Managing Proteobacteria Overgrowth

Dr Carly Polland ND in diet proteobacteria 20 Dec 2022 • 3 min read

Author Bio

Dr Carly Polland ND | Clinical Lead at Biomesight

Dr. Carly Polland is an integrative physician focused on the intersection of endocrinology and immunology with the microbiome. Early in her clinical practice, she focused on hormonal imbalances, but she quickly realized these patients also had digestive issues and autoimmune disease. She dug into the research and realized the microbiome was connecting these symptoms. Standard stool testing was not useful in decoding the microbiome so she upgraded to microbiome testing like Biomesight. She has used this technology for over 6 years to help her patients modulate their microbiomes and improve their symptoms.

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Overgrowth of Proteobacteria in the large intestine is one of the most clinically significant imbalances in the microbiome. This is due to one molecule—lipopolysaccharide (LPS). LPS is a structure composed of fat and sugar rings found in the cell wall of specific types of bacteria (Gram negative bacteria). LPS is considered a type of toxin (endotoxin) because of its interactions with the host’s immune system. For the bacteria, LPS provides structural integrity and protection, but for the host, LPS causes inflammation. Different bacteria have different LPS and Proteobacteria have the most inflammatory LPS. 

LPS interacts with the immune system via TLR-4, which increases inflammatory cytokines like TNF-⍺, NK-κβ, IL-6, and IL-8. This results in low grade inflammation throughout the body. High levels of LPS can damage the lining of the digestive tract, resulting in gastrointestinal inflammation and digestive symptoms. It may also increase risk of autoimmune diseases in the digestive tract, like inflammatory bowel disease (IBD). In the immune system in the digestive tract (GALT), we see a decrease in balancing immune cells (T regulatory cells) and an increase in autoinflammatory immune cells (Th17 lymphocytes).

The low grade systemic inflammation may result in brain inflammation, influencing depression, cognitive dysfunction, brain fog and fatigue. LPS also causes inflammation in the blood vessels, increasing risk for atherosclerosis and congestive heart failure. High blood levels of LPS are also associated with endometriosis, metabolic syndrome, obesity, type II diabetes and liver disease.

The more research we do, the more we are finding LPS may play a role in many, many different diseases throughout the body. So decreasing your inflammatory LPS levels by decreasing Proteobacteria may be extremely important to your health.

If you currently have elevated Proteobacteria, there are a few considerations to reduce how much LPS gets into your bloodstream. Limit or avoid saturated fat and alcohol since they both increase absorption of LPS. LPS absorption is also enhanced when the permeability of the small intestine is increased (aka leaky gut). So consider limiting your use of NSAIDs as they increase intestinal permeability. 

The liver is responsible for getting rid of LPS in the bloodstream. The liver will put some LPS directly into bile, which will then re-enter the gut. If the gut lining is intact, that LPS will be excreted from the body in the feces. But if the gut barrier is damaged, the LPS may reenter the bloodstream. Some LPS in the liver will be broken down. Immune cells in the liver (Kupffer cells) will break down LPS using an an enzyme called acyloxyacyl hydrolase (AOAH). AOAH breaks down LPS by a process called deacetylation. Liver cells also use the enzyme alkaline phosphatase (ALP) to break down LPS. 

So to help manage your LPS burden, consider optimizing liver function. Talk to your practitioner about supplements and herbs that may be helpful. Consider optimizing zinc status since ALP requires zinc to function.

There are two approaches to reducing Proteobacteria levels. One is to directly target Proteobacteria and the other is to create an environment in which Proteobacteria cannot thrive. While the direct approach can yield quicker results, it can have more side effects due to bacterial die-off temporarily increasing levels of LPS. The agents used in the direct approach can also cause side effects outside of bacterial die-off and may interact with medications. It is best to use the direct approach under the supervision of an experienced practitioner.

