematic Review. Arthroplast Today. 2021 Jan 9;7:69-75. 
40. Tubiana S, Blotière PO, Hoen B, Lesclous P, Millot S, Rudant J, Weill A, Coste J, Alla F, Duval X. Dental procedures, antibiotic prophylaxis, and endocarditis among people with prosthetic heart valves: nationwide population-based cohort and a case crossover study. BMJ. 2017 Sep 7;358:j3776.
41. Voth S, Gwin M, Francis CM, Balczon R, Frank DW, Pittet JF, Wagener BM, Moser SA, Alexeyev M, Housley N, Audia JP, Piechocki S, Madera K, Simmons A, Crawford M, Stevens T. Virulent Pseudomonas aeruginosa infection converts antimicrobial amyloids into cytotoxic prions. FASEB J. 2020 May 15. doi: 10.1096/fj.202000051RRR. Online ahead of print.
42. Revilla-García A, Fernández C, Moreno-Del Álamo M, de Los Ríos V, Vorberg IM, Giraldo R. Intercellular Transmission of a Synthetic Bacterial Cytotoxic Prion-Like Protein in Mammalian Cells. mBio. 2020 Apr 14;11(2):e02937-19.
43. Ruff WE, Kriegel MA. Autoimmune host-microbiota interactions at barrier sites and beyond. Trends Mol Med. 2015 Apr;21(4):233-44. 
44. Manfredo Vieira S, Hiltensperger M, Kumar V, Zegarra-Ruiz D, Dehner C, Khan N, Costa FRC, Tiniakou E, Greiling T, Ruff W, Barbieri A, Kriegel C, Mehta SS, Knight JR, Jain D, Goodman AL, Kriegel MA. Translocation of a gut pathobiont drives autoimmunity in mice and humans. Science. 2018 Mar 9;359(6380):1156-1161.
45. Wilson JC, Furlano RI, Jick SS, Meier CR. Inflammatory Bowel Disease and the Risk of Autoimmune Diseases. J Crohns Colitis. 2016 Feb;10(2):186-93.
46. Halling ML, Kjeldsen J, Knudsen T, Nielsen J, Hansen LK. Patients with inflammatory bowel disease have increased risk of autoimmune and inflammatory diseases. World J Gastroenterol. 2017 Sep 7;23(33):6137-6146.
47. Dinse GE, Parks CG, Weinberg CR, Co CA, Wilkerson J, Zeldin DC, Chan EKL, Miller FW. Increasing Prevalence of Antinuclear Antibodies in the United States. Arthritis Rheumatol. 2020 Jun;72(6):1026-1035.
48. Aguayo-Patrón SV, Calderón de la Barca AM. Old Fashioned vs. Ultra-Processed-Based Current Diets: Possible Implication in the Increased Susceptibility to Type 1 Diabetes and Celiac Disease in Childhood. Foods. 2017 Nov 15;6(11):100. 
49. Qiu CC, Caricchio R, Gallucci S. Triggers of Autoimmunity: The Role of Bacterial Infections in the Extracellular Exposure of Lupus Nuclear Autoantigens. Front Immunol. 2019 Nov 8;10:2608. 
50. Miyauchi E, Shimokawa C, Steimle A, Desai MS, Ohno H. The impact of the gut microbiome on extra-intestinal autoimmune diseases. Nat Rev Immunol. 2022 May 9. doi: 10.1038/s41577-022-00727-y. Epub ahead of print.
51. Ogrendik M. Antibiotics for the treatment of rheumatoid arthritis. Int J Gen Med. 2013 Dec 27;7:43-7.
52. Chen X, Liang D. Doxycycline Suppresses Ocular Inflammation by Stat3/MiR155/Th17 Pathway. Invest Ophthalmol Vis Sci July 2018, Vol.59, 2539
53. Stead R. Personal communication, 2020 and 2021.
54. Tetz G, Pinho M, Pritzkow S, Mendez N, Soto C, Tetz V. Bacterial DNA promotes Tau aggregation. Sci Rep. 2020 Feb 11;10(1):2369. 
55. Sampson TR, Challis C, Jain N, Moiseyenko A, Ladinsky MS, Shastri GG, Thron T, Needham BD, Horvath I, Debelius JW, Janssen S, Knight R, Wittung-Stafshede P, Gradinaru V, Chapman M, Mazmanian SK. A gut bacterial amyloid promotes α-synuclein aggregation and motor impairment in mice. Elife. 2020 Feb 11;9:e53111.
56. Wang C, Lau CY, Ma F, Zheng C. Genome-wide screen identifies curli amyloid fibril as a bacterial component promoting host neurodegeneration. Proc Natl Acad Sci U S A. 2021 Aug 24;118(34):e2106504118.
57. Oli MW, Otoo HN, Crowley PJ, Heim KP, Nascimento MM, Ramsook CB, Lipke PN, Brady LJ (2012) Functional amyloid formation by Streptococcus mutans. Microbiology 158, 2903–2916.
58. Fleury V, Zekeridou A, Lazarevic V, Gaïa N, Giannopoulou C, Genton L, Cancela J, Girard M, Goldstein R, Bally JF, Mombelli A, Schrenzel J, Burkhard PR. Oral Dysbiosis and Inflammation in Parkinson’s Disease. J Parkinsons Dis. 2021;11(2):619-631.
59. Rothschild D, Weissbrod O, Barkan E, Kurilshikov A, Korem T, Zeevi D, Costea PI, Godneva A, Kalka IN, Bar N, Shilo S, Lador D, Vila AV, Zmora N, Pevsner-Fischer M, Israeli D, Kosower N, Malka G, Wolf BC, Avnit-Sagi T, Lotan-Pompan M, Weinberger A, Halpern Z, Carmi S, Fu J, Wijmenga C, Zhernakova A, Elinav E, Segal E. Environment dominates over host genetics in shaping human gut microbiota. Nature. 2018 Mar 8;555(7695):210-215.
60. Shi H, Wang Q, Zheng M, Hao S, Lum JS, Chen X, Huang XF, Yu Y, Zheng K.J. Supplement of microbiota-accessible carbohydrates prevents neuroinflammation and cognitive decline by improving the gut microbiota-brain axis in diet-induced obese mice. Neuroinflammation. 2020 Mar 4;17(1):77. 
61. Reynolds A, Mann J, Cummings J, Winter N, Mete E, Te Morenga L. Carbohydrate quality and human health: a series of systematic reviews and meta-analyses. Lancet. 2019 Feb 2;393(10170):434-445.
62. Ho L, Zhao D, Ono K, Ruan K, Mogno I, Tsuji M, Carry E, Brathwaite J, Sims S, Frolinger T, Westfall S, Mazzola P, Wu Q, Hao K, Lloyd TE, Simon JE, Faith J, Pasinetti GM. Heterogeneity in gut microbiota drive polyphenol metabolism that influences α-synuclein misfolding and toxicity. J Nutr Biochem. 2019 Feb;64:170-181. 
63. Jun JY, Jung MJ, Jeong IH, Yamazaki K, Kawai Y, Kim BM. Antimicrobial and Antibiofilm Activities of Sulfated Polysaccharides from Marine Algae against Dental Plaque Bacteria. Mar Drugs. 2018 Aug 27;16(9):301.
64. https://www.youtube.com/watch?v=onRk0sjSgFU