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Sane et al. Microbiome Res Rep 2023;2:18 https://dx.doi.org/10.20517/mrr.2023.12 Page 9 of 12

compared to overweight healthy volunteers [18-21] . OA being related to bacterial detection in synovial fluid
[22]
and tissue, we speculated about a possible enhanced translocation . In our study, prevalence of
P. goldsteinii in Peyer’s patches was similar in both untreated and Lpps-protected rats. Moreover, plasma
LPS measurement gave similar values in both groups. But it does not disqualify a possible invasion of the
damaged knee through the lymphatic route, P. goldsteinii being able to cross the colon to mesenteric nodes
[23]
and fat in gnotobiotic mice, with possible dissemination through the lymph route .
Alternatively, OA progression can be related to both P. goldsteinii and Akkermansia localized in the lower
part of the digestive tract through their common end-products. P. goldsteinii mainly produces acetic and
succinic acids and minor amounts of isovaleric acid, propionic acid, and formic acid . Akkermansia is also
[24]
[25]
producing acetate and, to a higher extent, propionate . Therefore, decreased populations of P. goldsteinii
and Akkermansia induced by Lpps intake are likely to result in decreased acetate formation in the lower part
of the gut. A salient property of acetate is its ability to effectively promote effector T cells during an active
immune response but not in a steady state . OA is characterized as a low-grade inflammation. It is thus
[26]
expected that acetate will promote effector T cells, consequently aggravating cartilage degradation.

Additionally, PCA uncovered a possible involvement of B.thetaiotaomicron and E. plexicaudatum, as
contributing factors to OA prevention. Although there is no significant increase in their population
following Lpps intake, the fact that they are connected with the healthy status evokes the possible role of
tryptophan catabolism and butyrate formation. L-tryptophan (L-Trp) is associated with the
microenvironment of chronic inflammation in OA joints. Tryptophan is a nutritionally essential amino acid
that cannot be synthesized in vivo and must be provided through dietary sources. In an OA rat model,
serum Trp concentration was significantly higher than in the control counterparts . Depletion within the
[27]
gut by increased bacterial catabolism could alleviate cartilage degradation. B.thetaiotaomicron breaks down
tryptophan into indole, indole-3-acid-acetic (IAA), indole3-lactic acid (ILA), 3-methylindole (skatole) .
[28]
Lpps intake promoted the expansion of L. murinus, L.reuteri and L. johnsonii, all of them producing the
bioactive L-Trp metabolite, Indole-3-aldehyde (IAld) . Besides, L.reuteri produces IAA as L-Trp
[29]
metabolite. On one hand, the increased catabolism of L-tryptophan is expected to decrease its passage to the
bloodstream; on the other hand, L-Trp-derived indole and indole acid derivatives show selectivity to
binding and activating the Aryl Hydrocarbon Receptor (AhR). Agonism of the AhR in intestinal epithelial
cells can directly enhance barrier function through strengthening of junctional complexes (adherens and
tight junctions), expansion of goblet cells and mucus production, increased stem cell turnover, and the
promotion of epithelial cell regeneration [28,29] . Butyrate acts as a histone deacetylase HDAC inhibitor, leading
to increased recruitment of AhR to the target gene promoter in the presence of tryptophan-derived AhR
[30]
agonists . In addition, butyrate was already shown to reduce arthritis severity via the stimulation of AhR in
IL-10-producing regulatory B cells . Similarly, one might assume that E. plexicaudatum, by providing
[31]
butyrate, helps L-Trp metabolites produced by B.thetaoiotaomicron to induce tolerance. Once the
homeostasis is broken down by MIA injection, the intestinal barrier is likely more permeable to the passage
of luminal antigens and bacteria. We speculate that Lpps, by promoting lactobacilli, provide a supplement
in L-Trp metabolites indirectly, likely accentuating the intestinal barrier protection through the AhR
pathway. Demonstration in a proteoglycan-induced ankylosis spondylitis mouse model that the AhR
pathway is activated by IAA treatment and that the intestinal barrier function is improved further supports
our hypothesis .
[32]

At last, the increase in M. schaedlerii following Lpps intake likely also reflected the possible IAA increase
related to L. reuteri expansion. Administration of IAA led not only to an activation of the AhR pathway but
[33]
[32]
also to an increase in M. schaedlerii . In turn, M.shaedlerii could elicit T-dependent IgA . Most