The indirect approach may take longer to yield results but generally has less risks and side effects. The basis of the indirect approach is to bolster beneficial species such as butyrate producers, Lactobacillus, and Bifidobacterium to shift the pH of the large intestine. Proteobacteria cannot thrive in a more acidic environment. The optimal stool pH is 5-6.5. 

You can also combine both approaches but you need to make sure the agents you are using work synergistically. For example, many prebiotics that can boost butyrate producers can also boost Proteobacteria. 

To directly target Proteobacteria, you first need to identify the specific bacteria that are overgrown. The most common Proteobacteria overgrowths are Desulfovibrio, Sutterella, Parasutterella, Bilophila, Klebsiella, and Escherichia. In clinical practice, the following therapeutics may lower these bacteria:

• Sutterella: berberine, Bacillus subtilitis probiotic
• Parasutterella: berberine, Bacillus coagulans probiotic
• Klebsiella: berberine, neem, oregano, thyme
• Escherichia: berberine, neem, oregano, thyme
• Desulfovibrio: codonopsis, garlic, inulin, Bacillus coagulans probiotic
• Bilophila: chamomile, garlic, inulin, Lactobacillus rhamnosus GG probiotic

Certain supplements may increase these bacteria. Watch out for:

• Sutterella: triphala, slippery elm, GOS, psyllium 
• Parasutterella: licorice, triphala, GOS, lactobacillus acidophilus probiotic
• Klebsiella: GOS, licorice
• Escherichia: slippery elm
• Desulfovibrio: berberine, licorice, slippery elm, Bacillus subtilitis probiotic
• Bilophila: berberine, Bacillus subtilitis probiotic

It is important to note that many of the antimicrobial herbs (berberine, neem, oregano, thyme) may decrease beneficial bacteria like Bifidobacterium and butyrate producers, especially if used at high dose and for long term. You may be able to mitigate these negative side effects by using prebiotics and other tools to support those beneficial species while on antimicrobials. But make sure you are not working at cross purposes. For examples, don’t use GOS to feed Bifidobacterium if you are using berberine to decrease Sutterella. As you can see, it can get complicated so it is recommended to work under the supervision of an experienced practitioner. 

If you want to use indirect strategies to decrease Proteobacteria, nutrition and prebiotics are the best tools. Here are some basic nutrition recommendations:

• Decrease fat intake
• Increase fiber intake
• Increase polyphenol intake: blueberries, cherries, strawberries, blackberries, plums, red apples, grapes, chestnuts, hazelnuts, pecans, black tahini, purple carrots, red carrots, purple potatoes, cabbage, spinach, red onions, broccoli, orange carrots, red lettuce, red rice, black rice, red and black quinoa, black olives
• Increase prebiotic intake: garlic, onions, leeks, asparagus, artichokes, legumes, beets, sunflower seeds, pumpkin seeds
• Increase prebiotic-like foods: brown rice, almonds, cacao, green tea

Lactulose and fructooligosaccharides (FOS) may be helpful prebiotics to use. But use prebiotics with caution as they may feed certain Proteobacteria. Once you start a prebiotic, retest your microbiome within 2-4 weeks to make sure Proteobacteria levels are not going up. Also, do not use prebiotics if you have small intestine bacterial overgrowth (SIBO). With all prebiotics, it is best to start low and to start slow. Increased gas is a normal reaction to prebiotics, but significantly increased abdominal distention and bloating is not. 

Please talk to your practitioner before changing your diet or starting any new supplements or medications.

References

• LPS
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• Sutterella
  • berberine: Zhang L, Wu X, Yang R, et al. Effects of Berberine on the Gastrointestinal Microbiota. Frontiers in Cellular and Infection Microbiology. 2021;10. Accessed December 21, 2022. https://www.frontiersin.org/articles/10.3389/fcimb.2020.588517
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  • GOS: Canfora, E. E., van der Beek, C. M., Hermes, G. D. A., Goossens, G. H., Jocken, J. W. E., Holst, J. J., van Eijk, H. M., Venema, K., Smidt, H., Zoetendal, E. G., Dejong, C. H. C., Lenaerts, K., & Blaak, E. E. (2017). Supplementation of Diet With Galacto-oligosaccharides Increases Bifidobacteria, but Not Insulin Sensitivity, in Obese Prediabetic Individuals. Gastroenterology, 153(1), 87-97.e3. https://doi.org/10.1053/j.gastro.2017.03.051
• Parasutterella
  • berberine: Chen, H., Ye, C., Cai, B. et al. Berberine inhibits intestinal carcinogenesis by suppressing intestinal pro-inflammatory genes and oncogenic factors through modulating gut microbiota. BMC Cancer 22, 566 (2022). https://doi.org/10.1186/s12885-022-09635-9
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  • GOS: Cheng W, Lu J, Lin W, Wei X, Li H, Zhao X, Jiang A, Yuan J. Effects of a galacto-oligosaccharide-rich diet on fecal microbiota and metabolite profiles in mice. Food Funct. 2018 Mar 1;9(3):1612-1620. doi: 10.1039/c7fo01720k. Epub 2018 Feb 21. PMID: 29465126.
• Klebsiella
  • Berberine: Li Y, Wen H, Ge X. Hormesis Effect of Berberine against Klebsiella pneumoniae Is Mediated by Up-Regulation of the Efflux Pump KmrA. J Nat Prod. 2021;84(11):2885-2892. doi:10.1021/acs.jnatprod.1c00642
  • neem: Banna QR, Parveen F, Iqbal MJ. Growth inhibitory effect of ethanolic neem leaves extract on Klebsiella, Salmonella and Staphylococcus aureus. Bangladesh Journal of Pharmacology. 2014;9(3):347-350. doi:10.3329/bjp.v9i3.19454
  • oregano: Sakkas H, Gousia P, Economou V, Sakkas V, Petsios S, Papadopoulou C. In vitro antimicrobial activity of five essential oils on multi-drug resistant Gram-negative clinical isolates. J Intercult Ethnopharmacol. 2016;5(3):212. doi:10.5455/jice.20160331064446
  • thyme: Sakkas H, Gousia P, Economou V, Sakkas V, Petsios S, Papadopoulou C. In vitro antimicrobial activity of five essential oils on multi-drug resistant Gram-negative clinical isolates. J Intercult Ethnopharmacol. 2016;5(3):212. doi:10.5455/jice.20160331064446
  • GOS: Annet J. H. Maathuis, Ellen G. van den Heuvel, Margriet H. C. Schoterman, Koen Venema, Galacto-Oligosaccharides Have Prebiotic Activity in a Dynamic In Vitro Colon Model Using a ¹³C-Labeling Technique, The Journal of Nutrition, Volume 142, Issue 7, July 2012, Pages 1205–1212, https://doi.org/10.3945/jn.111.157420
• Escherichia
  • berberine: Zhang L, Wu X, Yang R, et al. Effects of Berberine on the Gastrointestinal Microbiota. Frontiers in Cellular and Infection Microbiology. 2021;10. Accessed December 21, 2022. https://www.frontiersin.org/articles/10.3389/fcimb.2020.588517
  • neem: Ravva SV, Korn A. Effect of Neem (Azadirachta indica) on the Survival of Escherichia coli O157:H7 in Dairy Manure. Int J Environ Res Public Health. 2015 Jul 10;12(7):7794-803. doi: 10.3390/ijerph120707794. PMID: 26184255; PMCID: PMC4515691.
  • oregano: Sakkas H, Gousia P, Economou V, Sakkas V, Petsios S, Papadopoulou C. In vitro antimicrobial activity of five essential oils on multi-drug resistant Gram-negative clinical isolates. J Intercult Ethnopharmacol. 2016;5(3):212. doi:10.5455/jice.20160331064446
  • thyme: Sakkas H, Gousia P, Economou V, Sakkas V, Petsios S, Papadopoulou C. In vitro antimicrobial activity of five essential oils on multi-drug resistant Gram-negative clinical isolates. J Intercult Ethnopharmacol. 2016;5(3):212. doi:10.5455/jice.20160331064446
• Desulfovibrio
  • codonopsis: Jing Y, Li A, Liu Z, et al. Absorption of Codonopsis pilosula Saponins by Coexisting Polysaccharides Alleviates Gut Microbial Dysbiosis with Dextran Sulfate Sodium-Induced Colitis in Model Mice. BioMed Research International. 2018;2018:e1781036. doi:10.1155/2018/1781036
  • garlic: Guillamón E, Andreo-Martínez P, Mut-Salud N, Fonollá J, Baños A. Beneficial Effects of Organosulfur Compounds from Allium cepa on Gut Health: A Systematic Review. Foods. 2021 Jul 21;10(8):1680. doi: 10.3390/foods10081680. PMID: 34441457; PMCID: PMC8392556.
  • inulin: Hiel S, Gianfrancesco MA, Rodriguez J, et al. Link between gut microbiota and health outcomes in inulin -treated obese patients: Lessons from the Food4Gut multicenter randomized placebo-controlled trial. Clinical Nutrition. 2020;39(12):3618-3628. doi:10.1016/j.clnu.2020.04.005
  • Bacillus coagulans probiotic: Zhang B, Zhang H, Yu Y, Zhang R, Wu Y, Yue M, Yang C. Effects of Bacillus Coagulans on growth performance, antioxidant capacity, immunity function, and gut health in broilers. Poult Sci. 2021 Jun;100(6):101168. doi: 10.1016/j.psj.2021.101168. Epub 2021 Mar 27. PMID: 33975039; PMCID: PMC8131733.
  • berberine: Wolf PG, Devendran S, Doden HL, et al. Berberine alters gut microbial function through modulation of bile acids. BMC Microbiology. 2021;21(1):24. doi:10.1186/s12866-020-02020-1 This effect has been observed clinically in some patients, not all.
• Bilophila
  • chamomile: Vamanu E, Dinu LD, Pelinescu DR, Gatea F. Therapeutic Properties of Edible Mushrooms and Herbal Teas in Gut Microbiota Modulation. Microorganisms. 2021 Jun 10;9(6):1262. doi: 10.3390/microorganisms9061262. PMID: 34200833; PMCID: PMC8230450.
  • garlic: Guillamón E, Andreo-Martínez P, Mut-Salud N, Fonollá J, Baños A. Beneficial Effects of Organosulfur Compounds from Allium cepa on Gut Health: A Systematic Review. Foods. 2021 Jul 21;10(8):1680. doi: 10.3390/foods10081680. PMID: 34441457; PMCID: PMC8392556.
  • inulin: Vandeputte D, Falony G, Vieira-Silva S, et al. Prebiotic inulin-type fructans induce specific changes in the human gut microbiota. Gut. 2017;66(11):1968-1974. doi:10.1136/gutjnl-2016-313271
  • Lactobacillus rhamnosus GG probiotic: Ni, Y., Wong, V.H.Y., Tai, W.C.S., Li, J., Wong, W.Y., Lee, M.M.L., Fong, F.L.Y., El-Nezami, H. and Panagiotou, G. (2017), A metagenomic study of the preventive effect of Lactobacillus rhamnosus GG on intestinal polyp formation in ApcMin/+ mice. J Appl Microbiol, 122: 770-784. https://doi.org/10.1111/jam.13386

  • berberine: Wolf PG, Devendran S, Doden HL, et al. Berberine alters gut microbial function through modulation of bile acids. BMC Microbiology. 2021;21(1):24. doi:10.1186/s12866-020-02020-1